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Background: X chromosome parent of origin (POX) has been proposed as a source of phenotypic variation within sex chromosome aneuploidies such as Klinefelter syndrome (XXY/KS) and between XX and XY individuals. However, previous studies have yielded conflicting results regarding the presence and nature of POX effects, which we sought to clarify in an expanded sample with deeper neurobehavioral phenotyping. Methods: A cohort of 58 individuals with XXY/KS underwent duo or trio genome sequencing with parents (n = 151), measurement of 66 neurobehavioral phenotypes by standardized research assessments, and measurement of over 1000 anatomical phenotypes by structural magnetic resonance imaging. We developed a novel algorithm, the uniparental disomy visualization for variant call format files, to determine proband POX and then systematically tested for POX associations with all neurobehavioral and neuroanatomical outcomes. Results: The uniparental disomy visualization for variant call format files algorithm showed maternal POX in 35 of 58 cases (60.3%). There were no statistically significant POX effects on any of the 66 subscale measures of cognition, psychopathology, or behavior. Neuroimaging analysis identified 2 regions in the right hemisphere with significantly higher surface area (mean effect size = 1.20) among individuals with paternal versus maternal POX (q = .021). Conclusions: Using deeper phenotyping in an expanded sample, we did not find evidence for substantial POX effects on neurobehavioral variability, except for localized unilateral modulations of surface area in the absence of co-occurring behavioral associations. These findings help to clarify previous inconsistencies in POX research and direct attention toward other sources of clinical variability in sex chromosome aneuploidies.

Human induced pluripotent stem cell (iPSC) lines were generated from peripheral blood mononuclear cells (PBMCs) isolated from two related patients diagnosed with either idiopathic ventricular fibrillation or catecholaminergic polymorphic ventricular tachycardia, carrying an unknown variant in the RYR2 gene, c.14201A>G (p.Y4734C) and one healthy related individual. Reprogramming was done using a commercially available Epi5 Reprogramming Kit. The pluripotency of the iPSC lines was verified by the expression of pluripotency markers and by their capacity to differentiate into all three embryonic germ layers in vitro. These iPSC lines are available for functional analysis and in vitro studies of RYR2 channelopathy.

Objective: Necrotizing enterocolitis (NEC) continues to have high surgical mortality despite progressive regionalization to children's hospitals. It is unclear whether outcomes for patients with NEC undergoing surgery vary depending on volume of these children's hospitals. This study aimed to examine the relationship between operative outcomes and a hospital's overall NEC patient volume, as well as operative volume for NEC across children's hospitals. Methods: A retrospective, cross sectional analysis was performed using the Pediatric Health Information System (PHIS). NEC patients were identified using ICD-10 codes from 2016-2021. Two hospital volume metrics were used: annual volume of NEC patients treated in the NICU, and annual volume of NEC patients undergoing surgery. Primary outcome was mortality and secondary outcome was complication. Regression models were estimated to determine the association between each volume metric and patient outcomes. Results: A total of 1780 children who had surgery for NEC from 47 tertiary children's hospitals were included. Overall mortality rate was 23.3%. Median overall and surgical NEC patient volume per hospital were 53 [IQR 41-65] and 11 [IQR 7-16], respectively. A chi-squared test comparing mortality to volume metrics for total NEC volume, and surgical NEC volume showed no significant associations (p=0.07, p=0.74). Simple logistic regression demonstrated total NEC patient volume to have best fit with mortality outcome. Conclusion: No statistically significant association was found between the two volume metrics and discharge mortality. This lack of association suggests that the volume in these tertiary children's hospitals may be higher than the threshold for optimized outcomes. Level of Evidence: III

Summary: Upon exposure to a bacterial pore-forming toxin, enterocytes rapidly purge their apical cytoplasm into the gut lumen, resulting in a thin intestinal epithelium. The enterocytes regain their original shape and thickness within 16 h after the ingestion of the bacteria. Here, we show that the regrowth of Drosophila enterocytes entails an inversion of metabolic fluxes from the organism back toward the intestine. We identify a proton-assisted transporter, Arcus, that is required for the reverse absorption of amino acids and the timely recovery of the intestinal epithelium. Arcus is required for a peak of amino acids appearing in the hemolymph shortly after infection. The regrowth of enterocytes involves the insulin signaling pathway and Myc. The purge decreases Myc mRNA levels, which subsequently remain at low levels in the arcus mutant. Interestingly, the action of arcus and Myc in the intestinal epithelium is not cell-autonomous, suggesting amino acid fluxes within the intestinal epithelium.

