Evaluation of Long-Term Surgical and Patient-Reported Outcomes after Pediatric Facial Reanimation.

BACKGROUND: Outcomes of pediatric facial reanimation beyond 10 years are not known. This cross-sectional study evaluated long-term surgical and patient-reported outcomes of adults who underwent smile reconstruction as children with either a cross-face nerve graft (CFNG) or masseter nerve transfer at least 10 years previously. METHODS: Commissure excursion was quantified with FACE-Gram software at 3 time points: preoperatively, early postoperatively within 2 years, and at long-term follow-up. Patient-reported outcomes were evaluated with validated questionnaires (Facial Clinimetric Evaluation Scale, FACE-Q 1.0) and thematic analysis of semistructured interviews. Results are reported as median (interquartile range [IQR]). RESULTS: A total of 42 patients were included (26 women and 16 men). Median long-term follow-up was 19.3 years (IQR, 8.8 years) for CFNG and 17.6 years (IQR, 5.8 years) for masseter nerve transfer. For both groups, commissure excursion increased significantly from preoperative to early postoperative time points and remained stable at long-term follow-up (P < 0.0001). Commissure excursion at long-term follow-up between the 2 groups was not significantly different (CFNG, 5.0 mm [IQR, 9.4 mm]; masseter nerve transfer, 8.4 mm [IQR, 4.1 mm]); P > 0.05). For patient-reported outcomes, median Facial Clinimetric Evaluation Scale score was 72 of 100, and 95% of respondents agreed with the statement "I am pleased with the result" on the FACE-Q 1.0. Overall quality of life was rated at 7 of 10 or greater by 97% of participants, and all participants would recommend the surgery to other children. CONCLUSIONS: Pediatric facial reanimation with CFNG or masseter nerve transfer reliably improves commissure excursion with longevity beyond 10 years. Adult patients report overall high satisfaction and social functioning.

Comparison of Surgical Wait Times and Procedure Length in the Management of Postaxial Polydactyly Using Local or General Anesthesia.

Introduction: For infants with ulnar polydactyly, surgical removal of the supernumerary digit can be performed under general or local anesthetic. This study evaluated the wait times, surgical duration, and sedation times associated with performing the procedure under local versus general anesthetic in infants with ulnar polydactyly. Methods: The databases of three surgeons at our institution were reviewed for children less than 2 years of age who underwent surgery for non-syndromic ulnar polydactyly. Data collection included patient demographics, wait times, duration of surgery and sedation and complications. Results: The study included children (n = 55) who received treatment under local (n = 22) or general (n = 33) anesthesia. The wait times for the local anesthetic group were significantly shorter than the general anesthetic group (p < 0.05) for: referral to first consultation appointment; referral to surgery date, and decision date to surgery date. The duration of surgery (17.9 ± 6.9 vs 36.6 ± 20.2 min) and sedation time (26.3 ± 11.1 vs 74.8 ± 29.1 min) were significantly shorter in the local anaesthetic group (p < 0.05). There were no differences in complication rates between the groups. Conclusion: In this single-institution retrospective analysis, treatment of non-syndromic ulnar polydactyly with local anesthetic and bottle sedation was associated with shorter wait times, and duration of surgery and sedation. Level of Evidence: III, retrospective chart review and quality improvement initiative.

Introduction : Chez les nourrissons présentant une polydactylie cubitale, il est possible de procéder à l'ablation chirurgicale du doigt excédentaire sous anesthésie locale ou générale. La présente étude visait à évaluer les temps d'attente, la durée de l'opération et la durée de la sédation associés à l'intervention lorsqu'elle était effectuée sous anesthésie locale ou générale chez les nourrissons présentant une polydactylie cubitale. méthodes : Les chercheurs ont fouillé les bases de données de trois chirurgiens de leur établissement pour en extraire les cas d'enfants de moins de deux ans ayant subi une opération de la polydactylie cubitale non syndromique. La collecte de données incluait les caractéristiques des patients, les temps d'attente, la durée de l'opération et de la sédation et les complications. Résultats : La présente étude incluait des enfants (n=55) qui avaient été traités sous anesthésie locale (n=22) ou générale (n=33). Le temps d'attente du groupe sous anesthésie locale était beaucoup plus court que celui du groupe sous anesthésie générale (p<0,05) pour ce qui est de la période entre l'orientation et la première consultation, l'orientation et la date de l'opération, ainsi que la date de la décision et la date de l'opération. La durée de l'opération (17,9 ± 6,9 minutes par rapport à 36,6 ± 20,2 minutes) et de la sédation (26,3 ± 11,1 minutes par rapport à 74,8 ± 29,1 minutes) était beaucoup plus courte dans le groupe sous anesthésie locale (p<0,05). Il n'y avait pas de différence entre les groupes à l'égard des taux de complications. Conclusion : Dans cette analyse rétrospective mono-institutionnelle, le traitement de la polydactylie cubitale non syndromique accompagné d'une anesthésie locale et d'une sédation par bonbonne était associé à une diminution du temps d'attente ainsi que de la durée d'opération et de sédation.

