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Objective: To validate externally the QUiPP App v.2 algorithms in an independent cohort of high‐risk asymptomatic women attending a preterm birth (PTB) surveillance clinic in Ireland. Methods: This was a retrospective, single‐center, observational study assessing discrimination and calibration of the QUiPP App v.2 at six predetermined clinical timepoints (PTB at < 30, < 34 and < 37 weeks of pregnancy and PTB within 1, 2 and 4 weeks of testing). Discrimination was assessed by estimating the area under the receiver‐operating‐characteristics curve (AUC) and sensitivity at fixed false‐positive rates of 5%, 10% and 20%. Model calibration was assessed to evaluate the concordance between expected and observed outcomes. P‐values < 0.05 were considered statistically significant. No adjustments for treatment effects were made. Results: Overall, 762 women with 1660 PTB surveillance clinic visits using the QUiPP App v.2 between 2019 and 2022 were analyzed. The study population included 142 (18.6%) patients who later experienced PTB. The QuiPP App's performance in the prediction of short‐term outcomes, such as birth within 1 week (AUC, 0.866 (95% CI, 0.755–0.955)), 2 weeks (AUC, 0.721 (95% CI, 0.569–0.854)) and 4 weeks (AUC, 0.775 (95% CI, 0.699–0.842)), and delivery at < 30 weeks (AUC, 0.747 (95% CI, 0.613–0.865)), was superior to its ability to predict longer‐term outcomes (PTB at < 37 weeks: AUC, 0.631 (95% CI, 0.596–0.668)). Calibration was generally good for low‐risk results, as the predicted risk in these patients tended to match the observed incidence. However, in women deemed to be at greater risk of PTB, the predicted probability superseded the observed incidence of PTB. Conclusions: The QUiPP App v.2 accurately discriminates women who are at short‐term risk of PTB. A 'treatment paradox' may influence calibration in high‐risk women. Further research is needed to ascertain if QuiPP treatment thresholds can be safely adjusted in women receiving prophylactic treatment to prevent PTB, and whether this improves the outcome. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

In kidney transplantation, pairing recipients with the highest longevity with low-risk allografts to optimize graft-donor survival is a complex challenge. Current risk prediction models exhibit limited discriminative and calibration capabilities and have not been compared to modern decision-assisting tools. We aimed to develop a highly accurate risk-stratification index using artificial intelligence (AI) techniques. Using data from the UNOS database (156,749 deceased kidney transplants, 2007-2021), we randomly divided transplants into training (80%) and validation (20%) sets. The primary measure was death-censored graft survival. Four machine learning models were assessed for calibration (integrated Brier score [IBS]) and discrimination (time-dependent concordance [CTD] index), compared with existing models. We conducted decision curve analysis and external validation using UK Transplant data. The Deep Cox mixture model showed the best discriminative performance (area under the curve [AUC] = 0.66, 0.67, and 0.68 at 6, 9, and 12 years post-transplant), with CTD at 0.66. Calibration was adequate (IBS = 0.12), while the kidney donor profile index (KDPI) model had lower CTD (0.59) and AUC (0.60). AI-based D-TOP outperformed the KDPI in evaluating transplant pairs based on graft survival, potentially enhancing deceased donor selection. Advanced computing is poised to influence kidney allocation schemes., Competing Interests: Disclosure: T.F. is a current employee of the United States Veterans Health Administration. However, the views and opinions expressed herewith do not reflect the official views or opinions of and are not endorsed by the United States Veteran Health Administration. The other authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

Purpose: To demonstrate the impact of implementing hypofractionated prescription regimens and advanced treatment techniques on institutional operational hours and radiotherapy personnel resources in a multi-institutional setting. The study may be used to describe the impact of advancing the standard of care with modern radiotherapy techniques on patient and staff resources., Methods: This study uses radiation therapy data extracted from the radiotherapy information system from two tertiary care, university-affiliated cancer centers from 2012 to 2021. Across all patients in the analysis, the average fraction number for curative and palliative patients was reported each year in the decade. Also, the institutional operational treatment hours are reported for both centers. A sub-analysis for curative intent breast and lung radiotherapy patients was performed to contextualize the impact of changes to imaging, motion management, and treatment technique., Results: From 2012 to 2021, Center 1 had 42 214 patient plans and Center 2 had 43 252 patient plans included in the analysis. Averaged over both centers across the decade, the average fraction number per patient decreased from 6.9 to 5.2 (25%) and 21.8 to 17.2 (21%) for palliative and curative patients, respectively. The operational treatment hours for both institutions increased from 8 h 15 min to 9 h 45 min (18%), despite a patient population increase of 45%., Conclusion: The clinical implementation of hypofractionated treatment regimens has successfully reduced the radiotherapy workload and operational treatment hours required to treat patients. This analysis describes the impact of changes to the standard of care on institutional resources., (© 2024 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: It is unknown how many people in treatment for opioid use disorder (OUD) have naloxone, use naloxone, and what their perceptions and barriers to obtaining it are., Methods: This was a survey of patients treated in a large telehealth OUD program. Between December 6, 2023 and January 6, 2024, all patients who had access to the program's phone app (n=17,899 individuals, of whom 12,887 were in active treatment), were invited to complete an anonymous online survey., Results: There were 701 individuals who completed the survey. Nearly all patients (n=693, 99%) knew what naloxone is, and the majority (n=601, 86%) knew how to administer it. A quarter of these patients (n=177, 25%) reported either having naloxone used on themselves or using it on someone else. 161 patients (23%) reported taking a naloxone training course. Of patients who recalled receiving a prescription, 72% (n=382) filled the prescription, and 85% (n=321) reported that insurance paid for all or part of it. If filled, the naloxone was reported as used by 30 (8%) patients. If not filled, reasons were: already had it (n=55, 37%), did not think it was needed (n=54, 37%) or too expensive (n=36, 23%). Patients who reported knowing how to administer naloxone (OR 2.63 (95% CI 1.35-5.00) were more likely to fill the prescription., Conclusions: Patients prescribed naloxone in a telehealth treatment program filled the prescription 72% of the time, and when it was filled, 8% used the naloxone. Education and cost policy changes may reduce barriers to obtaining naloxone., Competing Interests: All authors were employed by Bicycle Health, Inc at the time of this research. Dr. Clear serves as an officer, and Dr. Clear and Ms. Burke have equity interest. To reduce bias, the research team, comprised of Ms. Burke, Ms. Miller and Dr. Weiner, worked largely independently of the rest of the group. The research team was supervised by Dr. Clear, who is the only company officer on this paper. Dr. Clear did not modify the study’s findings in any way but did provide input on the study design and approval of the final manuscript. Furthermore, no one else from Bicycle Health edited or reviewed this work beyond the four authors., (© 2024 The Author(s).)