This paper investigates how horizontal and vertical individualism and collectivism predict self-report loneliness in addition to the variance accounted for by age and sex in 28 countries (N = 8,345). Horizontal and vertical aspects of individualism and collectivism had small but significant contributions to predicting loneliness. Horizontal-collectivism (for 19 country samples) and, to a lesser extent, horizontal-individualism (for seven country samples), significantly predicted lower loneliness scores. Vertical-individualism (for 16 country samples), and to a lesser extent, vertical-collectivism (for six country samples), predicted feeling more loneliness among our participants. Adjusted R2 values suggested that between 0.6% and 27.7% of self-report loneliness was predicted. These results suggest that those who value egalitarian social relations also tend to report being less lonely whereas those who value individuality and competitiveness endorse the loneliness items more. These results are of importance to those investigating and helping lonely individuals by appreciating the influence of perceived culture.

Summary: Background: Chikungunya virus (CHIKV) has expanded its geographical reach in recent decades and is an emerging global health threat. CHIKV can cause significant morbidity and lead to chronic, debilitating arthritis/arthralgia in up to 40% of infected individuals. Prevention, early identification, and clinical management are key for improving outcomes. The aim of this review is to evaluate the quality, availability, inclusivity, and scope of evidence-based clinical management guidelines (CMG) for CHIKV globally. Methods: We conducted a systematic review. Six databases were searched from Jan 1, 1989, to 14 Oct 2021 and grey literature until Sept 16, 2021, for CHIKV guidelines providing supportive care and treatment recommendations. Quality was assessed using the appraisal of Guidelines for Research and Evaluation tool. Findings are presented in a narrative synthesis. PROSPERO registration: CRD42020167361. Findings: 28 CMGs were included; 54% (15/28) were produced more than 5 years ago, and most were of low-quality (median score 2 out of 7 (range 1–7)). There were variations in the CMGs’ guidance on the management of different at-risk populations, long-term sequelae, and the prevention of disease transmission. While 54% (15/28) of CMGs recommended hospitalisation for severe cases, only 39% (11/28) provided guidance for severe disease management. Further, 46% (13/28) advocated for steroids in the chronic phase, but 18% (5/28) advised against its use. Interpretation: There was a lack of high-quality CMGs that provided supportive care and treatment guidance, which may impact patient care and outcomes. It is essential that existing guidelines are updated and adapted to provide detailed evidence-based treatment guidelines for different at-risk populations. This study also highlights a need for more research into the management of the acute and chronic phases of CHIKV infection to inform evidence-based care. Funding: The UK Foreign, Commonwealth and Development Office, Wellcome Trust [215091/Z/18/Z] and the Bill & Melinda Gates Foundation [OPP1209135].

Women who use drugs shoulder a disproportionate burden of the HIV epidemic in Tanzania. The mechanisms through which violence contributes to their excessively high rates of HIV have not been explored. In this paper, we use concepts of everyday, symbolic, and structural violence to critically examine the relationship between violence and heightened HIV vulnerability of women who use drugs in Dar es Salaam, Tanzania. We conducted cross-sectional surveys with 200 women who use drugs and follow-up, in-depth interviews with 30 survey participants who identified as living with HIV between November 2018 and March 2019. We drew from grounded theory methods to analyze qualitative data and complemented qualitative findings with survey results. Structural violence perpetuated constraints on women's economic opportunities and reduced their agency in sexual encounters manifesting in their disproportionately high rates of HIV. Nearly all women in our study engaged in sex work to meet basic needs and to support their drug use. Their involvement in overlapping drug use and sex work scenes exposed them to physical and sexual violence. Despite the pervasiveness of structural and everyday violence, some women reenacted agency by adopting strategies to maintain control and safety, and to exercise harm reduction. A multi-pronged, structural harm reduction strategy is critical to reducing violence experienced by women who use drugs and their ability to protect themselves from HIV.