B-cell-directed CAR T-cell therapy activates CD8+ cytotoxic CARneg bystander T cells in patients and nonhuman primates.

ABSTRACT: Chimeric antigen receptor (CAR) T cells hold promise as a therapy for B-cell-derived malignancies, and despite their impressive initial response rates, a significant proportion of patients ultimately experience relapse. Although recent studies have explored the mechanisms of in vivo CAR T-cell function, little is understood about the activation of surrounding CARneg bystander T cells and their potential to enhance tumor responses. We performed single-cell RNA sequencing on nonhuman primate (NHP) and patient-derived T cells to identify the phenotypic and transcriptomic hallmarks of bystander activation of CARneg T cells following B-cell-targeted CAR T-cell therapy. Using a highly translatable CD20 CAR NHP model, we observed a distinct population of activated CD8+ CARneg T cells emerging during CAR T-cell expansion. These bystander CD8+ CARneg T cells exhibited a unique transcriptional signature with upregulation of natural killer-cell markers (KIR3DL2, CD160, and KLRD1), chemokines, and chemokine receptors (CCL5, XCL1, and CCR9), and downregulation of naïve T-cell-associated genes (SELL and CD28). A transcriptionally similar population was identified in patients after a tisagenlecleucel infusion. Mechanistic studies revealed that interleukin-2 (IL-2) and IL-15 exposure induced bystander-like CD8+ T cells in a dose-dependent manner. In vitro activated and patient-derived T cells with a bystander phenotype efficiently killed leukemic cells through a T-cell receptor-independent mechanism. Collectively, to our knowledge, these data provide the first comprehensive identification and profiling of CARneg bystander CD8+ T cells following B-cell-targeting CAR T-cell therapy and suggest a novel mechanism through which CAR T-cell infusion might trigger enhanced antileukemic responses. Patient samples were obtained from the trial #NCT03369353, registered at www.ClinicalTrials.gov.

Gut enterotype-dependent modulation of gut microbiota and their metabolism in response to xanthohumol supplementation in healthy adults.

Xanthohumol (XN), a polyphenol found in the hop plant (Humulus lupulus), has antioxidant, anti-inflammatory, prebiotic, and anti-hyperlipidemic activity. Preclinical evidence suggests the gut microbiome is essential in mediating these bioactivities; however, relatively little is known about XN's impact on human gut microbiota in vivo. We conducted a randomized, triple-blinded, placebo-controlled clinical trial (ClinicalTrials.gov NCT03735420) to determine safety and tolerability of XN in healthy adults. Thirty healthy participants were randomized to 24 mg/day XN or placebo for 8 weeks. As secondary outcomes, quantification of bacterial metabolites and 16S rRNA gene sequencing were utilized to explore the relationships between XN supplementation, gut microbiota, and biomarkers of gut health. Although XN did not significantly change gut microbiota composition, it did re-shape individual taxa in an enterotype-dependent manner. High levels of inter-individual variation in metabolic profiles and bioavailability of XN metabolites were observed. Moreover, reductions in microbiota-derived bile acid metabolism were observed, which were specific to Prevotella and Ruminococcus enterotypes. These results suggest interactions between XN and gut microbiota in healthy adults are highly inter-individualized and potentially indicate that XN elicits effects on gut health in an enterotype-dependent manner.

Surgery for internal rotation contracture in infancy may obviate the need for brachial plexus nerve reconstruction: early experience.

BACKGROUND: Shoulder internal rotation contracture and subluxation in the first year of life has long been recognized in some patients with brachial plexus birth injury (BPBI). Surgical management of shoulder pathology has traditionally been undertaken following nerve reconstruction as necessary. In some patients; however, shoulder pathology may impair or obscure functional neuromuscular recovery of the upper extremity. As a proof of concept, we report a highly selected subset of patients with BPBI in whom shoulder surgery undertaken before one year of age obviated the need for neuroma resection and nerve grafting. METHODS: A retrospective review was performed of all patients with upper trunk BPBI who underwent shoulder surgery before one year of age from 2015 to 2018. Upper extremity motor function was evaluated with preoperative and postoperative Active Movement Scale scores, Cookie tests, and the requirement for subsequent neuroma resection and nerve grafting. RESULTS: Fifteen patients with BPBI meeting the inclusion criteria underwent shoulder surgery (including a subscapularis slide and tendon transfers of the teres major and latissimus dorsi muscles) before 1 year of age. Preoperatively, no patients of the appropriate age passed the Cookie test for elbow flexion. Thirteen patients either passed the Cookie test or scored Active Movement Scale score 7 for elbow flexion at or before the last available follow-up undertaken at a median age of 3.4 [1.4, 5.2] years. One of those 13 patients underwent single fascicular distal nerve transfer to improve elbow flexion before subsequently passing the Cookie test. Two patients did not have sufficient follow-up to assess elbow flexion. CONCLUSION: Although the exact role of shoulder surgery in infancy for BPBI remains to be defined, the findings from this study provide proof of concept that early, targeted surgical treatment of the shoulder may obviate the need for brachial plexus nerve reconstruction in a highly selected group of infants with BPBI.

