e3SIM: epidemiological-ecological-evolutionary simulation framework for genomic epidemiology.

Infectious disease dynamics are driven by the complex interplay of epidemiological, ecological, and evolutionary processes. Accurately modeling these interactions is crucial for understanding pathogen spread and informing public health strategies. However, existing simulators often fail to capture the dynamic interplay between these processes, resulting in oversimplified models that do not fully reflect real-world complexities in which the pathogen's genetic evolution dynamically influences disease transmission. We introduce the epidemiological-ecological-evolutionary simulator (e3SIM), an open-source framework that concurrently models the transmission dynamics and molecular evolution of pathogens within a host population while integrating environmental factors. Using an agent-based, discrete-generation, forward-in-time approach, e3SIM incorporates compartmental models, host-population contact networks, and quantitative-trait models for pathogens. This integration allows for realistic simulations of disease spread and pathogen evolution. Key features include a modular and scalable design, flexibility in modeling various epidemiological and population-genetic complexities, incorporation of time-varying environmental factors, and a user-friendly graphical interface. We demonstrate e3SIM's capabilities through simulations of realistic outbreak scenarios with SARS-CoV-2 and Mycobacterium tuberculosis, illustrating its flexibility for studying the genomic epidemiology of diverse pathogen types.

Predictors of residual neoplasia after noncurative (R1) endoscopic submucosal dissection of lesions in the gastrointestinal tract.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a minimally invasive resection technique that enables the en bloc resection of gastrointestinal lesions. Despite en bloc resection, pathological evaluation of lesions can reveal positive vertical or horizontal margins, which is referred to as R1 resection. Not all R1 lesions referred for surgical resection or endoscopic surveillance show evidence of residual tumor. We aimed to identify the predictors of residual neoplasia in patients with an R1 resection following ESD. PATIENTS AND METHODS: All lesions resected via ESD between June 2016 and September 2021 at a tertiary referral center were retrospectively identified. Lesions with an R1 resection and adequate follow-up were eligible for inclusion. Patient, lesion, and procedural characteristics were analyzed to identify predictors of residual neoplasia. RESULTS: Of 614 lesions, 163 (28%) had R1 resection. Of these, 56 lesions in 51 patients had complete follow-up and were included. Thirteen patients (25.5%) underwent surgical resection and the remainder underwent endoscopic surveillance. Seven (12.5%) patients had residual disease. All patients with residual disease had esophageal carcinoma. Positive deep and lateral margins, severe submucosal fibrosis, and moderate/poorly differentiated tumors were identified as significant predictors of residual neoplasia. CONCLUSION: Most R1 lesions (87.5%) resected by ESD did not have residual disease on follow-up. Those without identified risk factors for residual disease, such as esophageal carcinoma, severe submucosal fibrosis, or both histological margin positivity, may benefit from a strategy of close endoscopic surveillance rather than referral for surgical resection.

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.

Machine Learning-Assisted Decision Making in Orthopaedic Oncology.

¼ Artificial intelligence is an umbrella term for computational calculations that are designed to mimic human intelligence and problem-solving capabilities, although in the future, this may become an incomplete definition. Machine learning (ML) encompasses the development of algorithms or predictive models that generate outputs without explicit instructions, assisting in clinical predictions based on large data sets. Deep learning is a subset of ML that utilizes layers of networks that use various inter-relational connections to define and generalize data.¼ ML algorithms can enhance radiomics techniques for improved image evaluation and diagnosis. While ML shows promise with the advent of radiomics, there are still obstacles to overcome.¼ Several calculators leveraging ML algorithms have been developed to predict survival in primary sarcomas and metastatic bone disease utilizing patient-specific data. While these models often report exceptionally accurate performance, it is crucial to evaluate their robustness using standardized guidelines.¼ While increased computing power suggests continuous improvement of ML algorithms, these advancements must be balanced against challenges such as diversifying data, addressing ethical concerns, and enhancing model interpretability.

Home and School Pollutant Exposure, Respiratory Outcomes, and Influence of Historical Redlining.

