Chirurgie Plastique Esthétique

Endoscopic resection of forehead osteomas: Technical notes Publication date: Available online 14 May 2019 Source: Annales de Chirurgie Plastique Esthétique Author(s): J. Bouguila, H. Chahed Summary Introduction Forehead osteoma is an uncommon benign bone tumor that causes cosmetic disfigurement and occasional pain. Traditional excision directly over the lesion creates a visible scar on the forehead. Procedure We describe a method of endoscopic resection of the forehead osteoma, via incisions within the hairline. The access incision was hidden behind the frontal hairline and the dissection plane went in the subperiosteal layer. The injury of the nerve branch and vessel can be easily avoided and endorsed by manipulating the endoscope. Conclusion Aesthetic considerations are important features in the craniomaxillofacial region. Especially for patients who are not willing to accept the risk of a prominent forehead scar. Endoscopic resection of forehead osteomas might be a useful tool in forehead osteoma resections. It might be an alternative tool in an Oral and Maxillofacial Surgeon's and in a Plastic Surgeon's repertoire. Résumé Introduction L'ostéome frontal est une tumeur osseuse bénigne rare qui provoque une défiguration esthétique et des douleurs occasionnelles. L'abord direct de cette lésion crée une cicatrice visible sur le front et la voie coronale, parfois utilisée peut être responsable d'une zone alopécique disgracieuse. Technique opératoire Nous décrivons une méthode d'excision endoscopique de l'ostéome du front, via deux incisions minimes derrière la ligne capillaire. Le plan de dissection est sous-périosté. Les lésions nerveuses et vasculaires peuvent être facilement évitées en utilisant l'endoscopie. Conclusion Les considérations esthétiques sont des caractéristiques importantes de la région cranio-maxillo-faciale surtout pour les patients qui n'acceptent pas le risque d'une cicatrice frontale visible. La résection endoscopique des ostéomes du front peut être utile. Il peut s'agir d'un moyen alternatif dans le répertoire des chirurgiens maxillo-faciaux et des chirurgiens plasticiens.

An anatomic study of deep inferior epigastric artery diameters at the origin from external iliac and at the lateral border of rectus abdominis muscle by computed tomographic angiography from autologous breast reconstruction patients Publication date: Available online 30 April 2019 Source: Annales de Chirurgie Plastique Esthétique Author(s): F. Boucher, S. Brosset, H. Shipkov, R. Aimard, O. Rouvière, F. Braye, S. Guerid, A. Mojallal Summary Background Autologous breast reconstruction by means of microsurgical abdominal flaps is an very well described technique. The flap harvest dissection under inguinal ligament would cause the risk of parietal weakening in this zone and postoperative bulging. The goal of our study is to investigate whether the deep inferior epigastric artery diameter remains constant from its exit of the external iliac artery to its entrance in the rectus muscle sheath. Patients and method One hundred arteries were studied on fifty preoperative computed tomographic angiographies made before a DIEAP flap for breast reconstruction. We measured the caliber of the left and right deep inferior epigastric arteries at these two landmarks. The length of this artery between these was also calculated. This data were collected with specific angiography reconstruction. Results At the caudal landmark, the mean DIEA diameter was 2.1 ± 0.27 mm on the left side and 2.1 ± 0.31 mm on the right side. At the cephalic landmark, the mean DIEA diameter was 2.0 ± 0.28 mm on the left and 2.0 ± 0.27 mm on the right side (P = 0.00035 at left side; P = 0.0089 at right side). The mean pedicle length between the two landmarks was 22.3 ± 2.85 mm on the left side and 22.2 ± 2.98 mm on the right side. Conclusion This computed tomographic angiography study showed that the diameter of DIEA is equivalent at its origin and at the lateral border of muscle. Flap harvest without dissection under inguinal ligament provides sufficient pedicle length and caliber to allow for comfortable and reliable sutures. Résumé Introduction La reconstruction mammaire autologue au moyen de lambeaux abdominaux microchirurgicaux est une technique très bien décrite. La dissection par prélèvement du lambeau sous le ligament inguinal entraînerait un risque d'affaiblissement pariétal dans cette zone et de déhiscence pariétale postopératoire. Le but de notre étude est d'étudier si le diamètre de l'artère épigastrique inférieure profonde (AEIP) reste constant depuis sa sortie de l'artère iliaque externe jusqu'à son entrée dans la gaine du muscle grand droit. Patients et méthode Cent artères ont été étudiées sur 50 tomoangiographies préopératoires réalisées avant un lambeau DIEAP en vue d'une reconstruction mammaire. Nous avons mesuré le calibre des artères épigastriques inférieures profondes gauche et droite à ces deux points repère. La longueur de cette artère entre ces derniers a également été calculée. Ces données ont été recueillies avec une reconstruction tomoangiographique spécifique. Résultats Au niveau du repère caudal, le diamètre moyen de l'AEIP était de 2,1 ± 0,27 mm du côté gauche et de 2,1 ± 0,31 mm du côté droit. Au niveau du repère céphalique, le diamètre moyen de l'AEIP était de 2,0 ± 0,28 mm à gauche et de 2,0 ± 0,27 mm à droite (p = 0,00035 à gauche ; p = 0,0089 à droite). La longueur moyenne du pédicule entre les deux points repère était de 22,3 ± 2,85 mm du côté gauche et de 22,2 ± 2,98 mm du côté droit. Conclusion Cette étude d'angiographie tomographique informatisée a montré que le diamètre de l'AEIP est équivalent à son origine et au bord latéral du muscle. Le prélèvement d'un lambeau de DEIAP sans dissection sous le ligament inguinal fournit une longueur de pédicule et un calibre suffisants pour permettre des sutures confortables et fiables.

Analyse de l'activité de reconstruction microchirurgicale en hôpital universitaire : cohorte historique sur 14 ans Publication date: Available online 30 April 2019 Source: Annales de Chirurgie Plastique Esthétique Author(s): Q. Kopp, D. Montoya, M. Brix, G. Dautel, E. Simon Résumé Introduction Chaque centre hospitalier universitaire possède ses propres spécificités en reconstructions microchirurgicales. Les activités peuvent être axées sur la reconstruction mammaire, la reconstruction ORL ou les pertes de substances traumatiques. Cette étude analyse les spécificités au CHRU de Nancy, étudie les indications, les données opératoires et les taux d'échecs. Matériel et méthodes Nous avons effectué une cohorte historique de l'activité de reconstructions microchirurgicales au CHRU de Nancy de premier janvier 2004 au 31 décembre 2017. Tous les lambeaux libres ont été inclus et analysés. Résultats Au total 359 lambeaux libres ont été réalisés. Le taux d'échecs était de 9,47 %. Quarante-huit opérateurs différents ont été recensés. Les pertes de substances étaient essentiellement traumatiques (56,8 %). Au total, 20 lambeaux différents ont été réalisés avec 49 % de reconstruction osseuses. Le lambeau de fibula était le premier lambeau utilisé (26,5 %). Les anastomoses artérielles étaient réalisées en terminolatérales dans 44 % et les anastomoses veineuses étaient uniques dans 70,5 %. L'IMC élevé, le diabète, l'hypertension artérielle, l'athérosclérose, ainsi que l'utilisation d'un pontage artériel ou veineux apparaissent comme des facteurs de risque d'échec (p < 0,05). Le tabagisme et la réalisation de l'intervention par un opérateur jeune n'ont quant à eux, pas d'impact sur le taux de succès. Conclusion Notre spécificité est la reconstruction osseuse qui représente une part conséquente de notre activité. En centre universitaire, le nombre d'étiologie de perte de substance, d'opérateur et de lambeau utilisé est important, mais il permet tout de même d'obtenir des résultats en adéquation avec la littérature. Summary Introduction Each university hospital has its own specificities in microsurgical reconstructions. Activities may focus on breast reconstruction, ENT reconstruction or traumatic substance loss. This study analyzes the specificities at the University Hospital of Nancy, studies the indications, the operating data and the failure rates. Method We realized a historical cohort of microsurgical reconstructions at Nancy University Hospital from January 1, 2004 to December 31, 2017. All free flaps were included and analyzed. Results A total of 359 free flaps were made. The failure rate was 9.47%. Forty eight different operators have been identified. Substance losses were essentially traumatic (56.8%). A total of 20 different flaps were use with 49% bone reconstruction. The fibula flap was the first flap used (26.5%). Arterial anastomoses were performed in termino-lateral in 44% and venous anastomoses were single in 70.5%. High BMI, diabetes, high blood pressure, atherosclerosis, and arterial or venous graft were identified as risk factors for failure (P < 0.05). The smoking and the realisation of the intervention by a young operator have no impact on the success rate. Conclusion Our specificity is the bone reconstruction which represents a significant part of our activity. In the university center, the number of etiology of substance losses, operator and flap used is important but it still allows to obtain results in adequacy with the literature.

Operative versus conservative treatment for giant omphalocele: Study of French and Ivorian management Publication date: Available online 30 April 2019 Source: Annales de Chirurgie Plastique Esthétique Author(s): A. Binet, A. Scalabre, S. Amar, K. Alzahrani, C. Boureau, F. Bastard, F. Lefebvre, M. Koffi, S. Moufidath, D. Nasser, O. Ouattara, B.D. Kouame, H. Lardy Summary Introduction The giant omphalocele is currently a surgical challenge. The morbidity and mortality associated with its care is non-negligible. Nowadays, different studies have revived the debate between conservative and surgical management for giant omphalocele. The purpose of this study is to compare the conservative and surgical management of the giant omphalocele in terms of morbidity and mortality. Methods Retrospective study including all giant omphaloceles comparing surgical management (French University hospital centers) and tanning (Ivory Coast University hospital center). Epidemiology was studied as well as medical and surgical managements both intra and post operative. Results One hundred and forty-seven patients included (98 patients in the "tanning" group and 49 in the "surgery" group). Hospital length of stay is significantly shorter in the "tanning" group as they do not spend time in intensive care unit. Morbidity is higher in "surgery" group. The average duration for oral empowerment was acquired at 179 days in the "surgery" group, whereas in the "tanning" group 90% was immediately and exclusively breastfed. No significant differences in terms of epithelialization time. Conclusion The tanning treatment has its own place in the therapeutic arsenal in the management of the giant omphalocele no matter where it takes place. However, its realization in surgical environments prevents certain complications related to the technique or the pathology. Résumé Introduction L'omphalocèle géante est actuellement un défi chirurgical. La morbidité et la mortalité associé à sa prise en charge sont non-négligeables. Actuellement, différentes études ont relancé le débat entre la prise en charge conservatrice et chirurgicale de l'omphalocèle géant. Le but de cette étude est de comparer le traitement conservateur et chirurgical dans l'omphalocèle géante en termes de morbidité et la mortalité. Méthodes Étude rétrospective incluant toutes les omphalocèles géant gérées par fermeture chirurgicale (centres hospitaliers universitaires français) ou par tannage (centre hospitalier universitaire ivoirien). L'épidémiologie a été étudiée aussi bien que la gestion médicale et chirurgicale per- et postopératoire. Résultats Cent quarante-sept patients ont inclus (98 patients dans le groupe « tannage » et 49 dans le groupe « chirurgie »). La durée d'hospitalisation est significativement plus courte dans le groupe « tannage » avec une absence de passage aux soins intensifs. La morbidité est plus haute dans le groupe « chirurgie ». La durée moyenne pour l'autonomisation orale est de 179 jours dans le groupe « chirurgie », tandis que dans le groupe « tannage » 90 % des enfants ont été immédiatement et exclusivement allaités. Aucune différence significative en termes de temps d'épithélialisation n'est à noter. Conclusion Le traitement par tannage a sa place dans l'arsenal thérapeutique de l'omphalocèle géantes. Cependant, sa réalisation dans un environnement chirurgical permet la prise en charge des complications liées à la technique ou à la pathologie.

