Patients undergoing multiligament knee reconstruction injured during pivoting sports demonstrate similar clinical, functional and return to sport outcomes by 2 years compared with those undergoing anterior cruciate ligament reconstruction.

PURPOSE: This study investigates the clinical and activity-based outcomes after anterior cruciate ligament reconstruction (ACLR) versus multiligamentous knee reconstruction (MLKR) following a pivoting sports injury. METHODS: Fifty MLKR patients were included, of which 20 (40%) were injured during pivoting sports. A further 50 patients undergoing ACLR following an injury during pivoting sports were consecutively recruited for comparison. Patients were assessed before the surgery and at 6-, 12- and 24 months with patient-reported outcome measures (PROMs) including the International Knee Documentation Committee (IKDC) form, Tegner activity scale (TAS) and anterior cruciate ligament return to sport after injury (ACL-RSI) score. Knee movement, the single (SHD) and triple (THD) hop tests for distance, and peak isokinetic knee extensor and flexor strength were assessed, with Limb Symmetry Indices (LSIs) calculated. Outcomes were compared across groups: (1) ACLR (n = 50), (2) MLKR (n = 50) and (3) MLKR due to pivoting sport injury (n = 20). RESULTS: IKDC, TAS and ACL-RSI scores remained lower (p < 0.05) in the full MLKR versus ACLR cohort at all timepoints. Comparing the ACLR and MLKR cohort that had injuries specifically during pivoting sports, the IKDC (p < 0.001) and TAS (p = 0.009) were higher in the ACLR group at 6 months, and the ACL-RSI was higher at 6 (p < 0.001) and 12 (p = 0.007) months, there were no further differences. Hop and knee extensor strength LSIs were lower (p < 0.05) in the full MLKR (versus ACLR) cohort at all timepoints (apart from the 24-month SHD LSI). However, the ACLR group only demonstrated greater LSIs than the pivoting sport MLKR for the SHD at 6 months (p < 0.001), and knee extensor strength at 6 (p < 0.001) and 12 (p < 0.001) months. CONCLUSIONS: While the recovery of patients undergoing MLKR due to a pivoting sports injury is delayed compared with their ACLR counterparts, the clinical outcome and activity profile are similar by 24 months. LEVEL OF EVIDENCE: Level IV.

Trends in use of intensive care during hospitalizations at the end-of-life among older adults with advanced cancer.

BACKGROUND: High-intensity end-of-life (EOL) care, marked by admission to intensive care units (ICUs) or in-hospital death, can be costly and burdensome. Recent trends in use of ICUs, life-sustaining treatments (LSTs), and noninvasive ventilation (NIV) during EOL hospitalizations among older adults with advanced cancer and patterns of in-hospital death are unknown. METHODS: We used SEER-Medicare data (2003-2017) to identify beneficiaries with advanced solid cancer (summary stage 7) who died within 3 years of diagnosis. We identified EOL hospitalizations (within 30 days of death), classifying them by increasing intensity of care into: (1) without ICU; (2) with ICU but without LST (invasive mechanical ventilation, tracheostomy, gastrostomy, acute dialysis) or NIV; (3) with ICU and NIV but without LST; and (4) with ICU and LST use. We constructed a multinomial regression model to evaluate trends in risk-adjusted hospitalization, overall and across hospitalization categories, adjusting for sociodemographics, cancer characteristics, comorbidities, and frailty. We evaluated trends in in-hospital death across categories. RESULTS: Of 226,263 Medicare beneficiaries with advanced cancer, 138,305 (61.1%) were hospitalized at EOL [Age, Mean (SD):77.9(7.1) years; 45.5% female]. Overall, EOL hospitalizations remained high throughout, from 78.1% (95% CI: 77.4, 78.7) in 2004 to 75.5% (95% CI: 74.5, 76.2) in 2017. Hospitalizations without ICU use decreased from 49.3% (95% CI: 48.5, 50.2) to 35.0% (95% CI: 34.2, 35.9) while hospitalizations with more intensive care increased, from 23.7% (95% CI: 23.0, 24.4) to 28.7% (95% CI: 27.9, 29.5) for ICU without LST or NIV, 0.8% (95% CI: 0.6, 0.9) to 3.8% (95% CI: 3.4, 4.1) for ICU with NIV but without LST, and 4.3% (95% CI: 4.0, 4.7) to 8.0% (95% CI: 7.5, 8.5) for ICU with LST use. Among those who experienced in-hospital death, the proportion receiving ICU care increased from 46.5% to 65.0%. CONCLUSIONS: Among older adults with advanced cancer, EOL hospitalization rates remained stable from 2004-2017. However, intensity of care during EOL hospitalizations increased as evidenced by increasing use of ICUs, LSTs, and NIV.