Mental health and psychosocial support for children with upper limb musculoskeletal conditions.

This study describes mental health and psychosocial screening processes, access to care and interventions provided to children with upper limb musculoskeletal conditions. A cross-sectional e-survey study was conducted of 107 healthcare professionals who work with children with congenital hand and upper limb differences and brachial plexus birth injuries. Of them, 41 (38%) reported that they routinely screen for mental health and psychosocial concerns. Few (12%) reported the use of standardized outcome measures. In total, 51 (48%) healthcare professionals reported that there was a waiting list for mental health services at their institution. Collectively, healthcare professionals were unsatisfied with the staffing, access to care and types of interventions available. Reported barriers to care included the growing need for mental health support, lack of resources and poor continuity of care after referrals. Future research should focus on identifying and validating a mental health screening tool and investigating the processes affecting access to mental health care.Level of evidence: IV.

Zinc supplementation alters tissue distribution of arsenic in Mus musculus.

Arsenic occurs naturally in the environment and humans can be exposed through food, drinking water and inhalation of air-borne particles. Arsenic exposure is associated with cardiovascular, pulmonary, renal, immunologic, and developmental toxicities as well as carcinogenesis. Arsenic displays dose-depen toxicities in target organs or tissues with elevated levels of arsenic. Zinc is an essential micronutrient with proposed protective benefits due to its antioxidant properties, integration into zinc-containing proteins and zinc-related immune signaling. In this study, we tested levels of arsenic and zinc in plasma, kidney, liver, and spleen as model tissues after chronic (42-day) treatment with either arsenite, zinc, or in combination. Arsenite exposure had minimal impact on tissue zinc levels with the exception of the kidney. Conversely, zinc supplementation of arsenite-exposed mice reduced the amount of arsenic detected in all tissues tested. Expression of transporters associated with zinc or arsenic influx and efflux were evaluated under each treatment condition. Significant effects of arsenite exposure on zinc transporter expression displayed tissue selectivity for liver and kidney, and was restricted to Zip10 and Zip14, respectively. Arsenite also interacted with zinc co-exposure for Zip10 expression in liver tissue. Pairwise comparisons show neither arsenite nor zinc supplementation alone significantly altered expression of transporters utilized by arsenic. However, significant interactions between arsenite and zinc were evident for Aqp7 and Mrp1 in a tissue selective manner. These findings illustrate interactions between arsenite and zinc leading to changes in tissue metal level and suggest a potential mechanism by which zinc may offer protection from arsenic toxicities.

Intersection of physical and mental health of youth with brachial plexus birth injuries: A qualitative study.

Introduction: Youth with brachial plexus birth injuries (BPBI) have an increased risk of mental health issues such as depression, anxiety, and diminished self-confidence. Despite this evidence, current standards of care focus on physical interventions. Evaluation of psychological and emotional concerns is rarely prioritized in clinical settings. Therefore, mental health needs are unmet and poorly understood. Methods: An interpretivist qualitative approach was used to understand the perspectives of youth with BPBI and their caregivers on the barriers and facilitators of addressing mental health concerns, to inform practice guidelines, and promote meaningful participation within this population. Results: A purposeful sample of nine youth with BPBI between 10 to 20 years and eight caregivers participated in in-depth interviews. The interviews were semi-structured and an average of 60 min (35-85 min) long. Three themes emerged from these data: (i) physical disability identity and mental health; (ii) pursuit of "normal" body image; and (iii) paradox of advocacy. Findings illuminated the intersection of physical and mental health in these youth and provides actionable practice recommendations. Areas of need were identified including mental health support around the challenges of advocacy, body image, surgery, and preparation for the 'aging out' process for youth and their families. Conclusions: The well-being of youth with BPBI is a result of the intersection between their physical and mental health. Further research on optimizing mental health resources within physical health settings is needed to better support the holistic needs of these youth and their families.

A clinicogenomic model including GARD predicts outcome for radiation treated patients with HPV+ oropharyngeal squamous cell carcinoma.