Steps to follow in oncoplastic breast surgery to optimise oncological and cosmetic outcome Publication date: Available online 17 April 2019 Source: Annales de Chirurgie Plastique Esthétique Author(s): G. Franceschini, R. Masetti

Particularités des injections de toxine botulique pour le traitement esthétique du visage chez l'homme. Une mise au point de la littérature Publication date: Available online 17 April 2019 Source: Annales de Chirurgie Plastique Esthétique Author(s): M. Haiun, L. Cardon-Fréville, F. Picard, J.-P. Meningaud, B. Hersant Résumé Introduction Les injections de toxine botulique en médecine esthétique sont les produits les plus utilisés, devant l'acide hyaluronique, et la médecine esthétique est en augmentation constante, y compris dans la population masculine. L'objectif de cette mise au point était de montrer les spécificités décrites dans la littérature concernant les injections de toxine botulique chez l'homme. Matériel et méthode Une recherche systématique de la littérature a été réalisée grâce au moteur de recherche Pubmed. Les données ont ensuite été collectées afin de connaître les spécificités des injections de toxine botulique chez l'homme en fonction de la morphologie du visage masculin et des désirs de ces patients. Résultats Les études réalisées montrent qu'il est nécessaire d'injecter des doses plus importantes chez l'homme que chez la femme pour obtenir un résultat satisfaisant, en raison d'une masse musculaire plus importante. Cette mise au point donne le nombre de points à réaliser par zone d'injection, ainsi que le nombre de points à effectuer, en comparaison à la population féminine. Conclusion Les injections de toxine botulique à visée esthétique chez l'homme diffèrent par rapport à la femme. La prise en compte de ces particularités est indispensable à la satisfaction des patients. Summary Introduction Botulinum toxin injections in aesthetic medicine are the most widely used products, ahead of hyaluronic acid, and aesthetic medicine is constantly increasing, including in the male population. The objective of this development was to show the specificities described in the literature concerning botulinum toxin injections in men. Material and method A systematic literature search was carried out using the Pubmed search engine. Data were then collected to determine the specificities of botulinum toxin injections in men according to the morphology of the male face and the wishes of these patients. Results The studies conducted show that it is necessary to inject higher doses in men than in women to obtain a satisfactory result, due to a higher muscle mass. This adjustment gives the number of points to be performed per injection site, as well as the number of points to be performed, compared to the female population. Conclusion Botulinum toxin injections for aesthetic purposes in men are different from those in women. Taking these particularities into account is essential to patient satisfaction.

Traitement des nécroses du tendon d'Achille sans reconstruction tendineuse : à propos de quatre cas Publication date: April 2019 Source: Annales de Chirurgie Plastique Esthétique, Volume 64, Issue 2 Author(s): C. Monnerie, D. Le Nen, W. Hu, H. Letissier, N. Kerfant Résumé Introduction La prise en charge des pertes de substances combinées du tendon d'Achille et de la peau est difficile. Il ne s'agit pourtant pas de situations exceptionnelles après chirurgie du tendon d'Achille. Les données de la littérature sont vastes et il n'existe actuellement pas de consensus quant à la technique de reconstruction du tendon. Cas cliniques Nous rapportons quatre cas de nécrose purulente du tendon d'Achille compliquant un peignage ou la suture d'une rupture tendineuse. Après parage de l'ensemble des tissus nécrotiques, la perte de substance a été couverte par un lambeau perforant fascio-cutané ou par une greffe de peau mince sans reconstruction du tendon sous-jacent. Discussion et conclusion Les résultats fonctionnels sont très satisfaisants avec de bonnes mobilités articulaires et une reprise de la marche sans boiterie pour tous les patients. La fibrose permet de reconstituer un véritable néotendon confirmé à l'IRM. Les avantages sont nombreux par rapport à d'autres méthodes : un seul temps opératoire est nécessaire, la gestion postopératoire est simple et elle permet d'éviter certaines difficultés techniques liées à la reconstruction tendineuse. Une plus large série serait nécessaire pour conforter ces résultats. Summary Introduction Management of the combined loss of Achilles tendon and skin is difficult. However, these are not exceptional situations after Achilles tendon surgery. Data from the literature are extensive and there is currently no consensus on the technique of tendon reconstruction. Case reports We report four cases of purulent necrosis of the Achilles tendon complicating longitudinal incision or suturing of a tendon rupture. After debridement of necrotic tissue, the defect was covered either by a fasciocutaneous perforating flap or a thin skin graft without reconstruction of the underlying tendon. Discussion and conclusion The functional results are very satisfactory with good joint mobilities and a resumption of walking without lameness for all patients. Fibrosis can reconstitute a true neo-tendon confirmed on MRI. The advantages are many compared to other methods: a single operating time is necessary, the postoperative management is simple and it avoids certain technical difficulties related to tendon reconstruction. A larger series would be needed to support these results.

Étude de la rétraction cutanée en chirurgie carcinologique cutanée. Étude clinique de 79 cas Publication date: April 2019 Source: Annales de Chirurgie Plastique Esthétique, Volume 64, Issue 2 Author(s): A. Moret, M.-C. Charton-Bain, I. Lota, J.-P. De Cuttoli, P. Revol Résumé Objectifs La chirurgie des tumeurs cutanées est courante et bien codifiée. Il existe une discordance entre des recommandations sur les marges macroscopiques à appliquer et les décisions thérapeutiques prises sur des marges histologiques. Cette étude a pour vocation d'étudier la rétraction cutanée qui survient lors de l'exérèse puis dans le formol, pour comprendre la discordance anatomoclinique souvent retrouvée. Patients et méthodes Il s'agissait d'une étude prospective, d'un mois, incluant les patients bénéficiant d'une chirurgie cutanée. Pour chaque tumeur, le chirurgien effectuait 4 mesures de marges avant puis après l'exérèse ; marges mesurées à nouveau en histologie. Le critère de jugement était la différence de mesure de marges en préopératoire, postopératoire et histologie. Ces données étaient pondérées en fonction de facteurs liés au patient et à la tumeur. Résultats Soixante-dix-neuf tumeurs pour 61 patients ont été étudiées. L'étude a montré une rétraction significative entre les mesures préopératoires et postopératoires, de 0,4 à 0,6 mm. Elle n'est corrélée à aucun des autres facteurs testés. Une rétraction significative entre 0,4 et 0,5 mm a également été montrée entre les mesures préopératoires et histologiques. En revanche, il existe une augmentation significative entre les mesures postopératoires et histologiques. Conclusion Ce dernier résultat pourrait être lié à la zone péri-lésionnelle inflammatoire que le chirurgien considère comme étant tumoral donc exclut de sa marge alors que l'histologie peut montrer une zone saine. Devant ces résultats, un comité d'expert menant une étude plus importante pourrait inclure des recommandations sur les marges histologiques aux recommandations cliniques actuelles. Summary Background Skin tumors surgery is common and well established. There is discrepancy between recommendations on macroscopic margins to apply and therapeutic decisions taken on histological margins. The purpose of this study is to examine skin shrinkage upon exeresis, then in formalin, to understand the anatomo-clinical discrepancy, which is often found. Material and methods It was a prospective study, lasting a month, including patients receiving skin surgery. For each tumor, the surgeon carried out 4 margins measurements before and after exeresis ; margins measured again in histology. The evaluation criterion was the difference between preoperative, postoperative and histological margins measurement. These data was weighting according to factors linked to the patient and the tumor. Results Seventy-nine tumors for 61 patients had been studied. The study showed a significant shrinkage between preoperative measurements and postoperative, from 0.4 to 0.6 mm. It is correlated with no one tested factors. Significant shrinkage between 0.4 and 0.5 mm was also established between preoperative and histological measurements. However, there is a significant augmentation between postoperative and histological measurements. Conclusion This last result could be linked to the inflammatory peri-wound skin that surgeon consider as tumoral process so exclude of his margin, while histology could show a healthy area. In front of these results, an expert committee leading a more important study could include histological margins recommendations to the actual clinical recommendations.