Uncovering Nanoindention Behavior of Amorphous/Crystalline High-Entropy-Alloy Composites.

Amorphous/crystalline high-entropy-alloy (HEA) composites show great promise as structural materials due to their exceptional mechanical properties. However, there is still a lack of understanding of the dynamic nanoindentation response of HEA composites at the atomic scale. Here, the mechanical behavior of amorphous/crystalline HEA composites under nanoindentation is investigated through a large-scale molecular dynamics simulation and a dislocation-based strength model, in terms of the indentation force, microstructural evolution, stress distribution, shear strain distribution, and surface topography. The results show that the uneven distribution of elements within the crystal leads to a strong heterogeneity of the surface tension during elastic deformation. The severe mismatch of the amorphous/crystalline interface combined with the rapid accumulation of elastic deformation energy causes a significant number of dislocation-based plastic deformation behaviors. The presence of surrounding dislocations inhibits the free slip of dislocations below the indenter, while the amorphous layer prevents the movement or disappearance of dislocations towards the substrate. A thin amorphous layer leads to great indentation force, and causes inconsistent stacking and movement patterns of surface atoms, resulting in local bulges and depressions at the macroscopic level. The increasing thickness of the amorphous layer hinders the extension of shear bands towards the lower part of the substrate. These findings shed light on the mechanical properties of amorphous/crystalline HEA composites and offer insights for the design of high-performance materials.

Stress granule formation helps to mitigate neurodegeneration.

Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known. To address this, we took advantage of the alphavirus protein nsP3, which selectively binds dimers of the central stress granule nucleator protein G3BP and markedly reduces stress granule formation without directly impacting the protein translational inhibitory pathways that trigger stress granule formation. In Drosophila and rodent neurons, reducing stress granule formation with nsP3 had modest impacts on lifespan even in the setting of serial stress pathway induction. In contrast, reducing stress granule formation in models of ataxia, amyotrophic lateral sclerosis and frontotemporal dementia largely exacerbated disease phenotypes. These data support a model whereby stress granules mitigate, rather than promote, neurodegenerative cascades.

PRAME expression in melanoma is negatively regulated by TET2-mediated DNA hydroxymethylation.

Preferentially Expressed Antigen in Melanoma (PRAME) and Ten-Eleven Translocation (TET) dioxygenase-mediated 5-hydroxymethylcytosine (5hmC) are emerging melanoma biomarkers. We observed an inverse correlation between PRAME expression and 5hmC levels in benign nevi, melanoma in situ, primary invasive melanoma, and metastatic melanomas via immunohistochemistry and multiplex immunofluorescence: nevi exhibited high 5hmC and low PRAME, whereas melanomas showed the opposite pattern. Single-cell multiplex imaging of melanoma precursors revealed that diminished 5hmC coincides with PRAME upregulation in premalignant cells. Analysis of TCGA and GTEx databases confirmed a negative relationship between TET2 and PRAME mRNA expression in melanoma. Additionally, 5hmC levels were reduced at the PRAME 5' promoter in melanoma compared to nevi, suggesting a role for 5hmC in PRAME transcription. Restoring 5hmC levels via TET2 overexpression notably reduced PRAME expression in melanoma cell lines. These findings establish a function of TET2-mediated DNA hydroxymethylation in regulating PRAME expression and demonstrate epigenetic reprogramming as pivotal in melanoma tumorigenesis. Teaser: Melanoma biomarker PRAME expression is negatively regulated epigenetically by TET2-mediated DNA hydroxymethylation.

Quercetin enhances decidualization through AKT-ERK-p53 signaling and supports a role for senescence in endometriosis.