Background: Treatment decision-making in oropharyngeal squamous cell carcinoma (OPSCC) includes clinical stage, HPV status, and smoking history. Despite improvements in staging with separation of HPV-positive and -negative OPSCC in AJCC 8th edition (AJCC8), patients are largely treated with a uniform approach, with recent efforts focused on de-intensification in low-risk patients. We have previously shown, in a pooled analysis, that the genomic adjusted radiation dose (GARD) is predictive of radiation treatment benefit and can be used to guide RT dose selection. We hypothesize that GARD can be used to predict overall survival (OS) in HPV-positive OPSCC patients treated with radiotherapy (RT). Methods: Gene expression profiles (Affymetrix Clariom D) were analyzed for 234 formalin-fixed paraffin-embedded samples from HPV-positive OPSCC patients within an international, multi-institutional, prospective/retrospective observational study including patients with AJCC 7th edition stage III-IVb. GARD, a measure of the treatment effect of RT, was calculated for each patient as previously described. In total, 191 patients received primary RT definitive treatment (chemoradiation or RT alone, and 43 patients received post-operative RT. Two RT dose fractionations were utilized for primary RT cases (70 Gy in 35 fractions or 69.96 Gy in 33 fractions). Median RT dose was 70 Gy (range 50.88-74) for primary RT definitive cases and 66 Gy (range 44-70) for post-operative RT cases. The median follow up was 46.2 months (95% CI, 33.5-63.1). Cox proportional hazards analyses were performed with GARD as both a continuous and dichotomous variable and time-dependent ROC analyses compared the performance of GARD with the NRG clinical nomogram for overall survival. Results: Despite uniform radiation dose utilization, GARD showed significant heterogeneity (range 30-110), reflecting the underlying genomic differences in the cohort. On multivariable analysis, each unit increase in GARD was associated with an improvement in OS (HR = 0.951 (0.911, 0.993), p = 0.023) compared to AJCC8 (HR = 1.999 (0.791, 5.047)), p = 0.143). ROC analysis for GARD at 36 months yielded an AUC of 80.6 (69.4, 91.9) compared with an AUC of 73.6 (55.4, 91.7) for the NRG clinical nomogram. GARD≥64.2 was associated with improved OS (HR = 0.280 (0.100, 0.781), p = 0.015). In a virtual trial, GARD predicts that uniform RT dose de-escalation results in overall inferior OS but proposes two separate genomic strategies where selective RT dose de-escalation in GARD-selected populations results in clinical equipoise. Conclusions: In this multi-institutional cohort of patients with HPV-positive OPSCC, GARD predicts OS as a continuous variable, outperforms the NRG nomogram and provides a novel genomic strategy to modern clinical trial design. We propose that GARD, which provides the first opportunity for genomic guided personalization of radiation dose, should be incorporated in the diagnostic workup of HPV-positive OPSCC patients.

Academic Achievement in School-Aged Children with Single Suture Craniosynostosis Over Time.

Introduction: Children with single suture craniosynostosis (SSC) are at risk for neurocognitive problems. The reported magnitude of differences between children with SSC and their normative peers on standardized tests of academic and intellectual ability are small. Evaluation of real-world academic outcomes of these children and its impact on educational resources have not been conducted. Methods: A retrospective cohort study of academic outcomes of children with SSC was conducted using the data from Ontario's Education Quality and Accountability Office (EQAO) standardized provincial reading, writing and mathematics tests. The need for special education was identified by documentation of the child's need for an Identification, Placement, and Review Committee (IPRC). Results: Of 296 eligible children, 42 participated in the study. Half of the children had sagittal synostosis, while the remaining were 10 (24%) unicoronal, 9 (21%) metopic, and 2 (5%) lambdoid synostosis. Thirty-six (86%) underwent operative management. The EQAO scores of operated children with SSC met the provincial academic standards on the Grade 3 and 6 EQAO scores across the 3 academic subjects. Converted grade-matched EQAO scores decreased in reading and writing over time, while math improved. Of the 21 patients with special education data, one child required an IPRC in Grade 3, while an additional four (24%) required an IPRC in Grade 6. Conclusions: Operated children with SSC had average academic performance, however, their needs appeared to change over time. Future studies are needed to evaluate academic difficulties and special education needs as these children progress through grade school.

