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Nima Pourhabibi Zarandi,1,* Guillermo Galdon,1,* Stanley Kogan,1,2 Anthony Atala,1,2 Hooman Sadri-Ardekani1,2 1Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; 2Department of Urology, Wake Forest School of Medicine, Winston-Salem, NC, USA *These authors contributed equally to this work Abstract: While the survival rate of children with cancer is increasing, preserving fertility for prepubertal boys is still a challenge. Although intracytoplasmic sperm injection (ICSI) using frozen sperms has revolutionized infertility treatment, it is not applicable for the patients who undergo chemotherapy before puberty since spermatogenesis has not begun. Therefore, preserving spermatogonial stem cells (SSCs) as an experimental option can be provided to prepubertal patients at a risk of damage or loss of their SSCs due to cancer treatments and developmental or genetic disorders. Using frozen SSCs in testicular tissue, successful SSC autotransplantation in mouse and nonhuman primates has shown a promising future for SSC-based cell therapy. Cryopreservation of testicular tissue containing SSCs is the first step to translate SSC-based cell therapy into clinical male infertility treatment, and in the investigation into SSCs, it is very important to evaluate their quantity and functionality during this process. This systematic review summarizes the published data on cryopreservation techniques in human testis tissue for potential utilization in future clinical applications. Keywords: testis, spermatogonial stem cell, tissue banking, cryopreservation, male infertility, transplantation

Background and Aims: Wilson disease (WD) is a rare disorder of copper metabolism, leading to liver and neurological disease. Existing literature on WD in pregnancy is scarce, limiting preconception and obstetrical counselling. In this systematic review with meta-analysis, we determine the prevalence of various adverse pregnancy and neonatal outcomes in WD, as well as evaluate the impact of WD treatment on these outcomes., Methods: Scopus, MEDLINE and EMBASE were searched until 12 May 2023, for studies of pregnant individuals with WD and at least one pregnancy or neonatal outcome of interest. Meta-analysis of single proportions was conducted to pool prevalence data for each outcome. Outcome rates were compared between treated and untreated groups in a meta-analysis of dichotomous events., Results: Sixteen studies, published from 1975 to 2022, were included in the systematic review. Thirty-seven percent of pregnancies reported at least one adverse pregnancy outcome. Spontaneous abortions (20%), liver diseases of pregnancy (4.5%) and preterm births (2%) were the most frequent adverse pregnancy outcomes in patients with WD. The prevalence of spontaneous abortions was significantly lower in pregnant individuals with WD who received treatment during pregnancy (OR: .47, 95% CI: 35%-63%). The prevalence of any adverse pregnancy outcome was also significantly lower with treatment (OR: .53, 95% CI: .37-.76), which appears to be mostly driven by the reduction of spontaneous abortions., Conclusions: There is low to moderate quality evidence to suggest that preconception and obstetrical counselling for patients with WD should include a discussion on the potentially high frequency of adverse pregnancy outcomes in this population, as well as the importance of continuing WD treatment during pregnancy to ensure satisfactory pregnancy course and potentially minimize the risk of spontaneous abortions., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Burgeoning neuroimaging research documents the associations between working memory (WM)-associated neural and behavioral responses. However, these associations have yielded small and inconsistent effect sizes. We hypothesize that one reason for the weakened brain-behavior associations stems from different environmental contexts. Specifically, little research has examined how exposure to adverse rearing environments accounts for variability in brain-behavior relations. Deprivation, characterized by an absence of cognitive and positive social stimulation, has been shown to compromise children's neurocognitive development. Hence, informed by an ecological approach to developmental neuroscience, the present study aims to investigate if psychosocial and socioeconomic deprivation serves as moderators in the associations between neural responses and behaviors during a WM task. Using data from the Adolescent Brain Cognitive Development study (N = 11, 878, M age  = 9.48, 47.8% female, 52.0% White), we found that psychosocial, but not socioeconomic deprivation, significantly attenuated the positive association between WM-related neural activation within the frontoparietal network and attendant behavioral performance. Specifically, children exposed to higher levels of psychosocial deprivation exhibited weaker brain-behavior relations during a WM task. This finding suggests that a certain level of neural response during cognitive tasks may correspond to different levels of behavioral performance depending on children's rearing environment, highlighting the importance of contextual factors in understanding the brain and cognitive development., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: A lack of a "gold standard" operationalized index to measure structural racism (SR) in the current literature limits the comparison of the evidence available. This study aims to synthesize the measures of SR from the current literature to identify the measures used to date, study the indicators included, and investigate its expanding domain., Methods: A literature search of original quantitative studies in the Google Scholar and PubMed databases for articles dated January 1, 2000-July 31, 2023, was conducted with search terms: ["Institutionalized Racism" OR "Systemic Racism", OR "Structural Racism"] AND "Health" AND "United States." The studies were summarized and extracted based on the type of SR index used, the domains of SR incorporated, and the health outcomes studied., Results: A total of 74 articles were included in the final review. The historical redlining score, G-statistics, index of concentration, and structural racism index were common quantifiable measures of SR. These indices capture 56 indicators across 11 significant domains to measure SR. Similarly, SR indices are being used mostly to study the impact of SR on cardiovascular diseases and other chronic health conditions, women's and maternal health-related issues, and COVID-19 outcomes., Conclusion: Multiple indices have been developed to capture SR, and since the COVID-19 pandemic, we have observed an increased interest in understanding health disparities through the lens of SR. With the rise in evidence on experiences of minority races related to racism, there is a high need for a standard approach to measuring SR., (© 2024. W. Montague Cobb-NMA Health Institute.)