Comparison of venous couplers versus hand-sewn technique in free flap breast reconstruction Publication date: April 2019 Source: Annales de Chirurgie Plastique Esthétique, Volume 64, Issue 2 Author(s): G. Dimitropoulos, J.I. Efanov, L. Paek, J. Bou-Merhi, M.A. Danino Summary Introduction Despite positive outcomes reported in the literature, some surgeons remain reluctant to the systematic use of venous couplers in free flap tissue transfer. In our institution, the use of the coupler devices for venous anastomosis in free flap breast reconstruction has yet to be adopted by all surgeons. The purpose of the study was to compare postoperative outcomes of coupler-assisted venous anastomoses with hand-sewn techniques in free flap breast reconstruction. Methods An analysis of collected data was performed on cases of breast reconstruction with free tissue transfer after mastectomy in breast cancer or BRCA-positive patients from 2010 to 2016. Patients were divided into two groups: coupler device and hand-sewn. The primary outcome was survival rate of free flaps. Secondary outcomes included potential complications, as well as surgical characteristics (recipient artery/vein, coupler size, type of hand-sewn anastomosis, size of sutures, number of venous anastomoses, ischemia time, operative time) Results We included 289 cases in our study. There were no significant differences between groups in terms of post-operative complications or survival rate of the free flaps. Ischemia time was significantly lower in both immediate and delayed reconstruction cases. Operative and anesthesia times were significantly lower only in immediate unilateral cases. Conclusion Although ischemia time was reduced in the coupler group, we didn't find any significant difference in the operative and anesthesia time in the subgroup analysis, except for the group of immediate unilateral breast reconstruction. Couplers are safe and efficient; nevertheless, our study shows that their qualities cannot yet justify the disappearance of the manual sutures. Résumé Introduction/but de l'etude Malgré des études montrant les avantages des coupleurs veineux en microchirurgie, quelques chirurgiens restent hésitants à les utiliser de façon systématique. Dans notre établissement, les coupleurs ne sont pas utilisés par tous les chirurgiens pratiquant la reconstruction mammaire par lambeaux libres. Le but de cette étude était de comparer l'anastomose veineuse par coupleurs et la suture manuelle dans la reconstruction mammaire microchirurgicale par DIEP. Méthodes Une étude rétrospective a été conduite de 2010 à 2016. Les patientes ayant bénéficié d'une reconstruction du sein par lambeau libre DIEP ont été incluses dans l'étude. Les patientes ont été séparées en deux groupes: anastomose veineuse à l'aide d'un coupleur versus suture manuelle. L'objectif primaire recherché était de comparer le taux de survie des lambeaux. Les objectifs secondaires étaient d'évaluer les complications postopératoires ainsi que les caractéristiques chirurgicales (vaisseaux receveurs, taille du coupleur, type de la suture manuelle, taille du fil de suture, nombre des anastomoses veineuses, temps d'ischémie, temps opératoire). Résultats Au total, 289 cas ont été inclus dans notre travail. Il n'y avait pas de différence significative entre les deux groupes concernant les complications postopératoires ou le taux de survie des lambeaux. Le temps d'ischémie était plus court tant en reconstruction immédiate qu'en reconstruction secondaire. La durée opératoire ainsi qu' anesthésique était plus courte dans les cas de reconstruction immédiate unilatérale. Conclusion Alors que le temps d'ischémie était plus court pour le groupe des coupleurs, nous n'avons pas pu démontrer une différence significative pour les durées opératoires et anesthésiques sauf dans les cas de reconstruction immédiate unilatérale. Bien qu' étant reconnu comme une technique sécuritaire et efficace, notre étude montre que les coupleurs ne possèdent pas les avantages permettant de justifier la disparition de la suture manuelle.

De l'histoire des chirurgiens cachés derrières nos instruments du quotidien. Partie 1 : pinces et pincettes Publication date: April 2019 Source: Annales de Chirurgie Plastique Esthétique, Volume 64, Issue 2 Author(s): S. Rasteau, N. Sigaux Résumé Bien des instruments chirurgicaux portent les noms de leurs inventeurs, chirurgiens du passé souvent émérites de par leurs découvertes et leurs contributions à l'avancée des techniques chirurgicales. Cependant, ce rappel quotidien à l'histoire de la chirurgie est bien souvent oublié des praticiens contemporains. Nous nous proposons donc d'étudier, à travers une sélection d'instruments, de brèves biographies de ces précurseurs. Ce premier article se consacrera aux inventeurs des pinces de Debakey, Adson, Kocher, Péan, Tuffier et Halsted. Summary Many surgical instruments are named after their inventors, acclaimed surgeons of the past, because of their discoveries and their contributions in the field of surgical techniques. However, these daily reminders of History of Surgery are often forgotten by the modern practitioners. We propose to review, through a selection of instruments, short biographies of these precursors. This first original article will focus on the inventors of modern forceps: Debakey, Adson, Kocher, Péan, Tuffier and Halsted.

Cancer Epidemiology

Health-related predictors of cancer registry-notified cancer of unknown primary site (CUP) Publication date: August 2019 Source: Cancer Epidemiology, Volume 61 Author(s): C.M. Vajdic, O. Perez-Concha, J.J. Rhee, T. Dobbins, R.L. Ward, A.L. Schaffer, M.T. van Leeuwen, M.A. Laaksonen, G. Craigen, S.A. Pearson Abstract Background The relationship between comorbid disease and health service use and risk of cancer of unknown primary site (CUP) is uncertain. Methods A prospective cohort of 266,724 people aged 45 years and over in New South Wales, Australia. Baseline questionnaire data were linked to cancer registration, health service records 4–27 months prior to diagnosis, and mortality data. We compared individuals with incident registry-notified CUP (n = 327; 90% C80) to two sets of randomly selected controls (3:1): (i) incident metastatic cancer of known primary site (n = 977) and (ii) general cohort population (n = 981). We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results In fully adjusted models incorporating sociodemographic and lifestyle factors, people with cancer registry-notified CUP were more likely to have fair compared with excellent self-rated overall health (OR 1.78, 95% CI 1.01–3.14) and less likely to self-report anxiety (OR 0.48, 95% CI 0.24−0.97) than those registered with metastatic cancer of known primary. Compared to general cohort population controls, people registered with CUP were more likely to have poor rather than excellent self-rated overall health (OR 6.22, 95% CI 1.35–28.6), less likely to self-report anxiety (OR 0.28, 95% CI 0.12−0.63), and more likely to have a history of diabetes (OR 1.89, 95% CI 1.15–3.10) or cancer (OR 1.62, 95% CI 1.03–2.57). Neither tertiary nor community-based health service use independently predicted CUP risk. Conclusion Low self-rated health may be a flag for undiagnosed cancer, and an investigation of its clinical utility in primary care appears warranted.

Lung cancer patients' journey from first symptom to treatment: Results from a Greek registry Publication date: June 2019 Source: Cancer Epidemiology, Volume 60 Author(s): G. Kourlaba, I. Gkiozos, E. Kokkotou, G. Stefanou, A. Papaspiliou, K. Syrigos Abstract Background To map the patients' journey from symptoms onset to treatment initiation for the most frequent histological types of lung cancer in Greece and describe the initial treatment that patients receive. Methods The primary data source was a Greek hospital-based registry. Demographic, anthropometric, lifestyle, and diagnostic-related characteristics as well as treatment-related data were extracted from the registry for patients diagnosed with Adenocarcinoma, Squamous and Small Cell Lung Cancer (SCLC). The time intervals from symptoms onset to diagnosis (StD), diagnosis to treatment initiation (DtT), symptoms onset to treatment initiation (StT) and surgery to post–surgery treatment (SRGtT) were estimated. Results 231, 120 and 122 patients were diagnosed with Adenocarcinoma, SCLC and Squamous, respectively. The percentage of patients diagnosed at stage III/IV ranged from 75% in Adenocarcinoma to 97.5% in SCLC (p < 0.001). The median (IQR) StD was 52 (28–104) days and no difference was detected across the three histological types (p = 0.301). Cough as first symptom was the only determinant of StD (p = 0.001). The median (IQR) DtT was 23 (13–36) days, with this time interval being shorter among patients with SCLC compared to patients with Adenocarcinoma and Squamous (p < 0.001). The median (IQR) StT was 81 (51–139) days. Almost one third of patients with Adenocarcinoma and Squamous were subjected first to surgery and the median (IQR) SRGtT was 42 (34–55) days. Conclusions Our results indicate that time interval from symptoms onset to treatment initiation in Greece is substantially prolonged, highlighting the need for strategies to expedite lung cancer diagnosis and access to evidence-based treatment.

Key factors associated with social distress after prostate cancer: Results from the United Kingdom Life after Prostate Cancer diagnosis study Publication date: June 2019 Source: Cancer Epidemiology, Volume 60 Author(s): Penny Wright, Sarah Wilding, Eila Watson, Amy Downing, Peter Selby, Luke Hounsome, Richard Wagland, David H. Brewster, Dyfed Huws, Hugh Butcher, Rebecca Mottram, Therese Kearney, Majorie Allen, Anna Gavin, Adam Glaser Abstract Background More men are living following a prostate cancer (PCa) diagnosis. They may need support to maximize the quality of their survival. Physical and psychological impacts of PCa are widely documented. Less is known about social impacts. We aimed to identify key factors associated with social distress following PCa. Methods The Life After Prostate Cancer Diagnosis study is a UK national cross-sectional survey of men 18–42 months post diagnosis of PCa. Men (n = 58 930) were invited to participate by their diagnosing cancer centre including 82% of English NHS Trusts (n = 111) and 100% of all Health Boards in Northern Ireland (n = 5), Scotland (n = 14) and Wales (n = 6). Social distress was measured using the Social Difficulties Inventory (SDI-21), 16 item Social Distress scale with men assigned to 'socially distressed'/'not socially distressed' groups, according to published guidelines. Clinical and sociodemographic variables were collected from self-report and cancer registries. Results Response rate 60.8% (n = 35 823) of whom 97% (n = 29 351) completed the Social Distress scale (mean age = 71.2; SD = 7.88). The proportion of 'socially distressed' men was 9.4%. Multivariable logistic regression analysis revealed unemployment versus employment (odds ratio (OR): 11.58 [95% CI 9.16–14.63]) and ≥3 co-morbidities versus none (OR: 5.37 [95% CI 4.61–6.27]) as key associations. Others were Androgen Deprivation Therapy, External Beam Radiotherapy in combination with another treatment, age, prior mental health problems and living in a socio-economically deprived area. Conclusion Most men following PCa are socially resilient. A simple checklist could help clinicians identify men at risk of social distress.