BACKGROUND: Patients with endometriosis suffer with chronic pelvic pain and infertility, and from the lack of pharmacologic therapies that consistently halt disease progression. Differences in the endometrium of patients with endometriosis vs. unaffected controls are well-documented. Specifically, shed endometrial tissues (delivered to the pelvic cavity via retrograde menstruation) reveal that a subset of stromal cells exhibiting pro-inflammatory, pro-fibrotic, and pro-senescence-like phenotypes is enhanced in endometriosis patients compared to controls. Additionally, cultured biopsy-derived endometrial stromal cells from endometriosis patients exhibit impaired decidualization, a defined differentiation process required for human embryo implantation and pregnancy. Quercetin, a senolytic agent, shows therapeutic potential for pulmonary fibrosis, a disorder attributed to senescent pulmonary fibroblasts. In rodent models of endometriosis, quercetin shows promise, and quercetin improves decidualization in vitro. However, the exact mechanisms are not completely understood. Therefore, we investigated the effects of quercetin on menstrual effluent-derived endometrial stromal cells from endometriosis patients and unaffected controls to define the signaling pathways underlying quercetin's effects on endometrial stromal cells. METHODS: Menstrual effluent-derived endometrial stromal cells were collected and cultured from unaffected controls and endometriosis patients and then, low passage cells were treated with quercetin (25 µM) under basal or standard decidualization conditions. Decidualization responses were analyzed by measuring the production of IGFBP1 and PRL. Also, the effects of quercetin on intracellular cAMP levels and cellular oxidative stress responses were measured. Phosphokinase arrays, western blotting, and flow cytometry methods were performed to define the effects of quercetin on various signaling pathways and the potential mechanistic roles of quercetin. RESULTS: Quercetin significantly promotes decidualization of control- and endometriosis-endometrial stromal cells. Quercetin substantially reduces the phosphorylation of multiple signaling molecules in the AKT and ERK1/2 pathways, while enhancing the phosphorylation of p53 and total p53 levels. Furthermore, p53 inhibition blocks decidualization while p53 activation promotes decidualization. Finally, we provide evidence that quercetin increases apoptosis of endometrial stromal cells with a senescent-like phenotype. CONCLUSIONS: These data provide insight into the mechanisms of action of quercetin on endometrial stromal cells and warrant future clinical trials to test quercetin and other senolytics for treating endometriosis.

Effects of Planarization of the Triphenylamine Unit on the Electronic and Transport Properties of Triarylamine-Fluorene Copolymers in Both Doped and Undoped Forms.

Triarylamine-alt-fluorene (TAF) copolymers are widely used for hole injection and transport in organic electronics. Despite suggestions to planarize the triphenylamine moiety, little research has been conducted. Here, we report a comprehensive investigation of the effects of planarization on the electronic and transport properties of a model TAF polymer semiconductor core. We compared the conventional twisted-propeller N-4-methoxyphenyl-N,N-diphenylamine-4',4″-diyl (TA) unit and its planarized bridged analogue (bTA) where adjacent o,o'-positions are linked by 1,1-dimethylmethylene. We studied both polyelectrolyte and non-polyelectrolyte forms of this core in both doped and undoped states. We found that planarization leads to an unprecedented trap-free transport of holes, and a pronounced enhancement of their mobility in the undoped state though less so in the doped state. Planarization also induces a slight reduction in the ionization energy of the undoped polymer, consequently lowering the work function of the doped polymer. This is accompanied by small spectral shifts: a red shift in the first absorption band of the undoped polymer and a blue shift in the first absorption band of the polaron. Furthermore, this study unveils new fundamental features of TAF polymers: (i) Doping induces the formation of three polaron bands within the subgap. (ii) Absorption of both neutral and polaron segments exhibit a linear intensity relationship with doping level. (iii) Electrical conductivity reaches a maximum at the half-doped state, varying as σ ∼ (x (1 - x))3 for 0.1 ≲ x ≲ 0.9, where x is the doping level. Finally, we demonstrate the successful integration of these self-compensated hole-doped TAF polymers as efficient hole injection layers in organic semiconductor diodes.

Synchronized Temporal-spatial Analysis via Microscopy and Phoshoproteomics (STAMP) of Quiescence.

Tightly coordinated cell cycle regulation is essential for homeostasis. G 0 , or quiescence, is especially crucial for cells to respond to extracellular stimuli. Little is known about the mechanisms that establish the G 0 program, though the primary cilium (a key signaling hub formed only in G 0 ) is the most widely recognized marker. The study of ciliogenesis is challenging due to its small size, relative to the cell body. To address this gap in our understanding, we developed STAMP (Spatio-Temporal Analysis via Microscopy and Proteomics) to temporally map the changes in cellular landscape occurring in G 0 and ciliogenesis. Using synchronized RPE cells, we used fixed and live cell imaging combined with phosphoproteomics to uncover new signals and order them in these processes, which also allows further, more targeted, analyses (e.g., using genetic and pharmacological perturbations). We propose that STAMP is broadly applicable for studying temporal-spatial signaling processes and the underlying mechanisms in various biological contexts and cell types.