Introduction: We assessed the efficacy of taurolidine lock (TL) in preventing catheter-related bloodstream infections (CRBSIs) and related hospitalizations in children with parenteral nutrition (PN) in the home setting., Methods: This study is a retrospective case series study. All children with intestinal failure in a single center in southern Israel who were administered PN and treated with TL between 2017 and 2024 were included. The rates of CRBSI episodes, related hospitalizations and pathogen distribution in the pre-TL and post-TL periods were compared., Results: Overall, 14 patients were included. The median pre-TL and post-TL periods were 990 and 1260 days, respectively. The rate of CRBSI episodes due to bacterial infection per 1000 days declined by 45%, from 6.2 to 3.7, with p = 0.0008, while fungal CRBSI rates were low (<10% of all positive cultures) and did not decline significantly. Similarly, the hospitalization episode rate per 1000 days declined by 41%, from 7.6 to 4.5, with p = 0.001., Conclusions: Taurolidine lock treatment for children with central-line PN resulted in a substantial decrease in CRBSI episodes and related hospitalizations.

Study Design: Retrospective chart review., Objective: The management of pediatric facial fractures presents distinctive considerations compared to adults. This study aims to provide a unique perspective on the correlations between the mechanism of injury, types of facial fractures, and fracture interventions and management utilized in 2 North Carolina Level 1 Trauma Centers to determine the optimal management options for this patient population., Methods: An IRB-approved retrospective chart review was performed of pediatric facial trauma patients ages <18 years old between January 2020 and December 2022 at Atrium Health Wake Forest Baptist Medical Center and Atrium Health Charlotte Medical Center. Data on patient demographics, mechanism of injury, facial fractures, interventions, and outcomes were collected., Results: Of 2,977 pediatric facial trauma patients, 582 patients sustained at least 1 facial fracture at the time of injury. Adolescents were significantly less likely to be transferred from outside institutions and to be admitted for further care ( P = 0.002). Adolescents experienced higher levels of residual symptoms following initial discharge ( P = 0.001) and were less likely to have a symptom resolution within 1 year ( P < 0.0001). Neonates and infants were significantly more likely to receive conservative interventions and to sustain calvarium and skull base fractures ( P < 0.0001)., Conclusions: This study identifies differences in pediatric age groups related to transfers, admittance, fracture type, management, and outcomes. Our data suggests adolescent patients may experience a higher incidence of residual symptoms with lower levels of symptom resolution within 1 year. Further investigation into these differences may elicit optimized methods of fracture management in pediatric age groups and allow for effective, individualized care with improved long-term outcomes., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: The recently described frontal bossing index (FBI) and occipital bullet index (OBI) allow for quantification of scaphocephaly. A similar index examining biparietal narrowing has not been described. Addition of such an index measuring width would allow for direct evaluation of the primary growth restriction in sagittal craniosynostosis and the formation of an optimized global width/length measure., Methods: Computed tomography scans and three-dimensional photographs were used to recreate scalp surface anatomy. Equidistant axial, sagittal, and coronal planes were overlaid, creating a Cartesian grid. Points of intersection were analyzed for population trends in biparietal width. Using the most descriptive point coupled with the sellion protrusion to control for head size, the vertex narrowing index is formed. By combining this index with the FBI and OBI, the scaphocephalic index (SCI) is created as a tailored width/length measure., Results: Using 221 controls and 360 individuals with sagittal craniosynostosis, the greatest difference occurred superiorly and posteriorly at a point 70% of the head's height and 60% of the head's length. This point had an area under the curve of 0.97 and sensitivity and specificity of 91.2% and 92.2%, respectively. The SCI has an area under the curve of 0.9997, sensitivity and specificity greater than 99%, and interrater reliability of 0.995. The correlation coefficient between computed tomography imaging and three-dimensional photography was 0.96., Conclusions: The vertex narrowing index, FBI, and OBI evaluate regional severity, while the SCI is able to describe global morphology in patients with sagittal craniosynostosis. These measures allow for superior diagnosis, surgical planning, and outcome assessment, independent of radiation., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, yet few environmental risk factors have been identified. We previously found an association between early-life tobacco smoke exposure and frequency of somatic deletions of 8 leukemia driver genes among childhood ALL patients in the California Childhood Leukemia Study. To expand analysis genome-wide and examine potential mechanisms, we conducted tumor whole-genome sequencing in 35 ALL patients, including 18 with high prenatal tobacco exposure and 17 with low exposure as determined by established epigenetic biomarkers. High tobacco exposure patients had significantly more structural variants (P < .001) and deletions (P = .001) genome-wide than low exposure patients. Investigation of off-target RAG recombination revealed that 41% of deletions in the high tobacco exposure patients were putatively RAG-mediated (full RAG motif identified at one or both breakpoints) compared with only 21% in the low exposure group (P = .001). In a multilevel model, deletions in high tobacco exposure patients were 2.44-fold (95% CI:1.13-5.38) more likely to be putatively RAG-mediated than deletions in low exposure patients. No point mutational signatures were associated with prenatal tobacco exposure. Our findings suggest that early-life tobacco smoke exposure may promote leukemogenesis by driving development of somatic deletions in pre-leukemic lymphocytes via off-target RAG recombination., Competing Interests: Competing interests: The authors declare no competing interests in relation to the work described.