Jamaican fruit bats (Artibeus jamaicensis) naturally harbor a wide range of viruses of human relevance. These infections are typically mild in bats, suggesting unique features of their immune system. To better understand the immune response to viral infections in bats, we infected male Jamaican fruit bats with the bat-derived influenza A virus (IAV) H18N11. Using comparative single-cell RNA sequencing, we generated single-cell atlases of the Jamaican fruit bat intestine and mesentery. Gene expression profiling showed that H18N11 infection resulted in a moderate induction of interferon-stimulated genes and transcriptional activation of immune cells. H18N11 infection was predominant in various leukocytes, including macrophages, B cells, and NK/T cells. Confirming these findings, human leukocytes, particularly macrophages, were also susceptible to H18N11, highlighting the zoonotic potential of this bat-derived IAV. Our study provides insight into a natural virus-host relationship and thus serves as a fundamental resource for future in-depth characterization of bat immunology., (© 2024. The Author(s).)

Hutchinson-Gilford Progeria syndrome (HGPS) is a severe premature ageing disorder caused by a 50 amino acid truncated (Δ50AA) and permanently farnesylated lamin A (LA) mutant called progerin. On a cellular level, progerin expression leads to heterochromatin loss, impaired nucleocytoplasmic transport, telomeric DNA damage and a permanent growth arrest called cellular senescence. Although the genetic basis for HGPS has been elucidated 20 years ago, the question whether the Δ50AA or the permanent farnesylation causes cellular defects has not been addressed. Moreover, we currently lack mechanistic insight into how the only FDA-approved progeria drug Lonafarnib, a farnesyltransferase inhibitor (FTI), ameliorates HGPS phenotypes. By expressing a variety of LA mutants using a doxycycline-inducible system, and in conjunction with FTI, we demonstrate that the permanent farnesylation, and not the Δ50AA, is solely responsible for progerin-induced cellular defects, as well as its rapid accumulation and slow clearance. Importantly, FTI does not affect clearance of progerin post-farnesylation and we demonstrate that early, but not late FTI treatment prevents HGPS phenotypes. Collectively, our study unravels the precise contributions of progerin's permanent farnesylation to its turnover and HGPS cellular phenotypes, and how FTI treatment ameliorates these. These findings are applicable to other diseases associated with permanently farnesylated proteins, such as adult-onset autosomal dominant leukodystrophy., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Outcome prediction for live-donor kidney transplantation improves clinical and patient decisions and donor selection. However, the concurrently used models are of limited discriminative or calibration power and there is a critical need to improve the selection process. We aimed to assess the value of various artificial intelligence (AI) algorithms to improve the risk stratification index. We evaluated pre-transplant variables among 66 914 live-donor kidney transplants (performed between 01/12/2007-01/06/2021) from the United Network of Organ Sharing database, randomized into training (80%) and test (20%) sets. The primary outcome measure was death-censored graft survival. We tested four machine learning models for discrimination (time-dependent concordance index, CTD, and area under the ROC curve) and calibration (integrated Brier score, IBS). We used decision curve analysis to assess the potential clinical utility. Among the models, the deep Cox mixture model showed the best discriminative performance (AUC = 0.70, 0.68, and 0.68 at 5, 10, and 13 years post-transplant, respectively). CTD reached 0.70, 0.67, and 0.66 at 5, 10, and 13 years post-transplant. The IBS score was 0.09, indicating good calibration. In comparison, applying the Living Kidney Donor Profile Index (LKDPI) on the same cohort produced a CTD of 0.56 and an AUC of 0.55-0.58 only. Decision curve analysis showed an additional net benefit compared to the LKDPI, 'Treat all' and 'Treat None' approaches. Our AI-based deep Cox mixture model, termed Live-Donor Kidney Transplant Outcome Prediction outperforms existing prediction models, including the LKDPI, with the potential to improve decisions for optimum live donor selection by ranking potential transplant pairs based on graft survival. This model could be adopted to improve the outcomes of paired exchange programs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

