Impact of COVID-19 pandemic on physician-scientist trainees to faculty one year into the pandemic.

PURPOSE: Physician-scientists play a crucial role in advancing biomedical sciences. Proportionally fewer physicians are actively engaged in scientific pursuits, attributed to attrition in the training and retention pipeline. This national study evaluated the ongoing and longer-term impact of the COVID-19 pandemic on stress levels, research productivity, and optimism for physician-scientists at all levels of training. METHODS: A multi-institutional cross-sectional survey of medical students, graduate students, and residents/fellows/junior faculty (RFJF) was conducted from April to August 2021 to assess the impact of COVID-19 on individual stress, productivity, and optimism. Multivariate regression analyses were performed to identify associated variables and unsupervised variable clustering techniques were employed to identify highly correlated responses. RESULTS: A total 677 respondents completed the survey, representing different stages of physician-scientist training. Respondents report high levels of stress (medical students: 85%, graduate students: 63%, RFJF: 85%) attributed to impaired productivity concerns, concern about health of family and friends, impact on personal health and impairment in training or career development. Many cited impaired productivity (medical students: 65% graduate students: 79%, RFJF: 78%) associated with pandemic impacts on training, labs closures and loss of facility/resource access, and social isolation. Optimism levels were low (medical students: 37%, graduate students: 38% and RFJF: 39%) with females less likely to be optimistic and more likely to report concerns of long-term effects of COVID-19. Optimism about the future was correlated with not worrying about the long-term effects of COVID-19. Since the COVID-19 pandemic, all respondents reported increased prioritization of time with family/friends (67%) and personal health (62%) over career (25%) and research (24%). CONCLUSIONS: This national survey highlights the significant and protracted impact of the COVID-19 pandemic on stress levels, productivity, and optimism among physician-scientists and trainees. These findings underscore the urgent need for tailored support, including mental health, academic, and career development assistance for this biomedical workforce.

Access to Neurorehabilitation Interdisciplinary Outpatient Programs in British Columbia.

This survey explored access to British Columbia (BC) hospital-based neurorehabilitation outpatient programs (HB-NROPs). Fifteen rehabilitation-focused healthcare providers were interviewed. Wait times for HB-NROPs were up to 3 months for initial appointments, and inclusion criteria were variable. Two HB-NROPs had occasional access to specialized physicians. Informal communication methods were preferred modes of collaboration. BC HB-NROPs varied in access, use of interdisciplinary care, and outcome measures used to measure performance. The lack of coverage for nonphysician services may be a barrier to collaborative care in the community. Future projects should explore solutions to improve funding and equal access to BC HB-NROPs.

Two Distinct L-Lactate Dehydrogenases Play a Role in the Survival of Neisseria gonorrhoeae in Cervical Epithelial Cells.

L-lactate is an abundant metabolite in a number of niches in host organisms and represents an important carbon source for bacterial pathogens such as Neisseria gonorrhoeae. In this study, we describe an alternative, iron-sulfur cluster-containing L-lactate dehydrogenase (LutACB), that is distinct from the flavoprotein L-lactate dehydrogenase (LldD). Expression of lutACB was found to be positively regulated by iron, whereas lldD was more highly expressed under conditions of iron-limitation. The functional role of LutACB and LldD was reflected in in vitro studies of growth and in the survival of N gonorrhoeae in primary cervical epithelial cells.

Structural basis of thiol-based regulation of formaldehyde detoxification in H. influenzae by a MerR regulator with no sensor region.

Pathogenic bacteria such as Haemophilus influenzae, a major cause of lower respiratory tract diseases, must cope with a range of electrophiles generated in the host or by endogenous metabolism. Formaldehyde is one such compound that can irreversibly damage proteins and DNA through alkylation and cross-linking and interfere with redox homeostasis. Its detoxification operates under the control of HiNmlR, a protein from the MerR family that lacks a specific sensor region and does not bind metal ions. We demonstrate that HiNmlR is a thiol-dependent transcription factor that modulates H. influenzae response to formaldehyde, with two cysteine residues (Cys54 and Cys71) identified to be important for its response against a formaldehyde challenge. We obtained crystal structures of HiNmlR in both the DNA-free and two DNA-bound forms, which suggest that HiNmlR enhances target gene transcription by twisting of operator DNA sequences in a two-gene operon containing overlapping promoters. Our work provides the first structural insights into the mechanism of action of MerR regulators that lack sensor regions.

A role for lactate dehydrogenases in the survival of Neisseria gonorrhoeae in human polymorphonuclear leukocytes and cervical epithelial cells.