BACKGROUND: The discriminatory and racist policy of historical redlining in the United States (U.S.) during the 1930s played a role in perpetuating contemporary environmental health disparities. OBJECTIVE: Our objectives were to determine associations between home and school pollutant exposure (fine particulate matter (PM2.5), nitrogen dioxide (NO2)) and respiratory outcomes (Composite Asthma Severity Index (CASI), lung function) among school-aged children with asthma and examine whether associations differed between children who resided and/or attended school in historically redlined compared to non-redlined neighborhoods. METHODS: Children ages 6 to 17 with moderate-to-severe asthma (N=240) from 9 U.S. cities were included. Combined home and school exposure to PM2.5 and NO2 was calculated based on geospatially assessed monthly averaged outdoor pollutant concentrations. Repeated measures of CASI and lung function were collected. RESULTS: Overall, 37.5% of children resided and/or attended schools in historically redlined neighborhoods. Children in historically redlined neighborhoods had greater exposure to NO2 (median: 15.4 vs 12.1 ppb) and closer distance to a highway (median: 0.86 vs 1.23 km), compared to those in non-redlined neighborhoods (p<0.01). Overall, PM2.5 was not associated with asthma severity or lung function. However, among children in redlined neighborhoods, higher PM2.5 was associated with worse asthma severity (p<0.005). No association was observed between pollutants and lung function or asthma severity among children in non-redlined neighborhoods (p>0.005). CONCLUSIONS: Our findings highlight the significance of historical redlining and current environmental health disparities among school-aged children with asthma, specifically, the environmental injustice of PM2.5 exposure and its associations with respiratory health.

Noninvasive Ventilation or CPAP in the Initial Treatment Phase of Small Infants With Respiratory Failure.

BACKGROUND: Respiratory failure in infants is a common reason for admission to the pediatric ICU (PICU). Although high-flow nasal cannula (HFNC) is the preferred first-line treatment at our institution, some infants require CPAP or noninvasive ventilation (NIV). Here we report our experience using CPAP/NIV in infants < 10 kg. METHODS: We conducted a retrospective review of infants < 10 kg treated with CPAP/NIV in our PICUs between July 2017-May 2021 in the initial phase of treatment. Demographic, support type and settings, vital signs, pulse oximetry, and intubation data were extracted from the electronic health record. We compared subjects successfully treated with CPAP/NIV with those who required intubation. RESULTS: We studied 62 subjects with median (interquartile range) age 96 [6.5-308] d and weight 4.5 (3.4-6.6) kg. Of these, 22 (35%) required intubation. There were no significant differences in demographics, medical history, primary interface, pre-CPAP/NIV support, and device used to deliver CPAP/NIV. HFNC was used in 57 (92%) subjects before escalation to CPAP/NIV. Subjects who failed CPAP/NIV were less likely to have bronchiolitis (27% vs 60%, P = .040), less likely to be discharged from the hospital to home (68% vs 93%, P = .02), had a longer median hospital length of stay (LOS) (26.9 [21-50.5] d vs 10.4 [5.6-28.4] d, P = .002), and longer median ICU LOS (14.6 [7.9-25.2] d vs 5.8 [3.8-12.4] d, P = .004). Initial vital signs and FIO2 were similar, but SpO2 was lower and FIO2 higher at 6 h and 12 h after support initiation for subjects who failed CPAP/NIV. Initial CPAP/NIV settings were similar, but subjects who failed CPAP/NIV had higher maximum and final inspiratory/expiratory pressure. CONCLUSIONS: Most infants who failed initial HFNC support were successfully managed without intubation using NIV or CPAP. Bronchiolitis was associated with a lower rate of CPAP/NIV failure, whereas lower SpO2 and higher FIO2 levels were associated with higher rates of intubation.

Effects of aging on diaphragm hyperemia and blood flow distribution in male and female Fischer 344 rats.

Aging is associated with inspiratory muscle dysfunction, however, the impact of aging on diaphragm blood flow (BF) regulation, and whether sex-differences exist, is unknown. We tested the hypotheses in young animals, that diaphragm BF and vascular conductance (VC) would be greater in females and that aging would decrease the diaphragm's ability to increase BF with contractions. Young (4-6 months) and old (22-24 months) Fischer-344 rats were divided into four groups: Young Female (YF, n=7), Young Male (YM, n=8), Old Female (OF, n=9), and Old Male (OM, n=9). Diaphragm BF (ml/min/100g) and VC (ml/mmHg/min/100g) were determined, via fluorescent microspheres, at rest and during 1Hz contractions. In YF versus OF, aging blunted the increase in medial costal diaphragm BF (44 ± 5% vs. 16 ± 12%; P < 0.05) and VC (43 ± 7% vs. 21 ± 12%; P < 0.05). Similarly, in YM versus OM, aging blunted the increase in medial costal diaphragm BF (43 ± 6% vs. 24 ± 12%; P < 0.05) and VC (50 ± 6% vs. 34 ± 10%; P < 0.05). Compared to young, dorsal costal diaphragm BF was increased in OF while crural diaphragm BF was increased in OM (P < 0.05). Compared to age-matched females, dorsal costal diaphragm BF was lower in YM and OM (P < 0.05). Aging results in an inability to augment medial costal diaphragm BF and alters regional diaphragm BF distribution in response to muscular contractions. Further, sex differences in regional diaphragm BF are present in young and old animals.