The destructive impact of fungi in agriculture and animal and human health, coincident with increases in antifungal resistance, underscores the need for new and alternative drug targets to counteract these trends. Cellular metabolism relies on many intermediates with intrinsic toxicity and promiscuous enzymatic activity generates others. Fuller knowledge of these toxic entities and their generation may offer opportunities of antifungal development. From this perspective our observation of media-conditional lethal metabolism in respiratory mutants of the opportunistic fungal pathogen Candida albicans was of interest. C. albicans mutants defective in NADH:ubiquinone oxidoreductase (Complex I of the electron transport chain) exhibit normal growth in synthetic complete medium. In YPD medium, however, the mutants grow normally until early stationary phase whereupon a dramatic loss of viability occurs. Upwards of 90% of cells die over the subsequent four to six hours with a loss of membrane integrity. The extent of cell death was proportional to the amount of BactoPeptone, and to a lesser extent, the amount of yeast extract. YPD medium conditioned by growth of the mutant was toxic to wild-type cells indicating mutant metabolism established a toxic milieu in the media. Conditioned media contained a volatile component that contributed to toxicity, but only in the presence of a component of BactoPeptone. Fractionation experiments revealed purine nucleosides or bases as the synergistic component. GC-mass spectrometry analysis revealed acetal (1,1-diethoxyethane) as the active volatile. This previously unreported and lethal synergistic interaction of acetal and purines suggests a hitherto unrecognized toxic metabolism potentially exploitable in the search for antifungal targets., Competing Interests: The authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Kane et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Importance: Youth-onset type 2 diabetes is associated with poor glycemic control and early onset of complications. Identification of psychosocial factors associated with poor glycemic control is needed to inform efficacious interventions., Objective: To identify psychosocial factors associated with glycated hemoglobin (HbA1c) levels in young adults with youth-onset type 2 diabetes., Design, Setting, and Participants: For the iCount cohort study, HbA1c levels were measured twice (at baseline [T1] and at 1 year [T2]) during the last years (2017-2019) of the observational phase of the multicenter Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY2) study. Participants were young adults who had been diagnosed with type 2 diabetes during childhood or adolescence. Data were analyzed from December 2021 to September 2023., Main Outcomes and Measures: Glycemic control was examined categorically (high [≥8.0%] vs low [<8.0%] HbA1c), continuously (HbA1c level), and over time (change in HbA1c: decreased ≥0.5%, remained stable, or increased ≥0.5%). Psychosocial measures included beliefs about medicines, depression and anxiety symptoms, diabetes distress, diabetes self-efficacy, self-management support, and unmet material needs. Multivariable logistic and linear regression models evaluated the association of each psychosocial factor with the probability of T2 HbA1c of 8.0% or greater, T2 HbA1c level, and change in HbA1c., Results: Of the 411 TODAY2 participants approached, 381 enrolled in the iCount study, and 348 with T1 and T2 HbA1c data comprised the analysis group. The 348 participants had a mean (SD) age of 26.1 (2.5) years and a mean (SD) HbA1c of 9.4% (2.8%). Most participants (229 [65.8%]) were women. In adjusted multivariable regressions, greater beliefs that diabetes medicines are necessary (odds ratio [OR], 1.19 [95% CI, 1.03-1.37]; P = .02), concerns about medicines (OR, 1.20 [95% CI, 1.00-1.45]; P = .049), diabetes distress (OR, 1.08 [95% CI, 1.02-1.15]; P = .006), and high distress (OR, 2.18 [95% CI, 1.15-4.13]; P = .02) increased the odds of high HbA1c at T2. Greater support (OR, 0.67 [95% CI, 0.46-0.97]; P = .04) and diabetes self-efficacy (OR, 0.91 [95% CI, 0.84-0.99]; P = .02) decreased the odds of high HbA1c at T2. Diabetes distress was associated with higher HbA1c level at T2 (coefficient, 0.08 [95% CI, 0.02-0.13]; P = .01). Beliefs that diabetes medicines are necessary (OR, 1.20 [95% CI, 1.03-1.39]; P = .02) and concerns about medicines (OR, 1.22 [95% CI, 1.00-1.47]; P = .048) increased the odds of an HbA1c decrease of at least 0.5% over 1 year., Conclusions and Relevance: In this cohort study of young adults with youth-onset type 2 diabetes, beliefs about medicines, high diabetes distress, low diabetes self-efficacy, and self-management support were associated with high HbA1c over time. Future research should assess whether interventions that address these factors result in improved glycemic control in this at-risk group.

Introduction: Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is a particularly lethal disease that is often diagnosed late and is refractory to most forms of treatment. Tumour hypoxia is a key hallmark of PDAC and is purported to contribute to multiple facets of disease progression such as treatment resistance, increased invasiveness, metabolic reprogramming, and immunosuppression., Methods: We used the Buffa gene signature as a hypoxia score to profile transcriptomics datasets from PDAC cases. We performed cell-type deconvolution and gene expression profiling approaches to compare the immunological phenotypes of cases with low and high hypoxia scores. We further supported our findings by qPCR analyses in PDAC cell lines cultured in hypoxic conditions., Results: First, we demonstrated that this hypoxia score is associated with increased tumour grade and reduced survival suggesting that this score is correlated to disease progression. Subsequently, we compared the immune phenotypes of cases with high versus low hypoxia score expression (Hypoxia HI vs. Hypoxia LOW ) to show that high hypoxia is associated with reduced levels of T cells, NK cells and dendritic cells (DC), including the crucial cDC1 subset. Concomitantly, immune-related gene expression profiling revealed that compared to Hypoxia LOW tumours, mRNA levels for multiple immunosuppressive molecules were notably elevated in Hypoxia HI cases. Using a Random Forest machine learning approach for variable selection, we identified LGALS3 (Galectin-3) as the top gene associated with high hypoxia status and confirmed its expression in hypoxic PDAC cell lines., Discussion: In summary, we demonstrated novel associations between hypoxia and multiple immunosuppressive mediators in PDAC, highlighting avenues for improving PDAC immunotherapy by targeting these immune molecules in combination with hypoxia-targeted drugs., 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 © 2024 Sadozai, Acharjee, Kayani, Gruber, Gorczynski and Burke.)