Introduction: With advances in medical care and assisted reproductive technologies (ART), fertility prospects for prune-belly syndrome (PBS) men may be changing. This review aims to identify the factors influencing fertility and optimization of reproductive health for PBS patients., Material and Methods: A scoping review was performed on all records published over 70 years (1952-2022) analyzing fertility in PBS males. Records were summarized in a table and narrative describing cryptorchidism, orchiopexy, testicle histology; prostate characteristics; sex hormone function; semen analyses, ART, and conception ability. This review was registered on Open Science Framework (OSF) and conducted using PRISMA methodology., Results: 827 articles were identified and 83 were selected for data extraction. Before 2000, there were 0.85 publications/year whereas after 2000 there were 1.95 publications/year. Orchiopexy successfully relocated 86 % of PBS testicles into the scrotum. Testicular histology demonstrated 50 % of patients had no spermatogonia, while 47.2 % and 2.7 % had reduced or normal numbers respectively. Leydig hyperplasia and Sertoli only histology were found in 19.4 % of patients. Prostatic hypoplasia and prostatic urethral dilation were found in 93.6 % and 91.4 % of patients respectively. Testosterone, Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH) were normal in 93.9 %, 87.7 % and 77.9 % of patients respectively. Azoospermia and oligospermia was found in 75.7 % and 21.6 % of patients respectively while 60.7 % had antegrade ejaculation. ART successfully extracted sperm in 6 instances and resulted in 4 conceptions, while natural conception was reported twice., Conclusions: Data analysis indicates increased attention to fertility prospects for PBS males with evaluation of PBS patient's hormonal function, semen analyses, ART, and conception ability. The reviewed data suggest that PBS males may father biological offspring with contemporary management and also demonstrate the need for consistent reproductive management approaches to maximize their fertility prospects., (Copyright © 2024 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Patients affected by cleft lip and palate have a characteristic nasal deformity; however, the treatment timeline varies amongst providers. There has been a shift from a more conservative approach to earlier intervention in order to allow for more normal development of the nose. Form, function, and future development all must be considered. For this reason, this investigation was undertaken to present the current literature available on the effects to all aspects of primary septoplasty in the cleft nasal deformity., An initial list of 222 papers was identified, and it was determined that 16 papers fit the inclusion criteria. Studies were included in which the initial age of operation for the majority of patients was between 3 and 12 months and in which patients underwent septal repositioning at the time of cleft lip repair. These papers were all reviewed by a single author initially, and the results recorded. All results were then verified by a second author for accuracy and completeness., Symmetry was found to be improved by primary septoplasty. Growth was not found to be impaired in any study; data was insufficient to indicate that growth was improved. Obstruction was improved as determined both by imaging, endoscopy, and patient survey. Finally, reoperation rates occurred at an acceptable rate not exceeding that of primary rhinoplasty without septoplasty., Primary septoplasty leads to better aesthetic symmetry and function of the cleft nose without impairing growth. This change is maintained into adulthood often without the need for revisionary surgery., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Closed-incision negative pressure wound therapy (ciNPWT) has shown promise in reducing surgical wound complications. Among its numerous benefits, it allows for exudate management and tension offloading from wound edges. The purpose of this systematic review and meta-analysis was to assess the efficacy of prophylactic ciNPWT versus conventional dressings on abdominal donor site complications in microsurgical breast reconstruction (MR)., Methods: A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in January 2023. PubMed and Embase were searched to identify all relevant studies. Data collected included rates of total wound complications, wound dehiscence, infection, seroma, and length of hospital stay., Results: A total of 202 articles were screened, and eight studies (1009 patients) met the inclusion criteria. Use of ciNPWT was associated with a significantly lower rate of wound dehiscence (OR, 0.53; 95% confidence interval, 0.33-0.85; P = 0.0085, I 2  = 0%). There was no significant difference in the rate of total wound complications [odds ratio (OR), 0.63; 95% CI, 0.35-1.14; P = 0.12, I 2  = 69%], donor