Time-to-cure and cure proportion in solid cancers in France. A population based study Publication date: June 2019 Source: Cancer Epidemiology, Volume 60 Author(s): Gaëlle Romain, Olayidé Boussari, Nadine Bossard, Laurent Remontet, Anne-Marie Bouvier, Morgane Mounier, Jean Iwaz, Marc Colonna, Valérie Jooste, French Network of Cancer Registries (FRANCIM) Abstract Background In cancer care, the cure proportion (P) and time-to-cure (TTC) are important indicators for practitioners, patients, and healthcare policy makers. The recent definition of TTC as the time at which the probability of belonging to the cured group reaches 95% was used for the first time. Methods The data stem from the common database of French cancer registries including 335,358 solid tumours diagnosed between 1995 and 2009 at 27 sites. P and TTC were estimated through a flexible parametric net survival cure model for each cancer site, sex, and age at diagnosis with acceptable assumption of cure (excess mortality rate ≤0.05). Results TTC was ≤5 years and P was >80% for skin melanoma and thyroid and testis cancers. It was 0 for testis cancer in men <55 and for thyroid cancer in men <45 and women <65. TTC was between 5 and 10 years for all digestive cancers except small intestine and all gynaecologic cancers except breast. It was ≥10 years in prostate, breast, and urinary tract. The range of P according to age and sex was 37–79% for urinary tract 72–88% for prostate and breast, 4–16% for pancreatic and 47–62% for colorectal cancer. Conclusion Time-to-cure was estimated for the first time from a large national database and individual probabilities of cure. It was 0 in the younger patients with testis or thyroid cancer and <12 years in most cancer sites. These results should help improve access to credit and insurance for patients still alive past the estimated TTCs. Graphical abstract

Deprivation and mass screening: Survival of women diagnosed with breast cancer in France from 2008 to 2010 Publication date: June 2019 Source: Cancer Epidemiology, Volume 60 Author(s): Marie Poiseuil, Gaëlle Coureau, Catherine Payet, Marianne Savès, Marc Debled, Simone Mathoulin-Pelissier, Brice Amadeo Abstract Background Some studies have investigated the role of socio-demographic inequalities in the association between screening and survival. However, in France, no study has been conducted to describe the socio-demographic characteristics and survival of women with breast cancer based on their participation to mass screening. The aim of this study was to assess the impact of socio-demographic inequalities on the association between participation in mass screening program and survival of women with breast cancer. Methods Data for 2,244 women aged 50–74 years diagnosed with breast cancer over the period 2008–2010 were obtained from the cancer registry and the screening structure of Gironde. We used the aggregated European Deprivation Index (EDI) to define the deprivation level of women. Net survival rates were estimated with the Pohar-Perme method, with and without correcting for lead-time bias. Results Survival rates were lower for non-attenders than for screen-detected women (83.8% vs 97.3%, p < 0.0001), even after correcting for lead-time bias. Among the most deprived women, the survival rate was significantly different between non-attenders and screen-detected women (78.1% vs 95.6%, p = 0.0002), suggesting an important effect of mass screening in this group. Conclusion The introduction of incentive actions in deprived areas could play a key role in the adherence of women to mass screening and in improving their survival in case of a breast cancer diagnosis.

Differences in cancer incidence by age at diagnosis between Aboriginal and non-Aboriginal people for cancer types included in Australian national screening programs Publication date: June 2019 Source: Cancer Epidemiology, Volume 60 Author(s): Hanna E. Tervonen, Stephen Morrell, David Roder, Hui You, David C. Currow Abstract Background This study examined age distributions and age-specific incidence of screened cancers by Aboriginal status in New South Wales (NSW) to consider the appropriateness of screening target age ranges. Methods The NSW Cancer Registry identified invasive (female) breast, cervical and bowel cancers in people diagnosed in 2001–2014. Results Aboriginal people were younger at diagnosis with higher proportions of breast and bowel cancers diagnosed before the screening target age range (<50 years) compared with non-Aboriginal people (30.6% vs. 22.8%, and 17.3% vs. 7.3%, respectively). Age-specific incidence rate ratios (IRRs) were lower/similar for breast and bowel cancers in younger and higher in older Aboriginal than non-Aboriginal people. All age-specific cervical cancer IRRs were higher for Aboriginal compared with non-Aboriginal people. Conclusion Although higher proportions of breast and colorectal cancers were diagnosed before screening commencement age in Aboriginal people, this does not necessarily indicate a need for earlier screening commencement. Other aspects needing consideration include benefits, harms and cost-effectiveness.

LDCT lung cancer screening eligibility and use of CT scans for lung cancer among sexual minorities Publication date: June 2019 Source: Cancer Epidemiology, Volume 60 Author(s): Philip Veliz, Alicia K. Matthews, Cynthia Arslanian-Engoren, Rebecca J. Evans-Polce, Joseph G.L. Lee, Carol J. Boyd, Tonda Hughes, Vita V. McCabe, Sean Esteban McCabe Abstract Objective To compare eligibility for lung cancer screening and receipt of a CT scan for lung cancer among sexual minorities. Methods Secondary data analysis of cross-sectional data from older U.S. adults in the Behavioral Risk Factor Surveillance System survey during the 2017 cycle (n = 20,685). Results Rates of eligibility for low-dose helical computed tomography (LDCT) were roughly twice as high among sexual minorities than among heterosexuals (21.1% vs. 11.7%). The odds of gay men and lesbian women indicating eligibility for LDCT screening were four to five times higher when compared to their heterosexual peers. No statistically significant differences were found between sexual minorities and heterosexuals with respect to having a CT scan for lung cancer in the past year. Conclusions There are potential sexual-identity-related disparities in the utilization of lung cancer screening among eligible smokers. Interventions are needed to increase awareness and uptake of lung cancer screening in order to detect and manage this common form of cancer in the U.S.

Cancer fatalism and adherence to national cancer screening guidelines: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Publication date: June 2019 Source: Cancer Epidemiology, Volume 60 Author(s): Patricia I. Moreno, Betina Yanez, Steven J. Schuetz, Katy Wortman, Linda C. Gallo, Catherine Benedict, Carrie E. Brintz, Jianwen Cai, Sheila F. Castaneda, Krista M. Perreira, Patricia Gonzalez, Franklyn Gonzalez, Carmen R. Isasi, Frank J. Penedo Abstract Background Sociocultural factors, such as health insurance status, income, education, and acculturation, predict cancer screening among U.S. Hispanics/Latinos. However, these factors can be difficult to modify. More research is needed to identify individual-level modifiable factors that may improve screening and subsequent cancer outcomes in this population. The aim of this study was to examine cancer fatalism (i.e., the belief that there is little or nothing one can do to lower his/her risk of developing cancer) as a determinant of adherence to national screening guidelines for colorectal, breast, prostate, and cervical cancer among Hispanics/Latinos. Methods Participants were from the multi-site Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Sociocultural Ancillary Study (N = 5313). The National Cancer Institute (NCI) Health Interview National Trends Survey was used to assess cancer fatalism and receipt of cancer screening. Adherence was defined as following screening guidelines from United States Preventive Services Task Force and the American Cancer Society during the study period. Results Adjusting for well-established determinants of cancer screening and covariates (health insurance status, income, education, acculturation, age, Hispanic/Latino background), lower cancer fatalism was marginally associated with greater adherence to screening for colorectal (OR 1.13, 95% CI [.99–1.30], p = .07), breast (OR 1.16, 95% CI [.99–1.36], p = .08) and prostate cancer (OR 1.18, 95% CI [.97–1.43], p = .10), but not cervical cancer. Conclusions The associations of cancer fatalism were small and marginal, underlining that sociocultural factors are more robust determinants of cancer screening adherence among Hispanics/Latinos.

Future of cancer incidence in Shanghai, China: Predicting the burden upon the ageing population Publication date: June 2019 Source: Cancer Epidemiology, Volume 60 Author(s): Zhenqiu Liu, Yanfeng Jiang, Qiwen Fang, Huangbo Yuan, Ning Cai, Chen Suo, Weimin Ye, Xingdong Chen, Tiejun Zhang Abstract Aim The age-specific cancer patterns have changed significantly over the last few decades in urban Shanghai. Predicting the cancer incidence in an ageing population can help to anticipate future resource needs, evaluate primary prevention strategies, and inform further research studies. Materials and Methods Annual cancer cases and population data from 1988 to 2013 were collected from Shanghai Cancer Registry. A Bayesian age-period-cohort model was applied to project the future cancer incidence with demographical changes from 2014 to 2025. Results From 1988 through 2013, the urban population aged < 65 years decreased by 19.5%, while the population aged ≥ 65 years increased by 58.4%. In the same period, cancer cases increased by 66.0% (from 8315 to 13,806) and 88.6% (from 7448 to 14,048) in these two populations, respectively. From 2014–2025, the population size is expected to decrease by an additional 29.6% in people aged < 65 years, while it will increase by an additional 68.3% in people aged ≥ 65 years. Correspondingly, the model predicts an 87.5% and 143.4% increase in cancer cases for these two populations, respectively. The most pronounced increase was found in thyroid cancer in both sexes, followed by prostate, kidney, and colon cancer in men. In women, lung, kidney, and cervical cancer in women was expected to increase. Conclusions The number of cancer cases in urban Shanghai, especially in older people, is expected to significantly increase in the next decade. Particular strategies targeting the elderly are required to combat the cancers.

Body mass index and the risk of head and neck cancer in the Chinese population Publication date: June 2019 Source: Cancer Epidemiology, Volume 60 Author(s): Yuji Chen, Yuan-Chin Amy Lee, Shuang Li, Qian Li, Chien-Jen Chen, Wan-Lun Hsu, Pen-Jen Lou, Cairong Zhu, Jian Pan, Hongbing Shen, Hongxia Ma, Lin Cai, Baochang He, Yu Wang, Xiaoyan Zhou, Qinghai Ji, Baosen Zhou, Wei Wu, Jie Ma, Daisuke Kawakita Abstract Objective To investigate potential associations between body mass index (BMI) and head and neck cancer (HNC) risk in an East Asian population. Methods We conducted a hospital-based multicenter case-control study in East Asia including 921 cases and 806 controls. We estimated the odds ratios (ORs) and 95% confidence intervals (95% CI) for HNC risks by using logistic regression, adjusting on potential confounders. Results Compared to normal BMI at interview (18.5–<25 kg/m2), being underweight (BMI < 18.5 kg/m2) was associated with a higher HNC risk (OR = 2.71, 95% CI  1.40–5.26). Additionally, obesity (BMI > 30 kg/m2) was associated with a lower HNC risk (OR = 0.30, 95% CI  0.16–0.57). Being underweight at age 20 was also associated with an increased risk of HNC. However, being underweight at 5 years or 2 years before interview was not associated with a higher risk of HNC. Conclusion We observed an inverse association between BMI and HNC risk, which is consistent with previous studies in other geographic regions. Being underweight at age 20 was also associated with a higher risk of HNC, suggesting that reverse causality was not the main source of the association.