Background: Telehealth-only medication for opioid use disorder (teleMOUD) treatment with buprenorphine was first made possible in the United States during the COVID-19 Public Health Emergency. As a result, several large provider groups now treat opioid use disorder (OUD) patients in nearly every state using telehealth. This study evaluates the perceptions and experiences of providers working almost exclusively in a teleMOUD program., Methods: Qualitative interviews were conducted with 18 providers (physicians, physician assistants and nurse practitioners) using a semi-structured interview guide. Interviews were recorded, transcribed and reviewed. After reviewing the transcripts, a codebook was developed, interviews were coded, and coded excerpts were analyzed for key themes., Results: Inductive codes were used to organize provider responses and included patient-level codes, provider-level codes, and telehealth environment codes. For providers, there are benefits of a flexible and less stressful working environment, which contribute to a higher quality of life. Providers also expressed mixed feelings regarding professional identity and focusing specifically on OUD, differences in relationships with colleagues, and challenges related to policy changes and ambiguities. For patients, providers perceived greater access, less stigma, more convenience, and a unique provider-patient relationship compared to in-person treatment. These themes affect providers and patients on multiple levels of the social-ecological model., Conclusions: Multiple themes emerged in this study. This work is amongst the first to describe perspectives of providers working in the nascent teleMOUD setting, and can inform initiatives to improve provider wellness, provider retention, and quality of care for patients treated in the setting., Competing Interests: Declaration of Competing Interest All authors are employed by Bicycle Health, Inc, of which Dr. Clear serves as an officer, and Dr. Clear and Dr. Weiner have equity interest. To reduce bias, the research team, comprised of Ms. Burke, Ms. Miller and Dr. Weiner, works largely independently of the rest of the group. The research team is supervised by Dr. Clear, who is the only company officer on this paper. Dr. Clear did not modify the study’s findings in any way but did provide input on the study design and approval of the final manuscript. He also did not conduct any interviews and was not involved in the coding or interpretation of findings. Furthermore, no one else from Bicycle Health has edited or reviewed this work beyond the four authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The role of natural killer group 2D (NKG2D) in peripheral T cells as a costimulatory receptor is well established. However, its contribution to T cell thymic education and functional imprint is unknown. Here, we report significant changes in development, receptor signaling, transcriptional program, and function in T cells from mice lacking NKG2D signaling. In C57BL/6 (B6) and OT-I mice, we found that NKG2D deficiency results in Vβ chain usage changes and stagnation of the double-positive stage in thymic T cell development. We found that the expression of CD5 and CD45 in thymocytes from NKG2D deficient mice were reduced, indicating a direct influence of NKG2D on the strength of T cell receptor (TCR) signaling during the developmental stage of T cells. Depicting the functional consequences of NKG2D, peripheral OT-I NKG2D-deficient cells were unresponsive to ovalbumin peptide stimulation. Paradoxically, while αCD3/CD28 agonist antibodies led to phenotypic T cell activation, their ability to produce cytokines remained severely compromised. We found that OT-I NKG2D-deficient cells activate STAT5 in response to interleukin-15 but were unable to phosphorylate ERK or S6 upon TCR engagement, underpinning a defect in TCR signaling. Finally, we showed that NKG2D is expressed in mouse and human thymic T cells at the double-negative stage, suggesting an evolutionarily conserved function during T cell development. The data presented in this study indicate that NKG2D impacts thymic T cell development at a fundamental level by reducing the TCR threshold and affecting the functional imprint of the thymic progeny. In summary, understanding the impact of NKG2D on thymic T cell development and TCR signaling contributes to our knowledge of immune system regulation, immune dysregulation, and the design of immunotherapies., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

Objectives: Telehealth treatment with medication for opioid use disorder (teleMOUD) was made possible with regulations following the COVID-19 pandemic that permitted prescribing buprenorphine without an in-person visit. This study evaluates the self-reported outcomes of patients treated by teleMOUD using the Brief Addiction Monitor (BAM), a 17-question tool that assesses drug use, cravings, physical and psychological health, and psychosocial factors to produce 3 subset scores: substance use, risk factors, and protective factors., Methods: Patients treated by a teleMOUD provider group operating in >30 states were asked to complete an app-based version of BAM at enrollment and at 1 month. Patients who completed both assessments between June 2022 and March 2023 were included., Results: A total of 2556 patients completed an enrollment BAM and 1447 completed both assessments. Mean number of days from baseline BAM to follow-up was 26.7 days. Changes were significantly different across most questions. The substance use subscale decreased from mean 2.6 to 0.8 ( P  < .001), the risk factors subscale decreased from mean 10.3 to 7.5 ( P  < .001), and the protective factors subscale increased from mean 14.3 to 15.0. ( P  < .001). Substance use and risk factor subscale changes were significant across all sex and age groups, while protective factors subscale did not improve for those <25 and >54 years. Patient reports of at least 1 day of illegal use or misuse decreased, including marijuana (28.1% vs 9.0%), cocaine/crack (3.9% vs 2.6%), and opioids (49.8% vs 10.5%)., Conclusions: Among patients treated by teleMOUD who completed assessments at enrollment and 1 month, there was improvement in drug use, risk factor, and protective factor scores., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ms. Burke, Dr. Clear, Ms. Miller and Dr. Weiner are employed by Bicycle Health, and Dr. Clear and Dr. Weiner also have equity interest. Dr. Rollston is a former employee and consultant of Bicycle Health. Outside of this work, Dr. Weiner is also on the acute pain committee of Vertex Pharmaceuticals, Inc and scientific advisory board of Cessation Therapeutics, Inc.