site infection (OR, 0.91; 95% CI, 0.42-1.50; P = 0.47, I 2  = 13%), seroma (OR, 0.74; 95% CI, 0.22-2.49; P = 0.63, I 2  = 57%), or length of hospital stay (SMD, 0.089; 95% CI, -0.13-0.35; P = 0.37, I 2  = 29%)., Conclusions: Although exudate management by ciNPWT fails to reduce surgical site infection, seroma formation, and overall length of stay, ciNPWT tension offloading properties seem to be associated with lower rates of wound dehiscence when compared with conventional dressings in abdominal-based autologous breast reconstruction., Competing Interests: The authors have no financial interest to declare in relation to the content of this article. Disclosure statements are at the end of this article, following the correspondence information., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

With high success rates of autologous breast reconstruction, the focus has shifted from flap survival to improved patient outcomes. Historically, a criticism of autologous breast reconstruction has been the length of hospital stay. Our institution has progressively shortened the length of stay after deep inferior epigastric artery perforator (DIEP) flap reconstruction and began discharging select patients on postoperative day 1 (POD1). The purpose of this study was to document our experience with POD1 discharges and to identify preoperative and intraoperative factors that may identify patients as candidates for earlier discharge., Methods: An institutional review board-approved, retrospective chart review of patients undergoing DIEP flap breast reconstruction from January 2019 to March 2022 at Atrium Health was completed, consisting of 510 patients and 846 DIEP flaps. Patient demographics, medical history, operative course, and postoperative complications were collected., Results: Twenty-three patients totaling 33 DIEP flaps were discharged on POD1. The POD1 group and the group of all other patients (POD2+) had no difference in age, ASA score, or comorbidities. BMI was significantly lower in the POD1 group ( P = 0.039). Overall operative time was significantly lower in the POD1 group, and this remained true when differentiating into unilateral operations ( P = 0.023) and bilateral operations ( P = 0.01). No major complications occurred in those discharged on POD1., Conclusions: POD1 discharge after DIEP flap breast reconstruction is safe for select patients. Lower BMI and shorter operative times may be predictive in identifying patients as candidates for earlier discharge., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Experimental or traumatic nerve injury causes the degeneration of associated taste buds. Unlike most sensory systems, the sectioned nerve and associated taste buds can then regenerate, restoring neural responses to tastants. It was previously unknown whether injury-induced immune factors mediate this process. The proinflammatory cytokines, interleukin (IL)-1α and IL-1β, and their requisite receptor are strongly expressed by anterior taste buds innervated by the chorda tympani nerve. We tested taste bud regeneration and functional recovery in mice lacking the IL-1 receptor. After axotomy, the chorda tympani nerve regenerated but was initially unresponsive to tastants in both WT and Il1r KO mice. In the absence of Il1r signaling, however, neural taste responses remained minimal even >8 weeks after injury in both male and female mice, whereas normal taste function recovered by 3 weeks in WT mice. Failed recovery was because of a 57.8% decrease in regenerated taste buds in Il1r KO compared with WT axotomized mice. Il1a gene expression was chronically dysregulated, and the subset of regenerated taste buds were reinnervated more slowly and never reached full volume as progenitor cell proliferation lagged in KO mice. Il1r signaling is thus required for complete taste bud regeneration and the recovery of normal taste transmission, likely by impairing taste progenitor cell proliferation. This is the first identification of a cytokine response that promotes taste recovery. The remarkable plasticity of the taste system makes it ideal for identifying injury-induced mechanisms mediating successful regeneration and recovery. SIGNIFICANCE STATEMENT Taste plays a critical role in nutrition and quality of life. The adult taste system is highly plastic and able to regenerate following the disappearance of most taste buds after experimental nerve injury. Several growth factors needed for taste bud regeneration have been identified, but we demonstrate the first cytokine pathway required for the recovery of taste function. In the absence of IL-1 cytokine signaling, taste bud regeneration is incomplete, preventing the transmission of taste activity to the brain. These results open a new direction in revealing injury-specific mechanisms that could be harnessed to promote the recovery of taste perception after trauma or disease., (Copyright © 2023 the authors.)