Sharing Data from the Human Tumor Atlas Network through Standards, Infrastructure, and Community Engagement.

The Data Coordinating Center (DCC) of the Human Tumor Atlas Network (HTAN) has played a crucial role in enabling the broad sharing and effective utilization of HTAN data within the scientific community. Data from the first phase of HTAN are now available publicly. We describe the diverse datasets and modalities shared, multiple access routes to HTAN assay data and metadata, data standards, technical infrastructure and governance approaches, as well as our approach to sustained community engagement. HTAN data can be accessed via the HTAN Portal, explored in visualization tools-including CellxGene, Minerva, and cBioPortal-and analyzed in the cloud through the NCI Cancer Research Data Commons nodes. We have developed a streamlined infrastructure to ingest and disseminate data by leveraging the Synapse platform. Taken together, the HTAN DCC's approach demonstrates a successful model for coordinating, standardizing, and disseminating complex cancer research data via multiple resources in the cancer data ecosystem, offering valuable insights for similar consortia, and researchers looking to leverage HTAN data.

Increasing aggregate size reduces single-cell organic carbon incorporation by hydrogel-embedded wetland microbes.

Microbial degradation of organic carbon in sediments is impacted by the availability of oxygen and substrates for growth. To better understand how particle size and redox zonation impact microbial organic carbon incorporation, techniques that maintain spatial information are necessary to quantify elemental cycling at the microscale. In this study, we produced hydrogel microspheres of various diameters (100, 250, and 500 µm) and inoculated them with an aerobic heterotrophic bacterium isolated from a freshwater wetland (Flavobacterium sp.), and in a second experiment with a microbial community from an urban lacustrine wetland. The hydrogel-embedded microbial populations were incubated with 13C-labeled substrates to quantify organic carbon incorporation into biomass via nanoSIMS. Additionally, luminescent nanosensors enabled spatially explicit measurements of oxygen concentrations inside the microspheres. The experimental data were then incorporated into a reactive-transport model to project long-term steady-state conditions. Smaller (100 µm) particles exhibited the highest microbial cell-specific growth per volume, but also showed higher absolute activity near the surface compared to the larger particles (250 and 500 µm). The experimental results and computational models demonstrate that organic carbon availability was not high enough to allow steep oxygen gradients and as a result, all particle sizes remained well-oxygenated. Our study provides a foundational framework for future studies investigating spatially dependent microbial activity in aggregates using isotopically labeled substrates to quantify growth.

Malnutrition in hospitalized adults in the United States, 2016-2019.

BACKGROUND: Malnutrition in hospitalized patients is associated increased length of stay, cost, readmission, and death. No recent studies have examined trends in prevalence or outcomes of hospitalized patients with a diagnosis of malnutrition. OBJECTIVES: To study the prevalence of malnutrition diagnostic codes and associated hospital outcomes in the United States between 2016 and 2019. METHODS: We conducted a retrospective trends study to identify use of malnutrition codes in hospitalizations in the National Inpatient Sample between 2016 and 2019. We used direct standardization by logistic regression to adjust outcomes of percutaneous gastrostomy tube placement, mechanical ventilation, and death for age, Gagne comorbidity score, and sex. We then used linear regression to test for trends over time by malnutrition type. RESULTS: Across all hospitalizations, codes for diagnoses of non-severe malnutrition and severe malnutrition were present in 3.7% and 4.1% of hospitalizations, respectively. Codes for any malnutrition increased over time, from 6.6% in 2016 to 8.6% in 2018 (p = .03). Codes for severe malnutrition increased from 3.3% to 4.7% (p = .01). Among hospitalizations with coded severe malnutrition diagnoses, there was a statistically significant decrease in adjusted rate of death over time (-0.54% per year, p = .03) which was not seen in hospitalizations without coded malnutrition diagnoses. CONCLUSIONS: Use of malnutrition diagnosis codes increased significantly from 2016 to 2019. During this time, mortality among hospitalizations with a diagnosis code for severe malnutrition decreased. Though the increased prevalence of malnutrition codes may represent a change in the clinical characteristics of hospitalized patients, the decline in mortality suggests some of the increase may be due to lower threshold for coding and assignment of the diagnosis to less ill patients.

Modern multiligament knee injury surgical reconstruction techniques can achieve excellent knee function and patient satisfaction, with low complication rates.