Objective: Evaluate spectral scaling properties of scalp electroencephalogram (EEG) and electromyogram (EMG), optimal spacing of electrodes, and strategies for mitigating EMG. Methods: EEG was recorded referentially from 9 subjects with a 64 channel linear array (electrodes 3 mm apart) placed parasagittally or transversely on forehead or occiput, at rest with eyes open or closed, or with deliberate EMG. Temporal (PSDt) and spatial (PSDx) power spectral densities were calculated with one-dimensional fast Fourier transform (FFT) for comparison with earlier analyses of intracranial EEG. Results: Scaling of PSDt from scalp resembled that from pia: near-linear decrease in log power with increasing log frequency (1/f(alpha)). Scalp PSDx decreased non-linearly and more rapidly than PSDx from pia. Peaks in PSDt (especially 4-12 Hz) and PSDx (especially 0.1-0.4 cycles/cm) revealed departures from 1/f(alpha). EMG power in PSDt was more "white" than 1/f(alpha). Conclusions: Smearing by dura-skull-scalp distorts PSDx more than PSDt of scalp EEG from 1/f(alpha) scaling at the pia. Spatial spectral peaks suggest that optimal scalp electrode spacing might be similar to I cm to capture non-local EEG components having the texture of gyri. Mitigation of EMG by filtering is unsatisfactory. A criterion for measuring EMG may support biofeedback for training subjects to reduce their EMG. Significance: High-density recording and log-log spectral display of EEG provide a foundation for holist studies of global human brain function, as an alternative to network approaches that decompose EEG into localized, modular signals for correlation and coherence. (C) 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Science Ireland Ltd. All rights reserved.

A model named “KIII” of the olfactory system con-tains an array of 64 coupled oscillators simulating the olfactorybulb (OB), with negative and positive feedback through low-passfilter lines from single oscillators simulating the anterior olfactorynucleus (AON) and prepyriform cortex (PC). It is implementedin C to run on Macintosh, IBM, or UNIX platforms. The outputcan be set by parameter optimization to point, limit cycle,quasi-periodic, or aperiodic (presumably chaotic) attractors. Thefirst three classes of solutions are stable under variations ofparameters and perturbations by input, but they are biologicallyunrealistic. Chaotic solutions simulate the properties of time-dependent densities of olfactory action potentials and EEG’s,but they transit into the basins of point, limit cycle, or quasi-periodic attractors after only a few seconds of simulated run time.Despite use of double precision arithmetic giving 64-bit words, theKIII model is exquisitely sensitive to changes in the terminal bitof parameters and inputs. The global stability decreases as thenumber of coupled oscillators in the OB is increased, indicatingthat attractor crowding reduces the size of basins in the model to???the size of the digitizing step (??? ). Chaotic solutions havingbiological verisimilitude are robustly stabilized by introducing low-level, additive noise from a random number generator at two biologically determined points: rectified, spatially incoherent noise on each receptor input line, and spatially coherent noise to the AON, a global control point receiving centrifugal inputs from various parts of the forebrain. Methods are presented for evaluating global stability in the high dimensional system from measurements of multiple chaotic outputs. Ranges of stability are shown for variations of connection weights (gains) in the KIII model. The system is devised for pattern classification.