Endoscopically assisted craniofacial surgery (EACS) has numerous advantages over traditional, open approaches, such as fronto-orbital advancement in treating nonsyndromic craniosynostosis. However, several articles report high reoperation rates in syndromic patients treated with EACS. This meta-analysis and review examines undesirable outcome rates (UORs), defined as reoperation or Whitaker category III/IV, in syndromic patients undergoing primary EACS compared with procedures that actively expand the cranial vault., Methods: PubMed and Embase were searched in June 2022 to identify all articles reporting primary reoperation or Whitaker outcomes for syndromic patients undergoing cranial vault expanding surgery or suturectomy. A meta-analysis of proportions was performed comparing UORs, and a trim-and-fill adjustment method was used to validate sensitivity and assess publication bias., Results: A total of 721 articles were screened. Five EACS articles (83 patients) and 22 active approach articles (478 patients) met inclusion criteria. Average UORs for EACS and active approaches were 26% (14%-38%) and 20% (13%-28%), respectively ( P = 0.18). Reoperation occurred earlier in EACS patients (13.7 months postprimary surgery versus 37.1 months for active approaches, P = 0.003). Relapse presentations and reason for reoperation were also reviewed. Subjectively, EACS UORs were higher in all syndromes except Apert, and Saethre-Chotzen patients had the highest UOR for both approaches., Conclusions: There was no statistically significant increase in UORs among syndromic patients treated with EACS compared with traditional approaches, although EACS patients required revision significantly sooner. Uncertainties regarding the long-term efficacy of EACS in children with syndromic craniosynostosis should be revisited as more data become available., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: Men with Klinefelter Syndrome develop some degree of seminiferous tubule degeneration, hyalinization, and fibrosis by adulthood. However, the pathophysiology surrounding testicular fibrosis in Klinefelter Syndrome patients remains incompletely understood., Objectives: To perform a systematic review of literature studying the mechanisms of fibrosis initiation or propagation in Klinefelter Syndrome testes., Materials/methods: PubMed was searched systematically for articles specific to Klinefelter Syndrome and the process of fibrosis. Articles that did not contain original data or specifically addressed the target material were excluded. Additional references were extracted when pertinent from the reference lists of included studies., Results: Primary search yielded 139 articles for abstract review, which was narrowed to 16 for full-text review. Following full-text review, eight contained original data and met topic criteria, with one paper added from reference review for a total of nine papers., Discussion: The date range for included papers was 1992-2022. The proposed mechanisms of fibrosis mainly were centered around the impact of altered Sertoli cells on germ cells, the hormonal impact on Leydig cells, the inflammation mediated by mast cells, or the fibrous extracellular matrix deposition by peritubular myoid cells. Additionally, discussions of the role of the altered microvasculature and the specific proteins involved in the blood-testis barrier or the seminiferous tubule architecture are reviewed. Recent papers have incorporated advanced sequencing and offer future directions for targeted gene expression analysis. Still, much of the published data consists solely of immunohistological assessment by age range, creating difficulties in extrapolating causality., Conclusion: The specific initiating factors of fibrosis of the seminiferous tubules and the propagation mechanisms unique to Klinefelter Syndrome remain incompletely understood with a relative paucity of data. Nonetheless, academic interest is increasing in this field as it may further elucidate the pathophysiology behind Klinefelter syndrome., (© 2022 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Sepsis is a leading cause of mortality in children. Utilizing a screening tool for early recognition of sepsis is recommended. Our centre had no screening tool for sepsis nor a standardized protocol for sepsis management. In December 2020, a screening algorithm for sepsis was implemented. The algorithm consisted of vital signs measurements in children with an abnormal body temperature, a pop-up alert, nurse's and physician's evaluation, and activation of a workup protocol. The project's primary aim was to increase vital signs measurement rates in hospitalized children with abnormal body temperature from 40% to >90% within 6 months, by 1 June 2021, and sustain until 31 December 2021. Adherence to the algorithm and performance were monitored during 2021, and the outcomes were compared to the preceding 5 years and a control ward. The alert identified 324 children and 596 febrile episodes. Vital signs measurement adherence increased from 42.7% to >90% in 2 months. A nurse evaluated 86.4% of episodes, and a physician evaluated 83.0% of these. Paediatric intensive care unit (PICU) admission rates were lower in the intervention period vs. the pre-intervention period vs. the control ward (4.6% vs. 5.6% vs. 6.0%, respectively); the median PICU length of stay was shorter in the intervention vs. the control ward [2.0 (IQR 1, 4) vs. 5.5 (IQR 2, 7), respectively]. These differences were not statistically significant. During the intervention period, the adherence to vital signs measurements reached the goal of >90%. The alert system prompted an evaluation by caregivers and management according to the protocol. Further monitoring is needed to improve outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Sagittal craniosynostosis (SC) is associated with scaphocephaly, an elongated narrow head shape. Assessment of regional severity in the scaphocephalic head is limited by the use of serial computed tomographic (CT) imaging or complex computer programing. Three-dimensional measurements of cranial surface morphology provide a radiation-free alternative for assessing cranial shape. This study describes the