PURPOSE: To report on the recovery of strength and functional capacity symmetry following multiligament knee surgical reconstruction (MLKR), as well as the capacity of athletes to return to sport. METHODS: This prospective cohort study recruited 47 patients undergoing MLKR between February 2018 and July 2021. Forty patients had full outcome assessment postoperatively at 6, 12 and 24 months and were included in the analysis, 75% were knee dislocation one injuries and 60% were injured playing sport. Patient-reported outcome measures (PROMs) assessed included the International Knee Documentation Committee score, the Knee Outcome Survey, the Lysholm Knee Score and the Tegner Activity Scale (TAS). Patient satisfaction was also assessed. Objective assessment included assessment of active knee flexion and extension range of motion (ROM), the single (single horizontal hop for distance [SHD]) and triple (triple horizontal hop for distance [THD]) hop tests for distance and peak isokinetic knee flexor/extensor torque. RESULTS: All PROMs significantly improved (p < 0.001) from presurgery to 24 months postsurgery. At 24 months, 70% of patients were satisfied with their sports participation. Active knee flexion (p < 0.0001) and extension (p < 0.0001) ROM significantly improved over time, as did the limb symmetry indices (LSIs) for the SHD (p < 0.0001), THD (p < 0.0001), peak knee extensor (p < 0.0001) and flexor (p = 0.012) torque. While LSIs for the SHD, THD and knee flexor strength tended to plateau by 12 months, knee extensor strength continued to improve from 12 to 24 months. CONCLUSIONS: The majority of patients undergoing modern MLKR surgical techniques and rehabilitation can achieve excellent knee function, with low complication rates. LEVEL OF EVIDENCE: Level IV.

Income and Sex Moderate the Association Between Population Density and Reproduction: A Multilevel Analysis of Life History Strategies Across 23 Nations.

While previous studies guided by evolutionary life history theory have revealed several important socioecological moderators of the influence of population density (PD) on reproduction, absent is an understanding of how individual-level factors such as personal resources and sex differences might interact and play a role. Using data from a large sample of clients (N = 4,432,440) of an online dating company spanning 317 states nested within 23 countries, we contributed a robust multilevel analysis of life history effects by assessing the interaction between state-level PD and individual-level income on offspring quantity, and we further qualified this analysis by sex. Consistent with previous research, PD was negatively correlated with having children. Consistent with our novel hypotheses, this negative relationship was moderated by income such that the link between PD and low fertility became weaker with increasing levels of income and these patterns were stronger for men than for women. These results held despite controlling for a variety of country-level, state-level, and individual-level confounds. Findings are discussed together with theoretical and practical implications for the management of fertility based on evolutionary life history perspectives.

Cellular immune response to SARS-CoV-2 and clinical presentation in individuals exposed to endemic malaria.

Ghana and other parts of West Africa have experienced lower COVID-19 mortality rates than other regions. This phenomenon has been hypothesized to be associated with previous exposure to infections such as malaria. This study investigated the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the influence of previous malaria exposure. Blood samples were collected from individuals with asymptomatic or symptomatic COVID-19 (n = 217). A variety of assays were used to characterize the SARS-CoV-2-specific immune response, and malaria exposure was quantified using Plasmodium falciparum ELISA. The study found evidence of attenuated immune responses to COVID-19 among asymptomatic individuals, with elevated proportions of non-classical monocytes and greater memory B cell activation. Symptomatic patients displayed higher P. falciparum-specific T cell recall immune responses, whereas asymptomatic individuals demonstrated elevated P. falciparum antibody levels. Summarily, this study suggests that P. falciparum exposure-associated immune modulation may contribute to reduced severity of SARS-CoV-2 infection among people living in malaria-endemic regions.

Oral Cavity Squamous Cell Carcinoma: Impact of Clear Margin Distance on Locoregional Control in Patients Undergoing Postoperative Radiotherapy.

INTRODUCTION: Postoperative radiotherapy can improve locoregional control (LC) in oral cavity squamous cell carcinoma (OCSCC) patients with positive resection margins. The present study aimed to evaluate the impact of surgical margin size on LC in this patient population. METHODS: This retrospective study involved 162 patients with OCSCC who underwent postoperative radiotherapy between 2000 and 2020 at the Department of Radiation Oncology, University Hospital Heidelberg and the German Cancer Research Center. The study aimed to determine the impact of different resection margins on LC, as well as overall survival (OS), progression-free survival (PFS), and treatment-related toxicity (CTCAE 4.03). RESULTS: Seventy-seven patients (47.5%) had involved (<1 mm) margins, 22 patients (13.6%) close (≤5 mm) margins, and 63 patients (38.9%) clear (>5 mm) margins. A surgical margin ≤ 5 mm was a significant predictor for worse LC (HR 2.6, 95% CI 1.2, 6.1), but not for OS (HR 1.2, CI 0.7, 1.9) or PFS (HR 1.2, 0.7, 2.0). CONCLUSION: Patients who have narrow resection margins (1-5 mm) experience poor local control and should receive postoperative radiotherapy. It is necessary to conduct further prospective studies to determine whether a narrower margin window could be achieved to better determine the appropriate indication for adjuvant radiotherapy.