Lactate is an abundant metabolite, produced by host tissues and commensal organisms, and it represents an important potential carbon source for bacterial pathogens. In the case of Neisseria spp., the importance of the lactate permease in colonization of the host has been demonstrated, but there have been few studies of lactate metabolism in pathogenic Neisseria in the postgenomic era. We describe herein the characterization of genome-annotated, respiratory, and substrate-level lactate dehydrogenases (LDHs) from the obligate human pathogen Neisseria gonorrhoeae. Biochemical assays using N. gonorrhoeae 1291 wild type and isogenic mutant strains showed that cytoplasmic LdhA (NAD(+)-dependent D-lactate dehydrogenase) and the membrane-bound respiratory enzymes, LdhD (D-lactate dehydrogenase) and LldD (L-lactate dehydrogenase) are correctly annotated. Mutants lacking LdhA and LdhD showed greatly reduced survival in neutrophils compared with wild type cells, highlighting the importance of D-lactate metabolism in gonococcal survival. Furthermore, an assay of host colonization using the well-established human primary cervical epithelial cell model revealed that the two respiratory enzymes make a significant contribution to colonization of and survival within the microaerobic environment of the host. Taken together, these data suggest that host-derived lactate is critical for the growth and survival of N. gonorrhoeae in human cells.

Differential Effects of Ascites and Hepatic Encephalopathy on Waitlist Mortality in Liver Transplantation by MELD 3.0.

Background: MELD 3.0 introduces changes to address waitlist disparities for liver transplant (LT) candidates. Ascites and hepatic encephalopathy (HE) are important milestones in the natural history of cirrhosis regardless of the Model for End-Stage Liver Disease (MELD) score. We aim to assess the impact of ascites and HE and its interaction with MELD 3.0 on waitlist mortality. Methods: This is a retrospective study of patients listed for LT in the Organ Procurement and Transplantation Network database from 2016 to 2021. The primary outcome was waitlist mortality (death/delisting for too sick to LT). Ascites/HE were classified as moderate ascites without moderate HE (mAscites), moderate HE without moderate ascites (mHE), both moderate ascites/HE (mBoth), and neither. MELD 3.0 scores were categorized as <20, 20-29, 30-39, and ≥40. Results: Of 39 025 candidates, 29% had mAscites, 3% mHE, and 8% mBoth. One-year waitlist mortality was 30%, 38%, and 47%, respectively, compared with 17% (all P < 0.001) for those with neither. In multivariable Cox regression, the adjusted risk of waitlist mortality associated with mAscites (versus neither) was a hazard ratio (HR) of 1.76 (95% confidence interval [CI], 1.55-2.00) when the MELD 3.0 score was <20, significantly higher than when the MELD 3.0 score was 20-29 (HR 1.40; 95% CI, 1.27-1.54), 30-39 (HR 1.19; 95% CI, 1.04-1.35), and ≥40 (HR 1.14; 95% CI, 0.91-1.43, interaction P < 0.05 for all). A similar pattern was observed by MELD 3.0 for both moderate ascites/HE. Conclusions: The presence of moderate ascites alone, or combined with moderate HE, not only increases the risk of waitlist mortality but also has a differential effect by MELD 3.0, especially at lower MELD scores. Earlier strategies addressing this group and improving treatment plans or access to LT regardless of MELD remain needed.

Loss of Sarm1 reduces retinal ganglion cell loss in chronic glaucoma.

Glaucoma is one of the leading causes of irreversible blindness worldwide and vision loss in the disease results from the deterioration of retinal ganglion cells (RGC) and their axons. Metabolic dysfunction of RGC plays a significant role in the onset and progression of the disease in both human patients and rodent models, highlighting the need to better define the mechanisms regulating cellular energy metabolism in glaucoma. This study sought to determine if Sarm1, a gene involved in axonal degeneration and NAD+ metabolism, contributes to glaucomatous RGC loss in a mouse model with chronic elevated intraocular pressure (IOP). Our data demonstrate that after 16 weeks of elevated IOP, Sarm1 knockout (KO) mice retain significantly more RGC than control animals. Sarm1 KO mice also performed significantly better when compared to control mice during optomotor testing, indicating that visual function is preserved in this group. Our findings also indicate that Sarm1 KO mice display mild ocular developmental abnormalities, including reduced optic nerve axon diameter and lower visual acuity than controls. Finally, we present data to indicate that SARM1 expression in the optic nerve is most prominently associated with oligodendrocytes. Taken together, these data suggest that attenuating Sarm1 activity through gene therapy, pharmacologic inhibition, or NAD+ supplementation, may be a novel therapeutic approach for patients with glaucoma.

Laboratory evaluation of occupational exposure to hand-arm vibration (HAV) during grounds maintenance equipment operations.