Introduction: Les enfants ayant une craniosynostose simple (CSS) sont à risque de troubles neurocognitifs. Selon les tests standardisés des capacités scolaires et intellectuelles, les enfants ayant une CSS présentent des différences légères par rapport à leurs homologues en bonne santé. Les résultats scolaires concrets de ces enfants n'ont pas été évalués, ni leurs répercussions sur les ressources pédagogiques. Méthodologie: Les chercheurs ont effectué une étude de cohorte rétrospective des résultats des enfants ayant une CSS aux examens de lecture, d'écriture et de mathématique au moyen des données provinciales standardisées de l'Office de la qualité et de la responsabilité en éducation de l'Ontario (OQRÉO). Les besoins en éducation spécialisée étaient indiqués par un avis du comité d'identification, de placement et de révision (CIPR) au dossier de l'enfant. Résultats: Des 296 enfants admissibles, 42 ont participé à l'étude. La moitié des enfants présentaient une synostose sagittale (scaphocéphalie), tandis que dix (24 %) avaient une synostose unicoronale, neuf (21 %), une synostose métopique (trigonocéphalie), et deux (5 %), une synostose lambdoïde. Au total, 36 (86 %) ont été opérés. Les scores de l'OQRÉO des enfants opérés à cause d'une CSS respectaient les normes scolaires provinciales pour la 3e et la 6e années dans les trois matières scolaires. Les scores de l'OQRÉO convertis en fonction du degré ont diminué en lecture et en écriture au fil du temps, mais se sont améliorés en mathématiques. Des 21 patients sur qui les chercheurs possédaient des données en éducation spécialisée, un enfant a eu besoin d'un avis du CIPR en 3e année, et quatre (24 %), en 6e année. Conclusions: Les enfants opérés à cause d'une CSS avaient une performance scolaire moyenne, mais leurs besoins semblaient évoluer au fil du temps. D'autres études devront être réalisées pour évaluer les problèmes scolaires et les besoins d'éducation spécialisée des enfants au primaire.

Recent Advances in the Treatment of Brachial Plexus Birth Injury.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Describe methods of clinical evaluation for neurologic recovery in brachial plexus birth injury. 2. Understand the role of different diagnostic imaging modalities to evaluate the upper limb. 3. List nonsurgical strategies and surgical procedures to manage shoulder abnormality. 4. Explain the advantages and disadvantages of microsurgical nerve reconstruction and distal nerve transfers in brachial plexus birth injury. 5. Recognize the prevalence of pain in this population and the need for greater sensory outcomes evaluation. SUMMARY: Brachial plexus birth injury (BPBI) results from closed traction injury to the brachial plexus in the neck during an infant's vertex passage through the birth canal. Although spontaneous upper limb recovery occurs in most instances of BPBI, some infants do not demonstrate adequate motor recovery within an acceptable timeline and require surgical intervention to restore upper limb function. This article reviews major advances in the management of BPBI in the past decade that include improved understanding of shoulder pathology and its impact on observed motor recovery, novel surgical techniques, new insights in sensory function and pain, and global efforts to develop standardized outcomes assessment scales.

Chemoproteomic Profiling Reveals that Anticancer Natural Product Dankastatin†B Covalently Targets Mitochondrial VDAC3.

Chlorinated gymnastatin and dankastatin alkaloids derived from the fungal strain Gymnascella dankaliensis have been reported to possess significant anticancer activity but their mode of action is unknown. These members possess electrophilic functional groups that can might undergo covalent bond formation with specific proteins to exert their biological activity. To better understand the mechanism of action of this class of natural products, we mapped the proteome-wide cysteine reactivity of the most potent of these alkaloids, dankastatin B, by using activity-based protein profiling chemoproteomic approaches. We identified a primary target of dankastatin B in breast cancer cells as cysteine C65 of the voltage-dependent anion-selective channel on the outer mitochondrial membrane VDAC3. We demonstrated direct and covalent interaction of dankastatin B with VDAC3. VDAC3 knockdown conferred hypersensitivity to dankastatin B-mediated antiproliferative effects in breast cancer cells, thus indicating that VDAC3 was at least partially involved in the anticancer effects of this natural product. Our study reveals a potential mode of action of dankastatin B through covalent targeting of VDAC3 and highlights the utility of chemoproteomic approaches in gaining mechanistic understanding of electrophilic natural products.

Chemoproteomic Profiling Reveals that Anti-Cancer Natural Product Dankastatin B Covalently Targets Mitochondrial VDAC3.

Chlorinated gymnastatin and dankastatin alkaloids derived from the fungal strain Gymnascella dankaliensis have been reported to possess significant anti-cancer activity but their mode of action is unknown. These members possess electrophilic functional groups that may undergo covalent bond formation with specific proteins to exert their biological activity. To better understand the mechanism of action of this class of natural products, we mapped the proteome-wide cysteine-reactivity of the most potent of these alkaloids, dankastatin B, using activitybased protein profiling chemoproteomic approaches. We identified a primary target of dankastatin B in breast cancer cells as cysteine C65 of the voltage-dependent anion selective channel on the outer mitochondrial membrane VDAC3. We demonstrated direct and covalent interaction of dankastatin B with VDAC3. VDAC3 knockdown conferred hyper-sensitivity to dankastatin B-mediated anti-proliferative effects in breast cancer cells indicating that VDAC3 was at least partially involved in the anti-cancer effects of this natural product. Our study reveals a potential mode of action of dankastatin B through covalent targeting of VDAC3 and highlight the utility of chemoproteomic approaches in gaining mechanistic understanding of electrophilic natural products.