Health-related quality of life in ethnically diverse Black prostate cancer survivors: a convergent parallel mixed-methods approach.

PURPOSE: This study examined the health-related quality of life (HRQoL) among ethnically diverse Black men (BM) with prostate cancer (CaP) in the United States. METHODS: A convergent parallel mixed-methods design, employing both qualitative and quantitative research, involved recruiting Black CaP survivors through multiple channels. The target population was native-born BM (NBBM), African-born BM (ABBM), and Caribbean-born BM (CBBM). QoL for all men was assessed using The Functional Assessment Cancer Therapy-Prostate (FACT-P) measure, which includes five domains: physical- (PWB), emotional- (EWB), social-(SWB), and functional-wellbeing (FWB), and a CaP subscale (PCS). A subset of men completed qualitative interviews. Demographic and clinical characteristics were also collected. RESULTS: Black CaP survivors aged 49-85 participated in the study (n = 108), with a subset (n = 31) completing a qualitative interview. Participants were mainly NBBM (72.2%) and treated with radiotherapy (51.9%). The FACT-P scale total mean score (± SD) was 114 ± 24.1 (theoretical range 0-156), with lower scores reported on the SWB, FWB, and EWB domains. The mixed-methods findings approach included meta-inferences derived from integrating the corresponding quantitative and qualitative data, covering all the domains within the FACT-P. CONCLUSION: Black CaP survivors experienced significant burdens that impacted their overall HRQoL. The analysis revealed impacts on physical, social, and emotional well-being, with variations among ethnic groups suggesting the need for culturally tailored interventions. EWB was also profoundly impacted by CaP treatment, with universal emotional burdens emphasized across all groups. Healthcare providers must recognize and address these multifaceted needs to promote better outcomes and HRQoL for Black CaP survivors.

Neighborhood Archetypes and Cardiovascular Health in Black Breast Cancer Survivors.

Background: Maintaining cardiovascular health (CVH) is critical for breast cancer (BC) survivors, particularly given the potential cardiotoxic effects of cancer treatments. Poor CVH among Black BC survivors may be influenced by various area-level social determinants of health, yet the impact of neighborhood archetypes in CVH among this population remains understudied. Objectives: This study aimed to characterize the neighborhood archetypes where Black BC survivors resided at diagnosis and evaluate their associations with CVH. Methods: We assessed CVH 24 months post-diagnosis in 713 participants diagnosed between 2012 and 2017 in the Women's Circle of Health Follow-Up Study, a population-based study of Black BC survivors in New Jersey. Neighborhood archetypes, identified via latent class analysis based on 16 social and built environment features, were categorized into tertiles. Associations between neighborhood archetypes and CVH scores were estimated using polytomous logistic regression. Results: CVH scores were assessed categorically (low, moderate, and optimal) and as continuous variables. On average, Black BC survivors achieved only half of the recommended score for optimal CVH. Among the 4 identified archetypes, women in the Mostly Culturally Black and Hispanic/Mixed Land Use archetype showed the lowest CVH scores. Compared to this archetype, Black BC survivors in the Culturally Diverse/Mixed Land Use archetype were nearly 3 times as likely to have optimal CVH (relative risk ratio: 2.92; 95% CI: 1.58-5.40), with a stronger association observed in younger or premenopausal women. No significant CVH differences were noted for the other 2 archetypes with fewer built environment features. Conclusions: Neighborhood archetypes, integrating social and built environment factors, may represent crucial targets for promoting CVH among BC survivors.

Reversible Nyctalopia and Bilateral Optic Neuropathy due to Combined Vitamin A, Zinc, and Copper Deficiency: A Case Report.

Introduction: Combined nutritional deficiency is an uncommon cause of vision loss in the USA. Notably, vitamin A deficiency can produce nyctalopia but rarely causes bilateral central vision loss. The combination of these symptoms is unusual, although likely underreported. Case Presentation: We report an exceptionally rare case of bilateral central vision loss and nyctalopia caused by combined vitamin A, zinc, and copper deficiency, likely following bariatric surgery and alcohol use. Following mineral and vitamin supplementation, the patient's vision improved significantly and returned to baseline within 1 month. Vision loss resulting from this specific multicombination of vitamin and mineral deficiency has never been reported previously in the English-language ophthalmic literature. Conclusion: Given rising rates of bariatric surgery and alcohol use in the USA and abroad, clinicians should be aware that the combination of progressive nyctalopia and bilateral central vision loss may be produced by combined nutritional deficiency. Screening and supplementation of both vitamin and mineral deficiency may result in dramatic reversal of visual loss in such cases.