creation of an occipital bulleting index (OBI), a novel tool using surface morphology to assess the regional severity in patients with SC., Methods: Surface imaging from CT scans or 3D photographs of 360 individuals with SC and 221 normocephalic individuals were compared to identify differences in morphology. Cartesian grids were created on each individual's surface mesh using equidistant axial and sagittal planes. Area under the curve (AUC) analyses were performed to identify trends in regional morphology and create measures capturing population differences., Results: The largest differences were located in the medial regions posteriorly. Using these population trends, a measure was created to maximize AUC. The OBI has an AUC of 0.72 with a sensitivity of 74% and a specificity of 61%. When the frontal bossing index is applied in tandem, the two have a sensitivity of 94.7% and a specificity of 93.1%. Correlation between the two scores in individuals with SC was found to be negligible with an intraclass correlation coefficient of 0.018. Severity was found to be independent of age under 24 months, sex, and imaging modality., Conclusions: This index creates a tool for differentiating control head shapes from those with SC and has the potential to allow for objective evaluation of the regional severity, outcomes of different surgical techniques, and tracking shape changes in individuals over time, without the need for radiation., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The present study investigated the dyadic direct and indirect effects of enacted stigma on depressive symptoms via internalized homophobia and whether communal coping moderated the effects of enacted stigma on internalized homophobia and depressive symptoms. Hypotheses were tested using actor-partner interdependence models with a sample of 543 cisgender sexual minority male couples. Results showed both partners' enacted stigma experiences were associated with elevated levels of internalized homophobia via actor and partner effects. Internalized homophobia was only associated with elevated depressive symptoms via actor effects. Indirect effects analysis suggested that internalized homophobia mediated the actor and partner influence of enacted stigma on depressive symptoms. Communal coping moderated the direct effects of enacted stigma on internalized homophobia and attenuated the conditional indirect actor and partner effects of enacted stigma on depressive symptoms. Findings underscore the role of intimate relationship processes in understanding the impacts of enacted stigma on depressive symptoms., (© 2022 Family Process Institute.)

Objective: The development of depressive symptoms often increases in adolescence, and for Black American youth, can result in disproportionately long-lasting and deleterious outcomes. Despite the epidemiological trend, scant research has examined the longitudinal development of heterogeneous patterns of depressive symptoms among Black American youth. Moreover, less is known on the impact of contextual covariates on depressive symptom trajectories among Black American youth. The investigation into within-group differences of depressive symptoms is crucial for culturally informed interventions., Methods: The sample consisted of 472 Black American youth and their primary caregivers from eight counties in Georgia who provided data at five time points (i.e., youth ages 11 to 15). Hypotheses were tested with latent class growth analysis to investigate multiple trajectories of depressive symptoms, and examine sociocultural and familial covariates of trajectory group, including caregiver depressive symptoms, involved vigilant parenting, racial discrimination experiences, Black pride, and internalized racism., Results: Four-classes of depressive symptoms were identified including stable low (58.4%); high start, decreasing (20%); later onset (13%); and high and increasing (8.5%). Family and race-related predictors differentiated youth's depressive symptom trajectories class and identified warning signs for high-symptomology trajectories., Conclusions: Findings provide novel insights into developmental patterns of depressive symptoms and the role of contextual and sociocultural factors within a sample of Black American youth. Implications include treatment and prevention recommendations.

Objective: To study the prevalence of spermatogonia in adult subjects with Klinefelter syndrome (KS) using MAGE-A4 and UCHL1 (PGP9.5) immunohistochemistry as markers for undifferentiated spermatogonial cells. We aimed to compare this method to the gold standard of hematoxylin and eosin (H & E) staining with histologic analysis in the largest reported cohort of adult subjects with KS., Design: A retrospective cohort study., Setting: Infertility Clinic and Institute for Regenerative Medicine., Patient(s): This study consisted of 79 adult subjects with KS and 12 adult control subjects., Intervention(s): The subjects with KS (n = 79) underwent bilateral testicular biopsy in an initial effort to recover spermatozoa for in vitro fertilization and intracytoplasmic sperm injection. The institutional review board approved the use of a portion of the archived diagnostic pathology paraffin blocks for the study. The samples were superimposed onto microscopic slides and labeled with the PGP9.5 and MAGE-A4 antibodies. Subjects (n = 12) who had previously consented to be organ donors via the National Disease Research Interchange were selected as controls. Dedicated genitourinary pathologists examined the H & E-, PGP9.5-, and MAGE-A4-stained tissue for presence of undifferentiated spermatogonia and spermatozoa with the use of a virtual microscopy software., Main Outcome Measure(s): The primary outcome was the presence of MAGE-A4-positive or UCHL1-positive tubules that indicate undifferentiated spermatogonia. Supportive outcomes include assessing the biopsy specimen for the following: total surface area; total seminiferous tubule surface area; total interstitium surface area; the total number of seminiferous tubules; and MAGE-A4- negative or UCHL1-negative tubules. Additionally, clinical information, such as age, karyotype, height, weight, mean testicle size, and