Physical Medicine & Rehabilitation

Bilateral Quadriceps Muscle Strength and Pain Correlate with Gait Speed and Gait Endurance Early after Unilateral Total Knee Arthroplasty : A Cross-Sectional Study Objective The objective of this study was to determine the correlations between objective performance-based physical function, self-reported physical function, quality of life, and gait function at 1 month after unilateral total knee arthroplasty (TKA). Design Cross-sectional data from 195 patients who underwent unilateral primary TKA were analyzed. The isometric knee extensor and flexor strength of both knees, gait parameters, 6 minute walk test (6MWT), timed up-and-go (TUG) test, timed stair climbing test (SCT), knee flexion and extension range of motion (ROM) of surgical knee, Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) pain, stiffness, and functional levels, EuroQol five-dimensions (EQ-5D) questionnaire and visual analog scale (VAS) for knee pain were assessed. Results In bivariate analyses, both postoperative gait speed and gait endurance hadsignificant positive correlations with postoperative peak torque (PT) of the extensor and flexor of both knees, cadence, stride length, and significant negative correlation with TUG, SCT-ascent, SCT-descent, VAS, WOMAC pain, stiffness, and function levels.In the linear regression analyses, postoperative PT of the extensors of both knees and VAS for knee pain were factors correlated with postoperative gait speed and gait endurance. Conclusion Quadriceps muscle strength of both knees and knee pain were important factors correlated with gait function early after TKA. Please address all correspondence to: Bo Ryun Kim, MD. Ph. D., Department of Rehabilitation Medicine, Jeju National University School of Medicine, Regional Rheumatoid and Degenerative Arthritis Center, Jeju National University Hospital, Aran 13 gil 15, Jeju 63241, Republic of Korea, Phone: +82-64-717-2711, FAX: +82-64-717-1131, E-mail: brkim08@gmail.com Author disclosures Competing Interests: The aurthors certify that no party having a direct interest in the results of the research supporting this article has or will confer a benefit on them or on any organization with which they are associated Funding or grants or equipment provided for the project from any source: The authors received no funding for this work. Financial benefits to the authors; Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Making patients fit for surgery: introducing a four pillar multimodal prehabilitation program in colorectal cancer Background Considering the relation between preoperative functional capacity and postoperative complications, enhancing a patients functional capacity prior to surgery with a prehabilitation program may facilitate faster recovery and improve quality of life. However, time before surgery is short, mandating a multimodal and high-intensity training approach. This study investigated feasibility and safety of a prehabilitation program for colorectal cancer. Methods Multimodal prehabilitation was offered to patients eligible for participation. They were assigned to an intervention or control group by block randomisation. The prehabilitation program consisted of four interventions: in-hospital high-intensity endurance and strength training, high-protein nutrition, smoking cessation and psychological support. Program attendance, patient satisfaction, adverse events and functional capacity were determined. Results Fifty patients participated in this study (prehabiilitaiton 20, control 30). Program evaluation revealed a high (90%) attendance rate and high level of patient satisfaction. No adverse events occurred. Endurance and/or strength were improved. 86% of patients with prehabilitation recovered to their baseline functional capacity 4 weeks post-operatively, 40% in the control group (p<0.01). Conclusions Multimodal prehabilitation including high-intensity training for colorectal cancer patients is feasible, safe and effective. A randomized controlled trial (NTR5947) was initiated to determine whether prehabilitation may lower morbidity and mortality rates in colorectal surgery. Corresponding author + request for reprints: S.J. van Rooijen MD PhD, Máxima Medical Center, Department of Surgery, P.O. Box 7777, Veldhoven, the Netherlands, stefanvanrooijen@msn.com / prehab.resurge@mmc.nl This pilot was financially supported (MMC2620) by the National Foundation against Cancer (Nationaal Fonds tegen Kanker). FrieslandCampina provided the Refit®TMP 90 Shakes. The funding sources had no role in the design of this study and did not have any role during its execution, analyses, interpretation of the data, or decision to submit results. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Evaluating Physician Knowledge of Commonly Prescribed Inpatient Rehabilitation Unit Discharge Medication's Costs: An Observational Study The objective of this study was to assess physiatrists' knowledge of the cost of medications commonly prescribed at discharge from inpatient rehabilitation units across the spectrum of practice experience from residents to attending physicians. Investigators contacted 92 pharmacies across 4 major regions of the United States (U.S.) and averaged the cash price of each medication. An electronic survey was created highlighting 17 medications in which physicians estimated the cost of a medication per pill and per month for a 30-day supply. Surveys were sent to all ACGME-accredited programs across the U.S.; 43 participants responded to the survey. Most respondents overestimated the cost of the medications chosen for the survey. There was no significant difference between medication cost knowledge and practice experience (p = 0.497) or post-graduate year of training (p = 0.593). This raises awareness that physiatrists may not know the cost of medications they commonly prescribe at discharge, which may have implications on patient medication compliance, quality of care and patient satisfaction. Correspondence: Allison Capizzi, MD, University of Utah, 30 North 1900 East, Salt Lake City, UT, 84132. Office Phone: 801-585-2589. Mobile: 805-403-1763. Fax: 801-587-5757 Author Disclosures: No authors involved in this study have any competing interests, financial benefits, funding, grants or equipment to disclose. This material has not been presented at an AAPM&R Annual Assembly. Funding: No funding was acquired in completion of this project Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Clinical Practice Guidelines for the Rehabilitation of Lower Limb Amputation: An Update from the Department of Veterans Affairs and Department of Defense Between 2015 and 2017, the US Department of Veterans Affairs (VA) and the US Department of Defense (DoD) developed a Clinical Practice Guideline (CPG) for Rehabilitation of Lower Limb Amputation to address key clinical questions. A multidisciplinary workgroup of VA and DoD amputation care subject-matter-experts was formed and an extensive literature search was performed which identified 3,685 citations published from January 2007 through July 2016. Articles were excluded based upon established review criteria resulting in 74 studies being considered as evidence addressing one or more of the identified key issues. The identified literature was evaluated and graded utilizing the National Academies of Science GRADE criteria. Recommendations were formulated following extensive review. Eighteen recommendations were confirmed with four having strong evidence and workgroup confidence in the recommendation. Key recommendations address patient and caregiver education, consideration for the use of rigid and semi-rigid dressings, consideration for the use of microprocessor knees, and managed lifetime care that includes annual transdisciplinary assessments. In conclusion, this CPG utilized the best available evidence from the past 10 years to provide key management recommendations to enhance the quality and consistency of rehabilitation care for persons with lower limb amputation. Corresponding Author: Joseph B. Webster, M.D.; 1201 Broad Rock Boulevard, Richmond, VA 23112, 804-675-7036, joseph.webster@va.gov Disclosure: This work represents the opinions of the authors and not necessarily those of any government agency, academic institution or healthcare agency. This work was fully funded by the Departments of Defense and Veterans Affairs. No funding was received from any commercial entity. Material was presented at the 2018 AAPM&R Annual Assembly on October 26, 2018. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Authors' Response to the Letter to the Editor on "An Obvious and Potentially Neglected Cause of Buttock Pain: Gluteus Maximus Dysfunction" No abstract available

Impact of a Stroke Recovery Program Integrating Modified Cardiac Rehabilitation on All-cause Mortality, Cardiovascular Performance and Functional Performance Objective Using a feasibility analysis and matched subgroup analysis, this study investigated the implementation/safety/outcomes of a Stroke Recovery Program(SRP) integrating modified cardiac rehabilitation(CR) for stroke survivors. Design This prospective cohort study of 783 stroke survivors were discharged from an inpatient rehabilitation facility to an outpatient setting; 136 SRP-participants completed a feasibility study and received the SRP including modified CR, 473 chose standard of care rehabilitation(non-participants) and a group(n=174) were excluded. The feasibility study assessed: safety/mortality/pre-post cardiovascular-performance/pre-post function/patient/staff-perspective. In addition to the feasibility study, a non-randomized subgroup analysis compared SRP-participants(n=76) to matched pairs of non-participants(n=66, with 10 non-participants used more than once) for mortality/pre-post function. Results The feasibility study showed the SRP to have:1)excellent safety, 2)markedly low 1-year post-stroke mortality from hospital admission(1.47%) compared to national rate of 31%,1 3)improved cardiovascular-performance over 36 sessions(103% increase in Metabolic Equivalent of Tasks times minutes), 4)improved function in Activity Measure of Post-Acute Care(AM-PAC)TM domains(P<0.001), 5)positive reviews from SRP-participants/staff. Subgroup analysis showed the SRP to:1)positively impact mortality; non-participants had a 9.09 times higher hazard of mortality(P=0.039), and 2)improve function in AM-PACTM domains(P<0.001). Conclusion Stroke survivors receiving a SRP integrating modified CR may potentially benefit from reductions in all-cause mortality, and improvements in cardiovascular-performance and function. Corresponding Author: Sara J. Cuccurullo, M.D., JFK Johnson Rehabilitation Institute, 65 James Street, Edison, NJ 08818, Phone 732-321-7000 X62780; Fax 732-744-5846; Email: Sara.Cuccurullo@hackensackmeridian.org Disclosures: This study was supported in part by a Project Grant from the NorthEast Cerebrovascular Consortium (NECC) awarded to Dr. Cuccurullo and Dr. Fleming. NuStep® cross-training bicycles were provided in-kind. The statistical analysis performed for this study has not been presented in another format. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Comments on "An Obvious and Potentially Neglected Cause of Buttock Pain: Gluteus Maximus Dysfunction" No abstract available

Physical Medicine and Rehabilitation: Trends in Graduate Medical Education and Sub-Specialization Amidst Changing Demographics With an aging and growing U.S. population, American healthcare faces an impending physician shortage. This is important for the field of Physical Medicine and Rehabilitation (PM&R), as physiatrists' skills in managing chronic conditions and functional outcomes are especially relevant to an older population. The present study was designed to better understand the future PM&R workforce, by recording and analyzing the quantities of ACGME-accredited PM&R graduate medical education programs and positions between 2001-02 and 2017-18. Results indicated that PM&R graduate medical education has grown since 2001-02, especially in subspecialties such as Pediatric Rehabilitation and Sports Medicine. However, the growth in PM&R residency positions has been three-fold lower than that of total GME. In addition, sub-specialization has become increasingly prevalent, and residency positions have declined relative to the population of older adults. The future identity of PM&R will continue to develop as professional and demographic trends shape this important medical specialty. Correspondence to: Aldis H. Petriceks, Stanford University School of Medicine, 269 Campus Dr., CCSR 0135A, Stanford, CA 94305. Email: aldisp@stanford.edu. Phone: 650-796-0340. Fax: 650-498-5394. Author Disclosures: The authors declare no competing interests; no funding, grants, or equipment received for this project; no financial benefits incurred from this project; and no previous presentation of this research in any form. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