Introduction: As telehealth models for treatment of opioid use disorder (OUD) are expanding, the field does not know the reliability of urine drug screening (UDS) in this setting. The objective of this study is to determine the rate of falsification of UDS testing among patients with OUD in active treatment with buprenorphine via a telehealth provider., Methods: This is a prospective cohort study of 899 randomly selected eligible patients, of which 392 participated in the final cohort that the study team used for analysis. The study mailed patients a UDS cup and asked them to return the sample by mail. After the UDS sample was received, a buccal swab was mailed, and the study asked patients to schedule a virtual meeting in which consent was sought and an observed buccal swab was obtained. We evaluated urine for evidence of falsification, and used buccal swabs to genetically match individuals to urine samples., Results: After exclusion criteria, 395 (52.3 %) of 755 patients who received a UDS kit returned it for analysis prior to knowledge of the study. Of that, 392 samples had sufficient quantity for testing. We determined 383 (97.7 %) to be human urine containing buprenorphine without indication of exogenous buprenorphine addition and with evidence of compliance. A total of 374 patients received a buccal swab kit and 139 (37.2 %) attended the consent/observed buccal swab session. One hundred and thirty-two patients consented and completed the swab under video observation, and 120 successfully sent the swab back to the external laboratory. Of the 120 buccal swabs received, 109 (90.8 %) were a genetic match, 10 (8.3 %) were indeterminate, and 1 (0.8 %) was a genetic mismatch., Conclusions: This study of patients treated by a telehealth OUD provider demonstrated a low rate of urine test falsification., Competing Interests: Declaration of competing interest Dr. Weiner is an advisory committee member of Vertex Pharmaceuticals, Inc. and Cessation Therapeutics, Inc. Dr. Clear and Dr. Weiner have ownership interest in Bicycle Health, Inc. Other authors report no relevant conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Recently, the gut microbiome has emerged as a potent modulator of exercise-induced systemic adaptation and appears to be crucial for mediating some of the benefits of exercise. This study builds upon previous evidence establishing a gut microbiome-skeletal muscle axis, identifying exercise-induced changes in microbiome composition. Metagenomics sequencing of fecal samples from non-exercise-trained controls or exercise-trained mice was conducted. Biodiversity indices indicated exercise training did not change alpha diversity. However, there were notable differences in beta-diversity between trained and untrained microbiomes. Exercise significantly increased the level of the bacterial species Muribaculaceae bacterium DSM 103720. Computation simulation of bacterial growth was used to predict metabolites that accumulate under in silico culture of exercise-responsive bacteria. We identified acetate and succinate as potential gut microbial metabolites that are produced by Muribaculaceae bacterium, which were then administered to mice during a period of mechanical overload-induced muscle hypertrophy. Although no differences were observed for the overall muscle growth response to succinate or acetate administration during the first 5 days of mechanical overload-induced hypertrophy, acetate and succinate increased skeletal muscle mitochondrial respiration. When given as post-biotics, succinate or acetate treatment may improve oxidative metabolism during muscle hypertrophy., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Chemical fertilizers have been crucial for sustaining the current global population by supplementing overused farmland to support consistent food production, but their use is unsustainable. Pseudomonas chlororaphis is a nitrogen-fixing bacterium that could be used as a fertilizer replacement, but this microbe is delicate. It is sensitive to stressors, such as freeze-drying and high temperatures. Here, we demonstrate protection of P. chlororaphis from freeze-drying, high temperatures (50 o C), and high humidity using self-assembling metal-phenolic network (MPN) coatings. The composition of the MPN is found to significantly impact its protective efficacy, and with optimized compositions, no viability loss is observed for MPN-coated microbes under conditions where uncoated cells do not survive. Further, we demonstrate that MPN-coated microbes improve germination of seeds by 150% as compared to those treated with fresh P. chlororaphis . Taken together, these results demonstrate the protective capabilities of MPNs against environmental stressors and represent a critical step towards enabling the production and storage of delicate microbes under nonideal conditions., Competing Interests: The authors declare the following competing financial interest(s): A patent on MPNs has been filed through MIT by A.L.F., (© 2023 The Authors. Published by American Chemical Society.)