The structure of simple satellite variation in the human genome and its correlation with centromere ancestry.

Although repetitive DNA forms much of the human genome, its study is challenging due to limitations in assembly and alignment of repetitive short-reads. We have deployed k-Seek, software that detects tandem repeats embedded in single reads, on 2,504 human genomes from the 1,000 Genomes Project to quantify the variation and abundance of simple satellites (repeat units < 20 bp). We find that the ancestral monomer of Human Satellite 3 makes up the largest portion of simple satellite content in humans (mean of ∼8 Mb). We discovered ∼50,000 rare tandem repeats that are not detected in the T2T-CHM13v2.0 assembly, including undescribed variants of telomericand pericentromeric repeats. We find broad homogeneity of the most abundant repeats across populations, except for AG-rich repeats which are more abundant in African individuals. We also find cliques of highly similar AG- and AT-rich satellites that are interspersed and form higher-order structures that covary in copy number across individuals, likely through concerted amplification via unequal exchange. Finally, we use pericentromeric polymorphisms to estimate centromeric genetic relatedness between individuals and find a strong predictive relationship between centromeric lineages and pericentromeric simple satellite abundances. In particular, ancestral monomers of Human Satellite 2 and Human Satellite 3 abundances correlate with clusters of centromeric ancestry on chromosome 16 and chromosome 9, with some clusters structured by population. These results provide new descriptions of the population dynamics that underlie the evolution of simple satellites in humans.

UBXN3B is crucial for B lymphopoiesis.

BACKGROUND: The ubiquitin regulatory X (UBX) domain-containing proteins (UBXNs) are putative adaptors for ubiquitin ligases and valosin-containing protein; however, their in vivo physiological functions remain poorly characterised. We recently showed that UBXN3B is essential for activating innate immunity to DNA viruses and controlling DNA/RNA virus infection. Herein, we investigate its role in adaptive immunity. METHODS: We evaluated the antibody responses to multiple viruses and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza in tamoxifen-inducible global and constitutive B cell-specific Ubxn3b knockout mice; quantified various immune populations, B lineage progenitors/precursors, B cell receptor (BCR) signalling and apoptosis by flow cytometry, immunoblotting and immunofluorescence microscopy. We also performed bone marrow transfer, single-cell and bulk RNA sequencing. FINDINGS: Both global and B cell-specific Ubxn3b knockout mice present a marked reduction in small precursor B-II (>60%), immature (>70%) and mature B (>95%) cell numbers. Transfer of wildtype bone marrow to irradiated global Ubxn3b knockouts restores normal B lymphopoiesis, while reverse transplantation does not. The mature B population shrinks rapidly with apoptosis and higher pro and activated caspase-3 protein levels were observed following induction of Ubxn3b knockout. Mechanistically, Ubxn3b deficiency leads to impaired pre-BCR signalling and cell cycle arrest. Ubxn3b knockout mice are highly vulnerable to respiratory viruses, with increased viral loads and prolonged immunopathology in the lung, and reduced production of virus-specific IgM/IgG. INTERPRETATION: UBXN3B is essential for B lymphopoiesis by maintaining constitutive pre-BCR signalling and cell survival in a cell-intrinsic manner. FUNDING: United States National Institutes of Health grants, R01AI132526 and R21AI155820.

Development of a hepatic cryoinjury model to study liver regeneration.

The liver is a remarkable organ that can regenerate in response to injury. Depending on the extent of injury, the liver can undergo compensatory hyperplasia or fibrosis. Despite decades of research, the molecular mechanisms underlying these processes are poorly understood. Here, we developed a new model to study liver regeneration based on cryoinjury. To visualise liver regeneration at cellular resolution, we adapted the CUBIC tissue-clearing approach. Hepatic cryoinjury induced a localised necrotic and apoptotic lesion characterised by inflammation and infiltration of innate immune cells. Following this initial phase, we observed fibrosis, which resolved as regeneration re-established homeostasis in 30 days. Importantly, this approach enables the comparison of healthy and injured parenchyma with an individual animal, providing unique advantages to previous models. In summary, the hepatic cryoinjury model provides a fast and reproducible method for studying the cellular and molecular pathways underpinning fibrosis and liver regeneration.