TIME EFFECTOF INTRA-ARTICULAR INJECTION WITH TRIAMCINOLONE HEXACETONIDE AND ITS CORRELATIONS: A CASE – CONTROL PROSPECTIVE 12 MONTH STUDY Objective To assess the time effect of intra-articular (IA) injection with triamcinolone hexacetonide (TH) in rheumatic patients. Design A prospective case-control study with patients submitted to one IA injection with TH. Patients were followed monthly (12 months) for pain and swelling. Results 262 joints were assessed in 158 patients with mean age of 60 (±13.7) years. Remission were observed at 3, 6 and 12 months in 142 (54.19%), 111 (42.36%) and 105 (40.07%) joints, respectively.The mean time effect were 8 (±4.0) months; 8.4 (±3.9) for rheumatoid arthritis (RA) patients and 6.9 (±4.0) for osteoarthritis patients (p=0.012); and 10.4 (±2.7) months for small; 7.7 (±4.1) for medium and 6.8(±4.0) for large joints. The joints were divided into two groups: long-term group (LTG- time effect of IA injection longer than six months) and short-term group (STG).Variables associated (p <0.05) with LTG: RA, small and medium-sized joints, female gender, lower pain and swelling VAS scores and use of leflunomide. Variables associated with STG: receiving only one IA injection, hypertension, diabetes mellitus, biological therapy. Conclusion The time effect of IA injection with TH was 8.0 (±4.0) months. The associated predictors were RA, small and medium-sized joints, lower pain/swelling VAS scores, and use of leflunomide. Financial information: none Corresponding Author: Rita Nely Vilar Furtado, Universidade Federal de São Paulo, Rua Botucatu, 740 – 04023-900, São Paulo/SP – Brazil, Telephone contact/ Fax: 55-11-55764239, Email: rvfurtado@hotmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Time course and recovery of the movements of hyoid bone and thyroid cartilage during swallowing in a patient with sarcopenic dysphagia: a case report Sarcopenia is known to adversely affect swallowing function. In this report, we describe the treatment progress of an older patient with dysphagia caused by sarcopenia and the analysis results from videofluorographic examination images. An 89-year-old man who had been hospitalized for lumbar fracture experienced lower back pain, and thus had his oral intake reduced. After transfer to a rehabilitation hospital, he developed aspiration pneumonia and then sarcopenia with low nutrition and low activity. At the beginning of intervention, he aspirated food paste, but he recovered sufficiently to be able to ingest a normal meal via a nutritional approach combined with rehabilitation at the time of discharge. During this process, the maximum amounts of displacements and maximum moving velocities of his hyoid bone and thyroid cartilage during swallowing of moderately thick water were improved. Adequate nutrition intake and training for hyoid muscles are considered effective for the patient with sarcopenic dysphagia. It was concluded that measuring the maximum displacements and moving velocities of the hyoid bone and thyroid cartilage during swallowing in patients with sarcopenic dysphagia was an effective way to monitor their improvement. Correspondence : Enri Nakayama, Department of Dysphagia Rehabilitation/ Nihon University School of Dentistry/ 1-8-13, Kanda Surugadai, Chiyoda/ Tokyo/ 101-8310/ Japan. Tel: +81-3-3219-8198, FAX: +81-3-3219-8203, E-mail address: nakayama.enri@nihon-u.ac.jp Author Disclosures: Competing Interests: none (All authors) Funding or grants or equipment provided for the project from any source: This report was supported by Sato Fund and Dental Research Center, Nihon University School of Dentistry. (Enri Nakayama) Financial benefits to the authors: none (All authors) Details of any previous presentation of the research, manuscript, or abstract in any form: none (All authors) Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

European Radiology

Correction to: CT screening for lung cancer: comparison of three baseline screening protocols The original version of this article, published on 03 December 2018, unfortunately contained a mistake.

Correction to: Effect of training on ultrasonography (US) BI-RADS features for radiology residents: a multicenter study comparing performances after training The original version of this article, published on 07 January 2019, unfortunately contained a mistake.

Correction to: Diffusion-weighted imaging for assessment of synovial inflammation in juvenile idiopathic arthritis: a promising imaging biomarker as an alternative to gadolinium-based contrast agents The original version of this article, published on 12 June 2017, unfortunately contained a mistake.

Correction to: Ultrashort time-to-echo quantitative magnetic resonance imaging of the triangular fibrocartilage: differences in position The original version of this article, published on 03 September 2018, unfortunately contained a mistake.

Reply to "letter to the editor: use of artificial neural networks to predict anterior communicating artery aneurysm rupture: possible methodological issues"

Differentiation of two subtypes of intrahepatic cholangiocarcinoma: imaging approach Key Points • Mass-forming intrahepatic cholangiocarcinoma can be divided into two subgroups, namley, perihilar and peripheral types. • These two significantly differ in clinico-biological behaviors, and in patients' prognosis as well. • This differentiation may be achieved solely by contrast-enhanced MR imaging findings.

Hepatobiliary phase in cirrhotic patients with different Model for End-stage Liver Disease score: comparison of the performance of gadoxetic acid to gadobenate dimeglumine Abstract Objectives The purpose of this study was to compare the performance of gadobenate dimeglumine–enhanced MRI and gadoxetic acid–enhanced MRI in the hepatobiliary phase (HBP) in cirrhotic patients with different degrees of liver dysfunction. Methods In this retrospective cross-sectional study, we analyzed the unenhanced phase and the HBP of 131 gadobenate dimeglumine–enhanced MRI examinations (gadobenate dimeglumine group) and 127 gadoxetic acid–enhanced MRI examinations (gadoxetic acid group) performed in 249 cirrhotic patients (181 men and 68 women; mean age, 64.8 years) from August 2011 to April 2017. For each MRI, the contrast enhancement index of the liver parenchyma was calculated and correlated to the Model For End-Stage Liver Disease (MELD) score (multiple linear regression analysis). A qualitative analysis of the adequacy of the HBP, adjusted for the MELD score (logistic regression analysis), was performed. Results The contrast enhancement index was inversely related (r = − 0.013) with MELD score in both gadoxetic acid and gadobenate dimeglumine group. At the same MELD score, the contrast enhancement index in the gadoxetic acid group was increased by a factor of 0.23 compared to the gadobenate dimeglumine group (p < 0.001), and the mean odds ratio to have an adequate HBP with gadoxetic acid compared to gadobenate dimeglumine was 3.64 (p < 0.001). The adequacy of the HBP in the gadoxetic acid group compared to the gadobenate dimeglumine group increased with the increase of the MELD score (exp(b)interaction = 1.233; p = 0.011). Conclusion In cirrhotic patients, the hepatobiliary phase obtained with gadoxetic acid–enhanced MRI is of better quality in comparison to gadobenate dimeglumine–enhanced MRI, mainly in patients with high MELD score. Key Points • In cirrhotic patients, the adequacy of the hepatobiliary phase with gadoxetic acid–enhanced MRI is better compared to gadobenate dimeglumine–enhanced MRI. • Gadoxetic acid–enhanced MRI should be preferred to gadobenate dimeglumine–enhanced MRI in cirrhotic patients with MELD score > 10, if the hepatobiliary phase is clinically indicated. • In patients with high MELD score (> 15), the administration of the hepatobiliary agent could be useless; even though, if it is clinically indicated, we recommend to use gadoxetic acid given the higher probability of obtaining clinically relevant information.

Dual-energy CT for liver iron quantification in patients with haematological disorders Abstract Objectives To retrospectively quantify liver iron content in haematological patients suspected of transfusional haemosiderosis using dual-energy CT (DECT) and correlate with serum ferritin levels and estimated quantity of transfused iron. Methods One hundred forty-seven consecutive dual-source dual-energy non-contrast chest-CTs in 110 haematologic patients intended primarily for exclusion of pulmonary infection between September 2016 and June 2017 were retrospectively evaluated. Image data was post-processed with a software prototype. After material decomposition, an iron enhancement map was created and freehand ROIs were drawn including most of the partially examined liver. The virtual iron content (VIC) was calculated and expressed in milligram/millilitre. VIC was correlated with serum ferritin and estimated amount of transfused iron. Scans of patients who had not received blood products were considered controls. Results Forty-eight (32.7%) cases (controls) had not received any blood transfusions whereas 67.3% had received one transfusion or more. Median serum ferritin and VIC were 138.0 μg/dl (range, 6.0–2628.0 μg/dl) and 1.33 mg/ml (range, − 0.94–7.56 mg/ml) in the post-transfusional group and 27.0 μg/dl (range, 1.0–248.0 μg/dl) and 0.61 mg/ml (range, − 2.1–2.4) in the control group. Correlation between serum ferritin and VIC was strong (r = 0.623; p < 0.001) as well as that between serum ferritin and estimated quantity of transfused iron (r = 0.681; p < 0.001). Conclusions Hepatic VIC obtained via dual-energy chest-CT examinational protocol strongly correlates with serum ferritin levels and estimated amount of transfused iron and could therefore be used in the routine diagnosis for complementary evaluation of transfusional haemosiderosis. Key Points • Virtual liver iron content was measured in routine chest-CTs of haematological patients suspected of having iron overload. Chest-CTs were primarily intended for exclusion of pulmonary infection. • Measurements correlate strongly with the most widely used blood marker of iron overload serum ferritin (after exclusion of infection) and the amount of transfused iron. • Liver VIC could be used for supplemental evaluation of transfusional haemosiderosis in haematological patients.

Ascites relative enhancement during hepatobiliary phase after Gd-BOPTA administration: a new promising tool for characterising abdominal free fluid of unknown origin Abstract Objectives To correlate the degree of ascites enhancement during hepatobiliary phase after gadobenate dimeglumine (Gd-BOPTA) administration with ascites aetiology. Methods IRB-approved retrospective study, need for informed consent was waived. We included 74 consecutive ascitic patients who underwent Gd-BOPTA-enhanced liver MRI including hepatobiliary phase (HBP) images between January 2014 and December 2017. Ascites appearance on unenhanced and HBP images was classified as hypo-, iso- or hyperintense in comparison to paraspinal muscles. Ascites signal intensity on unenhanced and HBP images was measured using round ROIs and was normalised to paraspinal muscles (NSI). Normalised relative enhancement (NRE) between native phase and HBP was calculated. The results were related to ascites aetiology using Wilcoxon and Mann-Whitney tests. Results On native images, ascites appeared hypointense in 95.9% of the cases and isointense in 4.1%, whereas on HBP images, it appeared hyperintense in 59.4% of the cases, isointense in 36.5% and hypointense in 4.1%. Mean ascites NSI was 0.52 on unenhanced images and 1.50 on HBP ones (p < 0.0001). Mean ascites NRE was 201 ± 133%. Ascites of non-malignant aetiology showed mean NRE of 210 ± 134%, whereas malignant ascites showed mean NRE of 92 ± 20% (p = 0.001). ROC analysis showed that a NRE < 112.5% correlates with malignant aetiology with 100% sensitivity and 83.4% specificity (LR = 5.667). NRE did not show any significant correlation with ascites thickness, eGFR and time interval between contrast administration and HBP acquisition (p > 0.05). Conclusions Ascites NRE in HBP after Gd-BOPTA administration is significantly lower in patients with ascites secondary to peritoneal carcinomatosis than in patients with non-malignant ascites. Key Points • Ascites enhancement in the hepatobiliary phase after Gd-BOPTA administration may determine false positive findings when looking for biliary leaks. • Ascites enhancement in the hepatobiliary phase after Gd-BOPTA administration is lower in patients with peritoneal carcinomatosis than in patients with portal hypertension or congestive heart failure. • None of the patients with peritoneal carcinomatosis showed an ascites enhancement of more than 112% as compared with unenhanced images.