Insectivorous Old World horseshoe bats (Rhinolophus spp.) are the likely source of the ancestral SARS-CoV-2 prior to its spillover into humans and causing the COVID-19 pandemic. Natural coronavirus infections of bats appear to be principally confined to the intestines, suggesting fecal-oral transmission; however, little is known about the biology of SARS-related coronaviruses in bats. Previous experimental challenges of Egyptian fruit bats (Rousettus aegyptiacus) resulted in limited infection restricted to the respiratory tract, whereas insectivorous North American big brown bats (Eptesicus fuscus) showed no evidence of infection. In the present study, we challenged Jamaican fruit bats (Artibeus jamaicensis) with SARS-CoV-2 to determine their susceptibility. Infection was confined to the intestine for only a few days with prominent viral nucleocapsid antigen in epithelial cells, and mononuclear cells of the lamina propria and Peyer's patches, but with no evidence of infection of other tissues; none of the bats showed visible signs of disease or seroconverted. Expression levels of ACE2 were low in the lungs, which may account for the lack of pulmonary infection. Bats were then intranasally inoculated with a replication-defective adenovirus encoding human ACE2 and 5 days later challenged with SARS-CoV-2. Viral antigen was prominent in lungs for up to 14 days, with loss of pulmonary cellularity during this time; however, the bats did not exhibit weight loss or visible signs of disease. From day 7, bats had low to moderate IgG antibody titers to spike protein by ELISA, and one bat on day 10 had low-titer neutralizing antibodies. CD4+ helper T cells became activated upon ex vivo recall stimulation with SARS-CoV-2 nucleocapsid peptide library and exhibited elevated mRNA expression of the regulatory T cell cytokines interleukin-10 and transforming growth factor-β, which may have limited inflammatory pathology. Collectively, these data show that Jamaican fruit bats are poorly susceptible to SARS-CoV-2 but that expression of human ACE2 in their lungs leads to robust infection and an adaptive immune response with low-titer antibodies and a regulatory T cell-like response that may explain the lack of prominent inflammation in the lungs. This model will allow for insight of how SARS-CoV-2 infects bats and how bat innate and adaptive immune responses engage the virus without overt clinical disease., Competing Interests: The JAR laboratory received support from Tonix Pharmaceuticals, Xing Technologies and Zoetis, outside of the reported work. JAR is inventor of patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections, owned by Kansas State University, KS., (Copyright: © 2023 Burke et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Available literature comparing spinal anesthesia (SA) to general anesthesia (GA) in the pediatric population describes multiple benefits in appropriately selected patients including cost reduction, lower incidence of complications, and shorter operative times. In patients undergoing urologic procedures, data are sparse., Objective: Our goal was to expand on the paucity of existing urologic literature as SA appears to be uniquely suited for a substantial number of its common pediatric procedures., Methods: Within a single institution, patients who had a urologic procedure performed under SA between May 2019 and July 2021 and were less than 18 months old were compared with a matched cohort of patients who had GA. The SA and GA groups were compared by two-sample t-tests, chi-square test for independence, and Fisher's exact test., Results: There were a total of 184 SA and 202 GA patients. There was no significant difference in the demographics except that SA patients were younger and weighed less than GA patients. The patients in the SA group needed less opioids both during the surgery (0% vs 26.1% p N/A) and in the immediate postoperative period when compared with GA patients (0% vs 18.2% p N/A). The patients who had SA had fewer complications necessitating PICU admission, or cancellation of surgery (0% vs 6.8% p = 0.03). Total anesthesia and emergence time were lower for SA patients (41 vs 50.2 p = 0.001 & 3.4 vs 6.1 p = 0.001). Both surgery and total OR time were not different between the groups (37.6 vs 35.5 p = 0.35 and 56.3 vs 54.4 p = 0.49). Overall, raw material cost was also found to be lower per procedure in the SA group vs the GA group ($8.90 vs $38.8: 77% reduction). Adjusted total mean costs for the surgery were not different between groups. The reduction in opioid use postoperatively also suggests reduced cost in the management of postoperative pain in the SA group., Discussion: Total anesthesia time, opioid use, and serious complications were all significantly lower in the SA group. We did not find significant difference in total surgery cost between two groups. However, patients who had SA had better pain control and needed less rescue analgesics in the immediate postoperative period. No patients in either group were sent home with opioids., Conclusion: Spinal anesthesia was found to be an equally effective and appropriate alternative to GA with many proposed benefits for common pediatric urologic procedures. With further research, SA may prove to be a safer alternative in patients at risk for complications related to GA general anesthesia while also offering a cost benefit., Competing Interests: Conflicts of interest None to report., (Copyright © 2023 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Durotaxis is a phenomenon in which cells migrate toward substrates of increasing stiffness. However, how cells assimilate substrate stiffness as a directional cue remains poorly understood. In this study, we experimentally show that mouse embryonic fibroblasts can discriminate between different substrate stiffnesses and develop higher traction forces at regions of the cell adhering to the stiffer pillars. In this way, the cells generate a force imbalance between adhesion sites. It is this traction force imbalance that drives durotaxis by providing directionality for cell migration. Significantly, we found that traction forces are transmitted via LINC complexes to the cell nucleus, which serves to maintain the global force imbalance. In this way, LINC complexes play an essential role in anterograde nuclear movement and durotaxis. This conclusion is supported by the fact that LINC complex-deficient cells are incapable of durotaxis and instead migrate randomly on substrates featuring a stiffness gradient.

Purpose: This study analyzes the implementation of the routine use of quadratus lumborum blocks (QLBs) on postoperative pain and opioid consumption among children undergoing laparoscopic appendectomy compared to those not receiving regional anesthesia., Methods: Children undergoing laparoscopic appendectomy within a multi-hospital children's healthcare system were retrospectively reviewed from 2017 to 2021. Patients were stratified by appendicitis type (uncomplicated vs. complicated). Pain scores and opioid consumption in the post-anesthesia care unit (PACU) and within the first 24 h postoperatively were compared by block status (no block [NB] vs. QLB) and appendicitis type., Results: 2033 patients were reviewed, and 610 received a QLB. The frequency of rescue opioid use was reduced in the PACU (uncomplicated: QLB 46.6% vs. NB 54.6%, p = 0.005; complicated: QLB 28.5% vs. NB 39.9%, p = 0.01) and postoperatively (complicated: QLB 33.7% vs. NB 52.9%, p < 0.001) for those who received a QLB. This resulted in reduced opioid consumption as measured by morphine milligram equivalents per kilogram postoperatively., Conclusion: QLBs can be safely administered in children and provide improvements in opioid consumption postoperatively. QLBs should remain a strongly favored regional anesthetic technique because of their wide applicability for abdominal surgeries to minimize rescue opioid analgesic use., Type of Study: Retrospective comparative study., Level of Evidence: Level III., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Many studies evaluating opioid stewardship interventions' effects on postoperative pain rely on emergency department (ED) visits or readmissions, but patient-reported pain scores represent a more complete picture of the postoperative experience. This study compares patient-reported pain scores after ambulatory pediatric and urologic procedures and the effect of an opioid stewardship intervention that nearly eliminated the use of outpatient narcotics., Methods: This is a retrospective comparative study including 3173 pediatric patients who underwent ambulatory procedures from 2015 to 2019, during which there was an intervention to reduce narcotic prescriptions. Postoperative day one phone calls assessed pain levels using a four-point scale (no pain, mild pain, moderate pain controlled with medication, or severe pain uncontrolled with medication). We quantified the proportion of patients prescribed opioids pre-versus post-intervention and compared pain scores for patients receiving opioid versus non-opioid regimens., Results: Opioid prescription rates demonstrated a 6.5-fold reduction after opioid stewardship efforts. The majority of patients (2838) received non-opioids, with only 335 patients receiving opioids. Opioid patients reported moderate/severe pain slightly more than non-opioid patients (14.1% vs. 10.4%, p = 0.04). On by-procedure analyses, there were no subgroups in which non-opioid patients reported significantly higher pain scores., Conclusions: Non-opioid postoperative pain regimens appear to be effective, with only 10.4% of patients reporting moderate/severe pain after ambulatory procedures. Future studies assessing patient-reported outcomes are necessary to optimize pain control for all patients and to determine whether there is ever an indication for opioid prescription after ambulatory general pediatric or urologic surgery., Type of Study: Retrospective comparative study., Level of Evidence: Level III., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Genetically defined subgroups of inhibitory interneurons are thought to play distinct roles in learning, but heterogeneity within these subgroups has limited our understanding of the scope and nature of their specific contributions. Here we reveal that the chandelier cell (ChC), an interneuron type that specializes in inhibiting the axon-initial segment (AIS) of pyramidal neurons, establishes cortical microcircuits for organizing neural coding through selective axo-axonic synaptic plasticity. We found that organized motor control is mediated by enhanced population coding of direction-tuned premotor neurons, with tuning refined through suppression of irrelevant neuronal activity. ChCs contribute to learning-dependent refinements by providing selective inhibitory control over individual pyramidal neurons rather than global suppression. Quantitative analysis of structural plasticity across axo-axonic synapses revealed that ChCs redistributed inhibitory weights to individual pyramidal neurons during learning. These results demonstrate an adaptive logic of the inhibitory circuit motif responsible for organizing distributed neural representations. Thus, ChCs permit efficient cortical computation in a targeted cell-specific manner., (© 2023. The Author(s).)