Intracoronary Brachytherapy for Drug-Eluting Stent Restenosis: Outcomes and Clinical Correlates.

Background: This study aimed to report outcomes of intracoronary brachytherapy (ICBT) in treating drug-eluting stent (DES) in-stent restenosis (ISR) and identify correlated factors. Methods: Patients who underwent ICBT for DES ISR from 2010 to 2021 were included in this single-institution retrospective PCI registry. Patients were treated with balloon angioplasty, laser atherectomy, and/or rotational atherectomy, followed by ICBT at a dose of 18.4-25 Gy delivered at the site of ISR with dose determined by the reference vessel size. The primary outcome was 3-year target lesion failure rate (TLF). Secondary end points were 1-year TLF, target lesion revascularization (TLR), all-cause mortality, and cardiac mortality. Results: In total, 330 consecutive patients presented with 345 treated lesions; 70% were male, age was 66 ± 11 years, 55% were diabetic patients, 62% underwent previous bypass surgery, and 89% were placed with at least 2 stent layers at the treated site. The rate of TLF was 18% at 1 year and 46% at 3 years. All-cause mortality and cardiac mortality rates were 19.8% and 12.3% at 3 years. The number of stent layers was associated with 3-year TLF (1 layer, 33.3%; 2 layers, 47.0%, >3 layers, 60.2%; P = .045). Diabetes, repeat ICBT, final percent stenosis, lesion length, and intravascular imaging use were not correlated with the primary outcome. Lower ICBT dose (P = .035) and restenosis <1 year from previous percutaneous coronary intervention (P = .044) were correlated with early (1-year) TLF. Conclusion: ICBT for recurrent DES ISR provided low recurrence rates at 1 year, which increased substantially by 3 years. Outcomes were most closely correlated with the number of stent layers, but early restenosis and lower ICBT dose adversely affected early TLF.

The transcription factor VAX1 in VIP neurons of the suprachiasmatic nucleus impacts circadian rhythm generation, depressive-like behavior, and the reproductive axis in a sex-specific manner in mice.

Background: The suprachiasmatic nucleus (SCN) within the hypothalamus is a key brain structure required to relay light information to the body and synchronize cell and tissue level rhythms and hormone release. Specific subpopulations of SCN neurons, defined by their peptide expression, regulate defined SCN output. Here we focus on the vasoactive intestinal peptide (VIP) expressing neurons of the SCN. SCN VIP neurons are known to regulate circadian rhythms and reproductive function. Methods: To specifically study SCN VIP neurons, we generated a novel knock out mouse line by conditionally deleting the SCN enriched transcription factor, Ventral Anterior Homeobox 1 (Vax1), in VIP neurons (Vax1Vip; Vax1fl/fl:VipCre). Results: We found that Vax1Vip females presented with lengthened estrous cycles, reduced circulating estrogen, and increased depressive-like behavior. Further, Vax1Vip males and females presented with a shortened circadian period in locomotor activity and ex vivo SCN circadian period. On a molecular level, the shortening of the SCN period was driven, at least partially, by a direct regulatory role of VAX1 on the circadian clock genes Bmal1 and Per2. Interestingly, Vax1Vip females presented with increased expression of arginine vasopressin (Avp) in the paraventricular nucleus, which resulted in increased circulating corticosterone. SCN VIP and AVP neurons regulate the reproductive gonadotropin-releasing hormone (GnRH) and kisspeptin neurons. To determine how the reproductive neuroendocrine network was impacted in Vax1Vip mice, we assessed GnRH sensitivity to a kisspeptin challenge in vivo. We found that GnRH neurons in Vax1Vip females, but not males, had an increased sensitivity to kisspeptin, leading to increased luteinizing hormone release. Interestingly, Vax1Vip males showed a small, but significant increase in total sperm and a modest delay in pubertal onset. Both male and female Vax1Vip mice were fertile and generated litters comparable in size and frequency to controls. Conclusion: Together, these data identify VAX1 in SCN VIP neurons as a neurological overlap between circadian timekeeping, female reproduction, and depressive-like symptoms in mice, and provide novel insight into the role of SCN VIP neurons.

Research gaps and opportunities in precision nutrition: an NIH workshop report.