Assessment of renal function before contrast media injection: right decisions based on inaccurate estimates Abstract Objectives Information on renal function required before specified radiological examinations with contrast agents is usually obtained through prediction equations using serum creatinine and anthropometric data. The aim of our study was to demonstrate discrepancy between poor prediction and good diagnostic accuracy of glomerular filtration rate (GFR) estimated by prediction equations. Methods In 50 patients, reference GFR was measured as plasma clearance of 51-chromium labeled ethylene-diamine-tetraacetic-acid (51Cr-EDTA) and compared with GFR assayed by creatinine clearance (CC) and estimated by Cockcroft-Gault prediction equation (CG). For comparisons, CC and CG were considered as continuous, categorical, and binary variables. Accuracy of the reference GFR prediction was expressed in terms of prediction errors and diagnostic accuracy indices. Results As continuous variable, CG estimated individual values of GFR with large prediction error exceeding that of CC. As categorical variable, it classified the patient stage of chronic kidney disease (CKD) with medium diagnostic accuracy of 74% (CKD 3) and 62% (CKD 4). As binary variable, CG classified individual patient's GFR below 30 and 60 ml/min/1.73 m2 with good diagnostic accuracy of 80 and 94%, respectively. Performance of other prediction equations did not significantly differ from CG. Conclusions Despite large variance and poor prediction accuracy of individual GFR estimates, most of them correctly classified individual patient's GFR below specified level. Results of prediction equations thus should be used and reported exclusively as binary variables, while numerical values of GFR, if required, should be measured by more accurate radionuclide or laboratory methods. Key Points • Radiological guidelines on contrast media require estimation of glomerular filtration rate to assess kidney function before specified contrast examinations. • Estimated glomerular filtration rate is obtained through prediction equations using serum creatinine and anthropometric data as predictors. • While numerical estimates of glomerular filtration rate are inaccurate (their prediction accuracy is poor), diagnostic accuracy of binary estimates (ability to classify patient's glomerular filtration rate below or above a specified level) is very good.

Neuroscience

This Week in The Journal

A Hypothetical Model Concerning How Spike-Timing-Dependent Plasticity Contributes to Neural Circuit Formation and Initiation of the Critical Period in Barrel Cortex Spike timing is an important factor in the modification of synaptic strength. Various forms of spike timing-dependent plasticity (STDP) occur in the brains of diverse species, from insects to humans. In unimodal STDP, only LTP or LTD occurs at the synapse, regardless of which neuron spikes first; the magnitude of potentiation or depression increases as the time between presynaptic and postsynaptic spikes decreases. This from of STDP may promote developmental strengthening or weakening of early projections. In bidirectional Hebbian STDP, the magnitude and the sign (potentiation or depression) of plasticity depend, respectively, on the timing and the order of presynaptic and postsynaptic spikes. In the rodent barrel cortex, multiple forms of STDP appear sequentially during development, and they contribute to network formation, retraction, or fine-scale functional reorganization. Hebbian STDP appears at L4-L2/3 synapses starting at postnatal day (P) 15; the synapses exhibit unimodal "all-LTP STDP" before that age. The appearance of Hebbian STDP at L4-L2/3 synapses coincides with the maturation of parvalbumin-containing GABA interneurons in L4, which contributes to the generation of L4-before-L2/3 spiking in response to thalamic input by producing fast feedforward suppression of both L4 and L2/3 cells. After P15, L4-L2/3 STDP mediates fine-scale circuit refinement, essential for the critical period in the barrel cortex. In this review, we first briefly describe the relevance of STDP to map plasticity in the barrel cortex, then look over roles of distinct forms of STDP during development. Finally, we propose a hypothesis that explains the transition from network formation to the initiation of the critical period in the barrel cortex.

Mitotic Motor KIFC1 Is an Organizer of Microtubules in the Axon KIFC1 (also called HSET or kinesin-14a) is best known as a multifunctional motor protein essential for mitosis. The present studies are the first to explore KIFC1 in terminally postmitotic neurons. Using RNA interference to partially deplete KIFC1 from rat neurons (from animals of either gender) in culture, pharmacologic agents that inhibit KIFC1, and expression of mutant KIFC1 constructs, we demonstrate critical roles for KIFC1 in regulating axonal growth and retraction as well as growth cone morphology. Experimental manipulations of KIFC1 elicit morphological changes in the axon as well as changes in the organization, distribution, and polarity orientation of its microtubules. Together, the results indicate a mechanism by which KIFC1 binds to microtubules in the axon and slides them into alignment in an ATP-dependent fashion and then cross-links them in an ATP-independent fashion to oppose their subsequent sliding by other motors. SIGNIFICANCE STATEMENT Here, we establish that KIFC1, a molecular motor well characterized in mitosis, is robustly expressed in neurons, where it has profound influence on the organization of microtubules in a number of different functional contexts. KIFC1 may help answer long-standing questions in cellular neuroscience such as, mechanistically, how growth cones stall and how axonal microtubules resist forces that would otherwise cause the axon to retract. Knowledge about KIFC1 may help researchers to devise strategies for treating disorders of the nervous system involving axonal retraction given that KIFC1 is expressed in adult neurons as well as developing neurons.

Intracellular Zn2+ Signaling Facilitates Mossy Fiber Input-Induced Heterosynaptic Potentiation of Direct Cortical Inputs in Hippocampal CA3 Pyramidal Cells Repetitive action potentials (APs) in hippocampal CA3 pyramidal cells (CA3-PCs) backpropagate to distal apical dendrites, and induce calcium and protein tyrosine kinase (PTK)-dependent downregulation of Kv1.2, resulting in long-term potentiation of direct cortical inputs and intrinsic excitability (LTP-IE). When APs were elicited by direct somatic stimulation of CA3-PCs from rodents of either sex, only a narrow window of distal dendritic [Ca2+] allowed LTP-IE because of Ca2+-dependent coactivation of PTK and protein tyrosine phosphatase (PTP), which renders non-mossy fiber (MF) inputs incompetent in LTP-IE induction. High-frequency MF inputs, however, could induce LTP-IE at high dendritic [Ca2+] of the window. We show that MF input-induced Zn2+ signaling inhibits postsynaptic PTP, and thus enables MF inputs to induce LTP-IE at a wide range of [Ca2+]ivalues. Extracellular chelation of Zn2+ or genetic deletion of vesicular zinc transporter abrogated the privilege of MF inputs for LTP-IE induction. Moreover, the incompetence of somatic stimulation was rescued by the inhibition of PTP or a supplement of extracellular zinc, indicating that MF input-induced increase in dendritic [Zn2+] facilitates the induction of LTP-IE by inhibiting PTP. Consistently, high-frequency MF stimulation induced immediate and delayed elevations of [Zn2+] at proximal and distal dendrites, respectively. These results indicate that MF inputs are uniquely linked to the regulation of direct cortical inputs owing to synaptic Zn2+ signaling. SIGNIFICANCE STATEMENT Zn2+ has been mostly implicated in pathological processes, and the physiological roles of synaptically released Zn2+ in intracellular signaling are little known. We show here that Zn2+ released from hippocampal mossy fiber (MF) terminals enters postsynaptic CA3 pyramidal cells, and plays a facilitating role in MF input-induced heterosynaptic potentiation of perforant path (PP) synaptic inputs through long-term potentiation of intrinsic excitability (LTP-IE). We show that the window of cytosolic [Ca2+] that induces LTP-IE is normally very narrow because of the Ca2+-dependent coactivation of antagonistic signaling pairs, whereby non-MF inputs become ineffective in inducing excitability change. The MF-induced Zn2+ signaling, however, biases toward facilitating the induction of LTP-IE. The present study elucidates why MF inputs are more privileged for the regulation of PP synapses.

Axonal Degeneration Is Mediated by Necroptosis Activation Axonal degeneration, which contributes to functional impairment in several disorders of the nervous system, is an important target for neuroprotection. Several individual factors and subcellular events have been implicated in axonal degeneration, but researchers have so far been unable to identify an integrative signaling pathway activating this self-destructive process. Through pharmacological and genetic approaches, we tested whether necroptosis, a regulated cell-death mechanism implicated in the pathogenesis of several neurodegenerative diseases, is involved in axonal degeneration. Pharmacological inhibition of the necroptotic kinase RIPK1 using necrostatin-1 strongly delayed axonal degeneration in the peripheral nervous system and CNS of wild-type mice of either sex and protected in vitro sensory axons from degeneration after mechanical and toxic insults. These effects were also observed after genetic knock-down of RIPK3, a second key regulator of necroptosis, and the downstream effector MLKL (Mixed Lineage Kinase Domain-Like). RIPK1 inhibition prevented mitochondrial fragmentation in vitro and in vivo, a typical feature of necrotic death, and inhibition of mitochondrial fission by Mdivi also resulted in reduced axonal loss in damaged nerves. Furthermore, electrophysiological analysis demonstrated that inhibition of necroptosis delays not only the morphological degeneration of axons, but also the loss of their electrophysiological function after nerve injury. Activation of the necroptotic pathway early during injury-induced axonal degeneration was made evident by increased phosphorylation of the downstream effector MLKL. Our results demonstrate that axonal degeneration proceeds by necroptosis, thus defining a novel mechanistic framework in the axonal degenerative cascade for therapeutic interventions in a wide variety of conditions that lead to neuronal loss and functional impairment. SIGNIFICANCE STATEMENT We show that axonal degeneration triggered by diverse stimuli is mediated by the activation of the necroptotic programmed cell-death program by a cell-autonomous mechanism. This work represents a critical advance for the field since it identifies a defined degenerative pathway involved in axonal degeneration in both the peripheral nervous system and the CNS, a process that has been proposed as an early event in several neurodegenerative conditions and a major contributor to neuronal death. The identification of necroptosis as a key mechanism for axonal degeneration is an important step toward the development of novel therapeutic strategies for nervous-system disorders, particularly those related to chemotherapy-induced peripheral neuropathies or CNS diseases in which axonal degeneration is a common factor.