Previous work has shown systemic knockdown of the long form prolactin receptor (LFPRLR) in vivo markedly reduced metastasis in mouse models of breast cancer, but whether this translated to prolonged survival was unknown. Here we show that LFPRLR knockdown in the highly metastatic, immunocompetent 4T1 model prolonged survival and reduced recruitment of T regulatory cells (Tregs) to the tumor through effects on the production of CCL17. For the Tregs still recruited to the primary tumor, LFPRLR knockdown both directly and indirectly reduced their ability to promote tumor parenchymal epithelial to mesenchymal transition. Importantly, effects of prolactin on expression of mesenchymal genes by the tumor parenchyma were very different in the absence and presence of Tregs. While systemic knockdown of the LFPRLR downregulated transcripts important for immune synapse function in the remaining tumor Tregs, splenic Tregs seemed unaffected by LFPRLR knockdown, as demonstrated by their continued ability to suppress anti-CD3/CD28-stimulated effector cell proliferation at 1–5 months. These results demonstrate that knockdown of the LFPRLR achieves intra-tumor immunotherapeutic effects and suggest this occurs with reduced likelihood of peripheral inflammatory/autoimmune sequelae.

Fear is a powerful driver of human behavior, even more during times of crisis. Panic buying occurs when fear and panic influence behavior leading people to buy more things than usual. So far, no specific scale on this has been found in the major databases, thus the aim of this exploratory study is to develop a Panic Buying Scale (PBS) during COVID-19 pandemic. 393 Brazilians took part in this study (251 women and 142 men), answering a sociodemographic questionnaire and instruments of these variables: (1)panic buying, (2)impulse buying, (3)temporal focus, (4)optimism, (5)risk perception, (6)need for cognition. Data collection was conducted through an online questionnaire which was shared through social media networks, from April 10th to May 4th, 2020. Factorial exploratory and confirmatory analysis indicated that PBS has a unidimensional solution and showed satisfactory reliability indexes. Results revealed that men buy more by panic than women. PBS also was positively correlated with impulse buying, past and future temporal focus, and risk perception; as well as negatively correlated with optimism and age. Findings suggest that PBS is psychometrically acceptable in the Brazilian context. This new instrument can be useful to understand the psychosocial phenomena associated with consumer behavior. Future investigations could provide more evidences of validity in other contexts.

PACE4 is a proprotein convertase (PC) responsible for cleaving and activating proteins that contribute to enhance tumor progression. PACE4 overexpression significantly increased the susceptibility to carcinogenesis, leading to enhanced tumor cell proliferation and premature degradation of the basement membrane. In the present study, we sought to evaluate a novel approach to retard skin tumor progression based on the inhibition of PACE4. We used decanoyl-RVKR-chloromethylketone (CMK), a small-molecule PC inhibitor, for in vitro and in vivo experiments. We found that CMK-dependent blockage of PACE4 activity in skin squamous cell carcinoma cell lines resulted in impaired insulin-like growth factor 1 receptor maturation, diminished its intrinsic tyrosine dnase activity, and decreased tumor cell proliferation. Two-stage skin chemical carcinogenesis experiments, together with topical applications of CMK, demonstrated that this PC inhibitor markedly reduced tumor incidence, tumor multiplicity, and metastasis, pointing to a significant delay in tumor progression in wild-type and PACE4 transgenic mice. These results identify PACE4, together with other PCs, as suitable targets to slow down or block tumor progression, suggesting that PC inhibition is a potential approach for therapy for solid tumors.