Precision nutrition is an emerging concept that aims to develop nutrition recommendations tailored to different people's circumstances and biological characteristics. Responses to dietary change and the resulting health outcomes from consuming different diets may vary significantly between people based on interactions between their genetic backgrounds, physiology, microbiome, underlying health status, behaviors, social influences, and environmental exposures. On 11-12 January 2021, the National Institutes of Health convened a workshop entitled "Precision Nutrition: Research Gaps and Opportunities" to bring together experts to discuss the issues involved in better understanding and addressing precision nutrition. The workshop proceeded in 3 parts: part I covered many aspects of genetics and physiology that mediate the links between nutrient intake and health conditions such as cardiovascular disease, Alzheimer disease, and cancer; part II reviewed potential contributors to interindividual variability in dietary exposures and responses such as baseline nutritional status, circadian rhythm/sleep, environmental exposures, sensory properties of food, stress, inflammation, and the social determinants of health; part III presented the need for systems approaches, with new methods and technologies that can facilitate the study and implementation of precision nutrition, and workforce development needed to create a new generation of researchers. The workshop concluded that much research will be needed before more precise nutrition recommendations can be achieved. This includes better understanding and accounting for variables such as age, sex, ethnicity, medical history, genetics, and social and environmental factors. The advent of new methods and technologies and the availability of considerably more data bring tremendous opportunity. However, the field must proceed with appropriate levels of caution and make sure the factors listed above are all considered, and systems approaches and methods are incorporated. It will be important to develop and train an expanded workforce with the goal of reducing health disparities and improving precision nutritional advice for all Americans.

Revisional Surgery or Pharmacotherapy for Insufficient Weight Loss and Weight Regain After Primary Bariatric Procedure: a Descriptive Study.

PURPOSE: Bariatric surgery is the most effective and durable treatment option for clinically severe obesity. Unfortunately, some degree of weight regain (WR) is common after nadir weight is achieved. Pharmacotherapy and revision surgery are potential options to treat this phenomenon. We aim to determine the efficacy of both approaches in patients with WR versus insufficient weight loss (IWL). MATERIALS AND METHODS: We retrospectively reviewed a prospectively collected database of patients who underwent bariatric surgery from 2008 to 2018 with IWL or WR. RESULTS: Of 422 patients with WR or IWL after bariatric surgery, 150 patients were placed on pharmacotherapy and 27 underwent revisional surgeries. Mean age of patients was 41.4 years and mean BMI was 42.1 kg/m2. The most common conversion surgery was LSG to RYGB. % Total weight loss (TWL) was higher in IWL group (23.8% ± 11.0) compared to WR group (17.2% ± 7.9) in revisional surgery (p = 0.02). The converse was observed for pharmacotherapy, with %TWL 1.9% in the WR group compared to 0.7% in the IWL group (p = 0.0067). CONCLUSION: Patients with IWL or WR had modest weight loss with adjunctive use of pharmacotherapy after primary bariatric surgery. Conversely, revisional surgery is an effective treatment for both IWL and WR.

Impact of Before and After Photographs on Parents of Children With Cleft Lip.

Introduction: Cleft lip with or without palate (CL/P) is a common facial deformity requiring surgical intervention whose aesthetic outcomes are typically represented by Before and After Photographs (BAPhotos). With the growing presence of social media, there are concerns about the role of BAPhotos in plastic surgery and their impact on patient's expectations. Methods: A retrospective analysis of quality assurance survey and interview data was conducted to explore the impact of BAPhotos on parents and their expectations in the context of CL/P. Results: Thirty-five parents were interviewed regarding use of BAPhotos; 91% viewed BAPhotos on the following platforms: Google (n = 26), Facebook (n = 8), Instagram (n = 4), YouTube (n = 4), Snapchat (n = 1), and Other (n = 11). Half of the parents believed that BAPhotos influenced their treatment expectations and these parents were not less satisfied with their child's surgical outcome than those who did not perceive being influenced (Mann-Whitney U = 124.5, P = .05). A higher proportion of parents who viewed BAPhotos on social platforms felt that their treatment expectations were influenced by BAPhotos (χ2, X (df = 1) = 4.49, P = .03). Thematic analysis revealed that parents' emotional reaction to BAPhotos was shaped by the context of the photos; photos on social platforms that include patient stories (ie, Instagram, Facebook) were more often sources of emotional support. Conclusion: This study furthers our understanding of the impact BAPhotos have on parents of children with CL/P and areas of education regarding the dissemination of BAPhotos which have the potential to positively impact viewing of these photos.