Exploring the fragility of meta-analyses in ophthalmology: a systematic review.

OBJECTIVE: The fragility index (FI) of a meta-analysis evaluates the extent that the statistical significance can be changed by modifying the event status of individuals from included trials. Understanding the FI improves the interpretation of the results of meta-analyses and can help to inform changes to clinical practice. This review determined the fragility of ophthalmology-related meta-analyses. METHODS: Meta-analyses of randomized controlled trials with binary outcomes published in a journal classified as 'Ophthalmology' according to the Journal Citation Report or an Ophthalmology-related Cochrane Review were included. An iterative process determined the FI of each meta-analysis. Multivariable linear regression modeling evaluated the relationship between the FI and potential predictive factors in statistically significant and non-significant meta-analyses. RESULTS: 175 meta-analyses were included. The median FI was 6 (Q1-Q3: 3-12). This meant that moving 6 outcomes from one group to another would reverse the study's findings. The FI was 1 for 18 (10.2%) of the included meta-analyses and was ≤5 for 75 (42.4%) of the included meta-analyses. The number of events (p < 0.001) and the p-value (p < 0.001) were the best predictors of the FI in both significant and non-significant meta-analyses. CONCLUSION: The statistical significance of meta-analyses in ophthalmology often hinges on the outcome of a few patients. The number of events and the p-value are the most important factors in determining the fragility of the evidence. The FI is an easily interpretable measure that can supplement the reader's understanding of the strength of the evidence being presented. PROSPERO REGISTRATION: CRD42022377589.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Critical-like slowdown in thermal soft-sphere glasses via energy minimization.

Using hybrid molecular dynamics/SWAP Monte Carlo (MD/SMC) simulations, we show that while the terminal relaxation times τ(ϕ) for FIRE energy minimization of soft-sphere glasses can decrease by orders of magnitude as sample equilibration proceeds and the jamming density ϕ_{J} increases, they always scale as τ(ϕ)∼(ϕ_{J}-ϕ)^{-2}∼[Z_{iso}-Z_{ms}(τ)]^{-2}, where Z_{iso}=2d and Z_{ms}(τ) is the average coordination number of particles satisfying a minimal local mechanical stability criterion (Z≥d+1) at the top of the final potential-energy-landscape (PEL) sub-basin the system encounters. This scaling allows us to collapse τ datasets that look very different when plotted as a function of ϕ, and to address a closely related question: how does the character of the PEL basins that dense thermal glasses most typically occupy evolve as the glasses age at constant ϕ and T?

Improving Social and Personal Rhythm Dysregulation in Young and Old Adults with Bipolar Disorder: Post-Hoc Analysis of a Feasibility Randomized Controlled Trial Using Virtual Reality-Based Intervention.

Introduction: Rehabilitative interventions employing technology play a crucial role in bipolar disorder (BD) treatment. The study aims to appraise the virtual reality (VR)-based cognitive remediation (CR) and the interpersonal rhythm approaches to treatment outcomes of BD across different age groups. Methods: Post-hoc analysis of a 12-week randomizedcontrolled cross-over feasibility trial involving people with mood disorders (BD, DSM-IV) aged 18-75 years old: thirty-nine exposed to the experimental VR-based CR vs 25 waiting list controls. People with BD relapse, epilepsy or severe eye diseases (due to the potential VR risks exposure) were excluded. Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) was used to measure the outcome. Results: Cases and controls did not statistically significantly differ in age and sex distributions. Personal rhythm scores improved over the study follow-up in the experimental vs the control group (APC = 8.7%; F = 111.9; p < 0.0001), both in young (18-45 years) (APC = 5.5%; F = 70.46; p < 0.0001) and, to a lesser extent, older (>46 years) adults (APC = 10.5%; F = 12.110; p = 0.002). Conclusions: This study observed improved synchronization of personal and social rhythms in individuals with BD after a virtual reality cognitive remediation intervention, particularly in social activity, daily activities, and chronotype, with greater benefits in the younger population.