A Human TRPA1-Specific Pain Model The cation channel transient receptor potential ankyrin 1 (TRPA1) plays an important role in sensing potentially hazardous substances. However, TRPA1 species differences are substantial and limit translational research. TRPA1 agonists tested previously in humans also have other targets. Therefore, the sensation generated by isolated TRPA1 activation in humans is unknown. The availability of 2-chloro-N-(4-(4-methoxyphenyl)thiazol-2-yl)-N-(3-methoxypropyl)-acetamide (JT010), a potent and specific TRPA1 agonist, allowed us to explore this issue. To corroborate the specificity of JT010, it was investigated whether the TRPA1 antagonist (1E,3E)-1-(4-fluorophenyl)-2-methyl-1-penten-3-one oxime (A-967079) abolishes JT010-elicited pain. Sixteen healthy volunteers of both sexes rated pain due to intraepidermal injections of different concentrations and combinations of the substances. The study design was a double-blind crossover study. All subjects received all types of injections, including a placebo without substances. Injections of the TRPA1 agonist dose-dependently caused pain with a half-maximal effective concentration of 0.31 μm. Coinjection of A-967079 dose-dependently reduced and at a high concentration abolished JT010-induced pain. Quantification of JT010 by HPLC showed that a substantial part is adsorbed when in contact with polypropylene surfaces, but that this was overcome by handling in glass vials and injection using glass syringes. Isolated TRPA1 activation in humans causes pain. Thus, intradermal JT010 injection can serve as a tool to validate new TRPA1 antagonists concerning target engagement. More importantly, TRPA1-specific tools allow quantification of the TRPA1-dependent component in physiology and pathophysiology. SIGNIFICANCE STATEMENT This study showed that activation of the ion channel transient receptor potential ankyrin 1 (TRPA1) alone indeed suffices to elicit pain in humans, independent of other receptors previously found to be involved in pain generation. The newly established TRPA1-specific pain model allows different applications. First, it can be tested whether diseases are associated with compromised or exaggerated TRPA1-dependent painful sensations in the skin. Second, it can be investigated whether a new, possibly systemically applied drug directed against TRPA1 engages its target in humans. Further, the general possibility of quantitative inhibition of TRPA1 allows identification of the TRPA1-dependent disease component, given that the substance reaches its target. This contributes to a better understanding of pathophysiology, can lay the basis for new therapeutic approaches, and can bridge the gap between preclinical research and clinical trials.

Developmental Remodeling of Thalamic Interneurons Requires Retinal Signaling The dorsal lateral geniculate nucleus (dLGN) of the mouse is a model system to study the development of thalamic circuitry. Most studies focus on relay neurons of dLGN, yet little is known about the development of the other principal cell type, intrinsic interneurons. Here we examined whether the structure and function of interneurons relies on retinal signaling. We took a loss-of-function approach and crossed GAD67-GFP mice, which express GFP in dLGN interneurons, with math5 nulls (math5–/–), mutants that lack retinal ganglion cells and retinofugal projections. In vitro recordings and 3-D reconstructions of biocytin-filled interneurons at different postnatal ages showed their development is a multistaged process involving migration, arbor remodeling, and synapse formation. Arbor remodeling begins during the second postnatal week, after migration to and dispersion within dLGN is complete. This phase includes a period of exuberant branching where arbors grow in number, complexity, and field size. Such growth is followed by branch pruning and stabilization, as interneurons adopt a bipolar architecture. The absence of retinal signaling disrupts this process. The math5–/– interneurons fail to branch and prune, and instead maintain a simple, sparse architecture. To test how such defects influence connectivity with dLGN relay neurons, we used DHPG [(RS)-3,5-dihydroxyphenylglycine], the mGluR1,5 agonist that targets F2 terminals. This led to substantial increases in IPSC activity among WT relay neurons but had little impact in math5–/– mice. Together, these data suggest that retinal signaling is needed to support the arbor elaboration and synaptic connectivity of dLGN interneurons. SIGNIFICANCE STATEMENT Presently, our understanding about the development of the dorsal lateral geniculate nucleus is limited to circuits involving excitatory thalamocortical relay neurons. Here we show that the other principal cell type, intrinsic interneurons, has a multistaged developmental plan that relies on retinal innervation. These findings indicate that signaling from the periphery guides the maturation of interneurons and the establishment of inhibitory thalamic circuits.

Neuronal Adaptation Reveals a Suboptimal Decoding of Orientation Tuned Populations in the Mouse Visual Cortex Sensory information is encoded by populations of cortical neurons. Yet, it is unknown how this information is used for even simple perceptual choices such as discriminating orientation. To determine the computation underlying this perceptual choice, we took advantage of the robust visual adaptation in mouse primary visual cortex (V1). We first designed a stimulus paradigm in which we could vary the degree of neuronal adaptation measured in V1 during an orientation discrimination task. We then determined how adaptation affects task performance for mice of both sexes and tested which neuronal computations are most consistent with the behavioral results given the adapted population responses in V1. Despite increasing the reliability of the population representation of orientation among neurons, and improving the ability of a variety of optimal decoders to discriminate target from distractor orientations, adaptation increases animals' behavioral thresholds. Decoding the animals' choice from neuronal activity revealed that this unexpected effect on behavior could be explained by an overreliance of the perceptual choice circuit on target preferring neurons and a failure to appropriately discount the activity of neurons that prefer the distractor. Consistent with this all-positive computation, we find that animals' task performance is susceptible to subtle perturbations of distractor orientation and optogenetic suppression of neuronal activity in V1. This suggests that to solve this task the circuit has adopted a suboptimal and task-specific computation that discards important task-related information. SIGNIFICANCE STATEMENT A major goal in systems neuroscience is to understand how sensory signals are used to guide behavior. This requires determining what information in sensory cortical areas is used, and how it is combined, by downstream perceptual choice circuits. Here we demonstrate that when performing a go/no-go orientation discrimination task, mice suboptimally integrate signals from orientation tuned visual cortical neurons. While they appropriately positively weight target-preferring neurons, they fail to negatively weight distractor-preferring neurons. We propose that this all-positive computation may be adopted because of its simple learning rules and faster processing, and may be a common approach to perceptual decision-making when task conditions allow.

Neural Maps of Interaural Time Difference in the American Alligator: A Stable Feature in Modern Archosaurs Detection of interaural time differences (ITDs) is crucial for sound localization in most vertebrates. The current view is that optimal computational strategies of ITD detection depend mainly on head size and available frequencies, although evolutionary history should also be taken into consideration. In archosaurs, which include birds and crocodiles, the brainstem nucleus laminaris (NL) developed into the critical structure for ITD detection. In birds, ITDs are mapped in an orderly array or place code, whereas in the mammalian medial superior olive, the analog of NL, maps are not found. As yet, in crocodilians, topographical representations have not been identified. However, nontopographic representations of ITD cannot be excluded due to different anatomical and ethological features of birds and crocodiles. Therefore, we measured ITD-dependent responses in the NL of anesthetized American alligators of either sex and identified the location of the recording sites by lesions made after recording. The measured extracellular field potentials, or neurophonics, were strongly ITD tuned, and their preferred ITDs correlated with the position in NL. As in birds, delay lines, which compensate for external time differences, formed maps of ITD. The broad distributions of best ITDs within narrow frequency bands were not consistent with an optimal coding model. We conclude that the available acoustic cues and the architecture of the acoustic system in early archosaurs led to a stable and similar organization in today's birds and crocodiles, although physical features, such as internally coupled ears, head size, or shape, and audible frequency range, vary among the two groups. SIGNIFICANCE STATEMENT Interaural time difference (ITD) is an important cue for sound localization, and the optimal strategies for encoding ITD in neuronal populations are the subject of ongoing debate. We show that alligators form maps of ITD very similar to birds, suggesting that their common archosaur ancestor reached a stable coding solution different from mammals. Mammals and diapsids evolved tympanic hearing independently, and local optima can be reached in evolution that are not considered by global optimal coding models. Thus, the presence of ITD maps in the brainstem may reflect a local optimum in evolutionary development. Our results underline the importance of comparative animal studies and show that optimal models must be viewed in the light of evolutionary processes.

Homer1a Is Required for Establishment of Contralateral Bias and Maintenance of Ocular Dominance in Mouse Visual Cortex It is well established across many species that neurons in the primary visual cortex (V1) display preference for visual input from one eye or the other, which is termed ocular dominance (OD). In rodents, V1 neurons exhibit a strong bias toward the contralateral eye. Molecular mechanisms of how OD is established and later maintained by plastic changes are largely unknown. Here we report a novel role of an activity-dependent immediate early gene Homer1a (H1a) in these processes. Using both sexes of H1a knock-out (KO) mice, we found that there is basal reduction in the OD index of V1 neurons measured using intrinsic signal imaging. This was because of a reduction in the strength of inputs from the contralateral eye, which is normally dominant in mice. The abnormal basal OD index was not dependent on visual experience and is driven by postnatal expression of H1a. Despite this, H1a KOs still exhibited normal shifts in OD index following a short-term (2–3 d) monocular deprivation (MD) of the contralateral eye with lid suture. However, unlike wild-type counterparts, H1a KOs continued to shift OD index with a longer duration (5–6 d) of MD. The same phenotype was recapitulated in a mouse model that has reduced Homer1 binding to metabotropic glutamate receptor 5 (mGluR5). Our results suggest a novel role of H1a and its interaction with mGluR5 in strengthening contralateral eye inputs during postnatal development to establish normal contralateral bias in mouse V1 without much impact on OD shift with brief MD. SIGNIFICANCE STATEMENT Visual cortical neurons display varying degree of responsiveness to visual stimuli through each eye, which determines their ocular dominance (OD). Molecular mechanisms responsible for establishing normal OD are largely unknown. Development of OD has been shown to be largely independent of visual experience, but guided by molecular cues and spontaneous activity. We found that activity-dependent immediate early gene H1a is critical for establishing normal OD in V1 of mice, which show contralateral eye dominance. Despite the weaker contralateral bias, H1aKOs undergo largely normal OD plasticity. The basic phenotype of H1aKO was recapitulated by mGluR5 mutation that severely reduces H1a interaction. Our results suggest a novel role of mGluR5-H1a interaction in strengthening contralateral eye inputs to V1 during postnatal development.