hormonal panel (luteinizing hormone, follicle-stimulating hormone, and testosterone), was obtained and used in a single and multivariable analysis with linear regression to determine predictive factors for the number of UCHL1-positive tubules., Result(s): The mean age of the subjects in the KS group was 32.9 ± 0.7 years (range, 16-48). UCHL1 (PGP9.5) and MAGE-A4 staining showed that 74.7% (n = 59) and 40.5% (n = 32) of the subjects with KS, respectively, were positive for undifferentiated spermatogonia compared with 100% (n = 12) of the control subjects who were positive for both the markers. Hematoxylin and eosin with microscopic analysis showed that only 10.1% (n = 8) of the subjects were positive for spermatogonia. The mean number of positive tubules per subject with KS was 11.8 ± 1.8 for UCHL1 and 3.7 ± 1.0 for MAGE-A4. Secondary analysis showed 7 (8.9%) adult subjects with KS as positive for spermatozoa on biopsy. The population having negative testicular sperm extraction results (n = 72) showed a spermatogonia-positive rate of 1.4%, (n = 1), 72.2% (n = 52), and 34.7% (n = 25) using H & E, UCHL1, and MAGE-A4, respectively. Further analysis showed that 54 (75.0%) subjects were either positive for UCHL1 or MAGE-A4. Twenty (27.8%) subjects were positive for both UCHL1 and MAGE-A4. Multivariate analysis with linear regression showed no significant correlation between clinical variables and the number of UCHL1-positive tubules found on biopsy specimens., Conclusion(s): We report a cohort of adult subjects with KS undergoing analysis for the presence of undifferentiated spermatogonia. UCHL1 and MAGE-A4 immunostaining appear to be an effective way of identifying undifferentiated spermatogonia in testicular biopsy specimens of subjects with KS. Despite observing deterioration in the testicular architecture, many patients remain positive for undifferentiated spermatogonia, which could be harvested and potentially used for infertility therapy in a patient with KS who is azoospermic and has negative testicular sperm extraction results., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Klinefelter Syndrome (KS) is characterized by a masculine phenotype, supernumerary sex chromosomes (47, XXY), and impaired fertility due to loss of spermatogonial stem cells (SSCs). Early testicular cryopreservation could be an option for future fertility treatments in these patients, including SSCs transplantation or in vitro spermatogenesis. It is critically essential to adapt current in vitro SSCs propagation systems as a fertility option for KS patients. KS human testicular samples (13,15- and 17-year-old non-mosaic KS boys) were donated by patients enrolled in an experimental testicular tissue banking program. Testicular cells were isolated from cryopreserved tissue and propagated in long-term culture for 110 days. Cell-specific gene expression confirmed the presence of all four main cell types found in testes: Spermatogonia, Sertoli, Leydig, and Peritubular cells. A population of ZBTB16 + undifferentiated spermatogonia was identified throughout the culture using digital PCR. Flow cytometric analysis also detected an HLA - /CD9 + /CD49f + population, indicating maintenance of a stem cell subpopulation among the spermatogonial cells. FISH staining for chromosomes X and Y showed most cells containing an XXY karyotype with a smaller number containing either XY or XX. Both XY and XX populations were able to be enriched by magnetic sorting for CD9 as a spermatogonia marker. Molecular karyotyping demonstrated genomic stability of the cultured cells, over time. Finally, single-cell RNAseq analysis confirmed transcription of ID4, TCN2, and NANOS 3 within a population of putative SSCs population. This is the first study showing successful isolation and long-term in vitro propagation of human KS testicular cells. These findings could inform the development of therapeutic fertility options for KS patients, either through in vitro spermatogenesis or transplantation of SSC, in vivo ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Galdon, Deebel, Zarandi, Teramoto, Lue, Wang, Swerdloff, Pettenati, Kearns, Howards, Kogan, Atala and Sadri-Ardekani.)

The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints 1,2 . Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function 3-10 . Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment., (© 2022. The Author(s).)

The prevalence of female hair loss and hair thinning increases with advancing age and is most common among post-menopausal women. Recent statistics show that by age 60, an estimated 80% of women experience hair loss. A previous publication detailing the results of the 6-month randomized, double-blind, placebo-controlled phase of this study demonstrated the ability of a nutraceutical supplement to significantly improve hair growth and shedding compared to placebo. Here, we present results from a subsequent 6-month, open-label extension phase assessing the continued safety and efficacy of this nutraceutical for promoting and improving hair growth and evaluate potential long-term benefits on quality of life and menopausal symptoms. After a total of 12 months with the active nutraceutical, subjects had progressive improvements in hair growth, quality, and shedding. Quality of life measures and menopausal symptoms also improved over the duration of the study. When transitioned to daily intake of the supplement, subjects previously treated with placebo achieved significant increases in all hair counts, a significant decrease in shedding, and significant improvement in blinded investigator global hair growth and quality assessments. The results of this long-term study demonstrate that continued use of a novel nutraceutical provides significant incremental improvement over the beneficial effects achieved during the initial 6-month randomized, placebo-controlled phase. Continued use may provide ongoing improvements in hair growth and exert a positive effect on secondary symptoms of menopause, and quality of life in perimenopausal, menopausal, and postmenopausal women with selfperceived thinning hair (ClinicalTrials.gov Identifier: NCT04048031). J Drugs Dermatol. 2022;21(7):776-783. doi:10.36849/JDD.6912.