Climate change has been associated with both latitudinal and elevational shifts in species' ranges. The extent, however, to which climate change has driven recent range shifts alongside other putative drivers remains uncertain. Here, we use the changing distributions of 378 European breeding bird species over 30 years to explore the putative drivers of recent range dynamics, considering the effects of climate, land cover, other environmental variables, and species' traits on the probability of local colonisation and extinction. On average, species shifted their ranges by 2.4 km/year. These shifts, however, were significantly different from expectations due to changing climate and land cover. We found that local colonisation and extinction events were influenced primarily by initial climate conditions and by species' range traits. By contrast, changes in climate suitability over the period were less important. This highlights the limitations of using only climate and land cover when projecting future changes in species' ranges and emphasises the need for integrative, multi-predictor approaches for more robust forecasting., (© 2023. The Author(s).)

This study retrospectively reviewed data from men with localized prostate cancer treated with external beam radiotherapy (EBRT). We identified 359 men with localized prostate cancer treated with curative EBRT at the Cross Cancer Institute between 2010-2011. The volume of seminal vesicles (SVs) treated as well as dose values were extracted. These volumes were compared to gold standard contours drawn by a trained expert based on consensus European Society for Radiotherapy and Oncology (ESTRO) contouring guidelines. Patient and tumor characteristics were extracted for these patients. Memorial Sloan Kettering prostate cancer nomogram was used to assign a predicted risk of SV involvement for each patient based on baseline tumor characteristics. In patients with a predicted risk of SV involvement greater than 15% ( n = 184), 86.5% (SD = 18.6) of the base of the SVs were treated with EBRT, compared to 66.7% (SD = 32.6) for patients with a predicted risk of SV involvement less than 15% ( n = 175, p < 0.0001). Similarly, the mean percentage of proximal and total SV volumes treated with EBRT was 75.6% (SD = 24.4) and 68.7% (SD = 26.0) for patients with a predicted risk of SV involvement of greater than 15%, compared to 50.3% (SD = 31.0, p < 0.0001) and 41.0% (SD = 27.8, p < 0.0001) for patients with a risk of less than 15%. The results indicate that all parts of the SVs are more likely to be contoured in men with >15% risk of SV involvement than those with <15% risk. However, radiation oncologists still contour a high percentage of SVs in men with <15% risk of SV involvement, suggesting that there may be over-treatment of SVs that increases the risk of rectal or bladder toxicity.

Aims/hypothesis: The Latino population has been systematically underrepresented in large-scale genetic analyses, and previous studies have relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) released the largest multi-ancestry genotype reference panel representing a unique opportunity to analyse rare genetic variations in the Latino population. We hypothesise that a more comprehensive analysis of low/rare variation using the TOPMed panel would improve our knowledge of the genetics of type 2 diabetes in the Latino population., Methods: We evaluated the TOPMed imputation performance using genotyping array and whole-exome sequence data in six Latino cohorts. To evaluate the ability of TOPMed imputation to increase the number of identified loci, we performed a Latino type 2 diabetes genome-wide association study (GWAS) meta-analysis in 8150 individuals with type 2 diabetes and 10,735 control individuals and replicated the results in six additional cohorts including whole-genome sequence data from the All of Us cohort., Results: Compared with imputation with 1000G, the TOPMed panel improved the identification of rare and low-frequency variants. We identified 26 genome-wide significant signals including a novel variant (minor allele frequency 1.7%; OR 1.37, p=3.4 × 10 -9 ). A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improved the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance., Conclusions/interpretation: Our results demonstrate the utility of TOPMed imputation for identifying low-frequency variants in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores., Data Availability: Full summary statistics are available through the Common Metabolic Diseases Knowledge Portal ( https://t2d.hugeamp.org/downloads.html ) and through the GWAS catalog ( https://www.ebi.ac.uk/gwas/ , accession ID: GCST90255648). Polygenic score (PS) weights for each ancestry are available via the PGS catalog ( https://www.pgscatalog.org , publication ID: PGP000445, scores IDs: PGS003443, PGS003444 and PGS003445)., (© 2023. The Author(s).)