Introduction: La fissure labiale ­ avec ou sans fissure palatine ­ est une difformité faciale courante qui nécessite une intervention chirurgicale, dont les résultats esthétiques sont habituellement illustrés à l'aide de photos avant-après. En raison de la place grandissante qu'occupent les médias sociaux dans nos vies, certains s'inquiètent du rôle que jouent les photos avant-après dans le domaine de la chirurgie plastique ainsi que de l'impact de celles-ci sur les attentes des patients. Méthodologie: Une analyse rétrospective portant sur des données provenant d'enquêtes et d'entrevues effectuées dans le cadre d'un processus d'assurance de la qualité a été réalisée afin d'étudier l'impact des photos avant-après sur les parents et leurs attentes vis-à-vis des interventions dans les cas de fissure labiale avec ou sans fissure palatine. Résultats: Trente-cinq parents ont été interviewés au sujet de l'utilisation des photos avant-après; 91 % d'entre eux ont regardé de telles photos sur les plates-formes suivantes: Google (n = 26), Facebook (n = 8), Instagram (n = 4), YouTube (n = 4), Snapchat (n = 1) et autres plate-formes de médias sociaux (n = 11). La moitié des parents estimaient que les photos avant-après avaient influencé leurs attentes à l'égard du traitement. Ces derniers ne se disaient pas moins satisfaits des résultats de la chirurgie subie par leur enfant que ceux qui n'avaient pas l'impression d'avoir été influencés par de telles photos (test U de Mann-Whitney = 124,5, P = ,05). Une proportion plus élevée de parents ayant vu des photos avant-après sur les plates-formes de médias sociaux estimaient que leurs attentes vis-à-vis le traitement étaient influencées par ces photos (khi carré X [df = 1] = 4,49, P = ,03). Une analyse thématique a révélé que la réaction émotionnelle des parents aux photos avant-après était fonction du contexte desdites photos; celles qui étaient publiées sur les plate-formes de médias sociaux, accompagnées d'histoires de patients (p. ex. Instagram, Facebook), offraient plus souvent une source de soutien émotionnel que celles publiées sans histoires. Conclusion: Cette étude consolide notre compréhension de l'impact des photos avant-après sur les parents d'enfants présentant une fissure labiale avec ou sans fissure palatine, ainsi que sur les domaines de l'éducation au chapitre de la diffusion de telles photos, qui peuvent influencer positivement la consultation de celles-ci.

Coronary intravascular brachytherapy for in-stent restenosis: A review of the contemporary literature.

Intracoronary stent restenosis (ISR) is a clinically relevant challenge in the modern era. Heterogeneity in patient- and lesion-specific factors can further compound this clinical challenge. Coronary intravascular brachytherapy (IVBT) was the standard therapeutic approach for ISR prior to the advent of drug-eluting stents (DES). Despite prospective data describing the superiority of DES over IVBT for treating de novo ISR, IVBT remains a treatment option for patients with complex disease. The purpose of this review is to evaluate the historical and contemporary literature surrounding IVBT in order to elucidate its role in modern cardiac care and to describe opportunities for future investigations to improve patient selection. Herein, we provide a review of the contemporary literature describing IVBT as a safe and effective treatment option for patients with recurrent, refractory ISR after multilayer DES and no good surgical or mechanical option. Combination therapy with emerging technologies such as DCBs may further increase efficacy.

Randomized Crossover Trial Evaluating Detoxification of Tobacco Carcinogens by Broccoli Seed and Sprout Extract in Current Smokers.

Consumption of cruciferous vegetables, rich in the isothiocyanate glucoraphanin, is associated with reduced risk of tobacco-related cancers. Sulforaphane, released by hydrolysis of glucoraphanin, potently induces cytoprotective phase II enzymes. Sulforaphane decreased the incidence of oral cancer in the 4NQO carcinogenesis model. In residents of Qidong, China, broccoli seed and sprout extracts (BSSE) increased detoxification of air pollutants benzene and acrolein, also found in tobacco smoke. This randomized, crossover trial evaluated detoxification of tobacco carcinogens by the BSSE Avmacol® in otherwise healthy smokers. Participants were treated for 2 weeks with both low and higher-dose BSSE (148 µmol vs. 296 µmol of glucoraphanin daily), separated by a 2-week washout, with randomization to low-high vs. high-low sequence. The primary endpoint was detoxification of benzene, measured by urinary excretion of its mercapturic acid, SPMA. Secondary endpoints included bioavailability, detoxification of acrolein and crotonaldehyde, modulation by GST genotype, and toxicity. Forty-nine participants enrolled, including 26 (53%) females with median use of 20 cigarettes/day. Low and higher-dose BSSE showed a mean bioavailability of 11% and 10%, respectively. Higher-dose BSSE significantly upregulated urinary excretion of the mercapturic acids of benzene (p = 0.04), acrolein (p < 0.01), and crotonaldehyde (p = 0.02), independent of GST genotype. Retention and compliance were high resulting in early study completion. In conclusion, BSSE significantly upregulated detoxification of the tobacco carcinogens benzene, acrolein, and crotonaldehyde in current tobacco smokers.