Background: Direct-acting oral anticoagulants are first-line agents for prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF), but data are limited for the oldest patients, and with reduced dosing., Objectives: To determine steady-state apixaban peak and trough concentrations during routine care of older adults with NVAF, compare concentrations to clinical trial concentrations, and explore factors associated with concentrations., Methods: A cross-sectional study of medically stable older adults with NVAF (≥75 years or ≥70 years if Black) receiving apixaban. Peak (2-4.4 hours post-dose) and trough (before next dose) concentrations were determined by anti-Xa activity calibrated chromogenic assay. Patient characteristics associated with concentrations were determined by multivariate modeling., Results: The median age of patients (n = 115) was 80 (interquartile range: 77-84) years. The cohort comprised 46 women and 69 men; of which 98 are White, 11 Black, and 6 Asian. With 5 mg twice daily per labelling (n = 88), peak concentrations were higher in women: 248 ± 105 vs 174 ± 67 ng/mL in men ( P < 0.001) and exceeded expected 95% range in 6 of 30 vs 0 of 55 men ( P = 0.002). With 2.5 mg twice daily per label (n = 11), concentrations were <5 mg twice daily (peak: 136 ± 87 vs 201 ± 90 ng/mL, P = 0.026; trough: 65 ± 28 vs 109 ± 56 ng/mL, P < 0.001), but not different than 2.5 mg twice daily without reduction criteria (n = 13; peak: 132 ± 88; trough: 65 ± 31 ng/mL). Covariates associated with concentrations included sex, number of daily medications, and creatinine clearance., Conclusions: Older women had higher than expected peak apixaban concentrations, and 2.5 mg twice daily produced lower concentrations than standard dosing. Factors not currently included in dosing recommendations affected concentrations. The impact of apixaban concentrations on outcomes needs evaluation.

Objective: The goal of this study was to assess the perceived efficacy of a standardized nutraceutical to improve hair growth and quality in men and women of various ethnicities with self-perceived hair thinning., Methods: This prospective, single-blind study enrolled healthy men aged 20 to 55 years (n=47) and premenopausal women aged 20 to 45 years (n=51) with self-perceived, mild-to-moderate hair thinning and included African American, Asian, Hispanic Caucasian and Non-Hispanic Caucasian participants. The nutraceutical supplement (Nutrafol® Men or Women Capsules, Nutraceutical Wellness Inc., New York, New York) was taken daily for six months. Subjects were evaluated in the clinic at baseline and Weeks 12 and 24 with two self-assessments at Weeks 4 and 8. Study endpoints were standardized digital imaging and investigator rated assessments. Self-assessment questionnaires rated hair growth, hair satisfaction, and lifestyle factors., Results: Investigator ratings for baseline hair growth, coverage, density, and volume were significant at Weeks 12 and 24 for all subjects (for each, p <0.001). These significant improvements were seen in 83.7 percent of men and 79.5 percent of women at Week 24. Results were similar across ethnic subgroups with significant benefit at Weeks 12 and 24 (for each, p <0.05). All subjects reported significant improvements in baseline hair appearance/quality, volume/fullness, scalp coverage, thickness, and shedding at Weeks 4, 8, 12 and 24 (for each, p <0.01)., Conclusion: A standardized nutraceutical supplement improved visible hair growth with less notable shedding based on subjects' and investigators' overall perception of treatment benefit for men and women of various ethnic backgrounds., Competing Interests: DISCLOSURES: Ms. Berkowitz and Drs. Marshall, Kogan, and Raymond are employees of Nutraceutical Wellness, LLC., (Copyright © 2022. Matrix Medical Communications. All rights reserved.)

Klinefelter syndrome (KS) is characterized by a masculine phenotype, supernumerary sex chromosomes (usually XXY), and spermatogonial stem cell (SSC) loss in their early life. Affecting 1 out of every 650 males born, KS is the most common genetic cause of male infertility, and new fertility preservation strategies are critically important for these patients. In this study, testes from 41, XXY prepubertal (3-day-old) mice were frozen-thawed. Isolated testicular cells were cultured and characterized by qPCR, digital PCR, and flow cytometry analyses. We demonstrated that SSCs survived and were able to be propagated with testicular somatic cells in culture for up to 120 days. DNA fluorescent in situ hybridization (FISH) showed the presence of XXY spermatogonia at the beginning of the culture and a variety of propagated XY, XX, and XXY spermatogonia at the end of the culture. These data provide the first evidence that an extra sex chromosome was lost during innate SSC culture, a crucial finding in treating KS patients for preserving and propagating SSCs for future sperm production, either in vitro or in vivo. This in vitro propagation system can be translated to clinical fertility preservation for KS patients.