INTRODUCTION AND OBJECTIVE: About 2.5 million workers in the USA are exposed to hand-arm vibration (HAV) from power tools. The aims of the study were to evaluate occupational exposure to HAV during grounds maintenance equipment operations and the effect of general work gloves on vibration magnitude under controlled laboratory conditions. MATERIAL AND METHODS: A simulation of grass trimmer, backpack blower, and chainsaw operations was conducted by two participants to measure vibration total value (ahv) using vibration dosimeters wearing gloves. ahv was also measured on the bare hands during grass trimmer and backpack blower operations. RESULTS: ahv of the gloved hand was 3.5-5.8, 1.1-2.0, and 3.0-3.6 m/s2 during the grass trimmer, backpack blower, and chainsaw operations, respectively. ahv of the bare hand was 4.5-7.2 and 1.2-2.3 m/s2 for the grass trimmer and blower operations, respectively. CONCLUSIONS: The highest HAV exposure was observed during the grass trimmer operation which showed higher vibration attenuation of the gloves.

Tracking B Cell Memory to SARS-CoV-2 Using Rare Cell Analysis System.

Rapid mutations within SARS-CoV-2 are driving immune escape, highlighting the need for in-depth and routine analysis of memory B cells (MBCs) to complement the important but limited information from neutralizing antibody (nAb) studies. In this study, we collected plasma samples and peripheral blood mononuclear cells (PBMCs) from 35 subjects and studied the nAb titers and the number of antigen-specific memory B cells at designated time points before and after vaccination. We developed an assay to use the MiSelect R II System with a single-use microfluidic chip to directly detect the number of spike-receptor-binding domain (RBD)-specific MBCs in PBMCs. Our results show that the number of spike-RBD-specific MBCs detected by the MiSelect R II System is highly correlated with the level of nAbs secreted by stimulated PBMCs, even 6 months after vaccination when nAbs were generally not present in plasma. We also found antigen-specific cells recognizing Omicron spike-RBD were present in PBMCs from booster vaccination of subjects, but with a high variability in the number of B cells. The MiSelect R II System provided a direct, automated, and quantitative method to isolate and analyze subsets of rare cells for tracking cellular immunity in the context of a rapidly mutating virus.

Impact of COVID-19 Pandemic on Physician-Scientist Trainees to Faculty One Year into the Pandemic.

Purpose: Physician-scientists play a crucial role in advancing biomedical sciences. Proportionally fewer physicians are actively engaged in scientific pursuits, attributed to attrition in the training and retention pipeline. This national study evaluated the ongoing and longer-term impact of the COVID-19 pandemic on research productivity for physician-scientists at all levels of training. Methods: A survey of medical students, graduate students, and residents/fellows/junior faculty (RFJF) was conducted from April to August 2021 to assess the impact of COVID-19 on individual stress, productivity, and optimism. Multivariate regression analyses were performed to identify associated variables and unsupervised variable clustering techniques were employed to identify highly correlated responses. Results: A total 677 respondents completed the survey, representing different stages of physician-scientist training. Respondents report high levels of stress (medical students: 85%, graduate students: 63%, RFJF: 85%) attributed to impaired productivity concerns, concern about health of family and friends, impact on personal health and impairment in training or career development. Many cited impaired productivity (medical students: 65% graduate students: 79%, RFJF: 78%) associated with pandemic impacts on training, labs closures and loss of facility/resource access, and social isolation. Optimism levels were low (medical students: 37%, graduate students: 38% and RFJF: 39%) with females less likely to be optimistic and more likely to report concerns of long-term effects of COVID-19. Optimism about the future was correlated with not worrying about the long-term effects of COVID-19. Since the COVID-19 pandemic, all respondents reported increased prioritization of time with family/friends (67%) and personal health (62%) over career (25%) and research (24%). Conclusions: This national survey highlights the significant and protracted impact of the COVID-19 pandemic on stress levels, productivity, and optimism among physician-scientists and trainees. These findings underscore the urgent need for tailored support, including mental health, academic, and career development assistance for this biomedical workforce.

Phenotypic characterization of a copA mutant of Neisseria gonorrhoeae identifies a link between copper and nitrosative stress.

NGO0579 is annotated copA in the Neisseria gonorrhoeae chromosome, suggesting that it encodes a cation-transporting ATPase specific for copper ions. Compared to wild-type cells, a copA mutant was more sensitive to killing by copper ions but not to other transition metals. The mutant also accumulated a greater amount of copper, consistent with the predicted role of CopA as a copper efflux pump. The copA mutant showed a reduced ability to invade and survive within human cervical epithelial cells, although its ability to form a biofilm on the surface of these cells was not significantly different from that of the wild type. In the presence of copper, the copA mutant exhibited increased sensitivity to killing by nitrite or nitric oxide. Therefore, we concluded that copper ion efflux catalyzed by CopA is linked to the nitrosative stress defense system of Neisseria gonorrhoeae. These observations suggest that copper may exert its effects as an antibacterial agent in the innate immune system via an interaction with reactive nitrogen species.

A community-based study on associations between PM2.5 and PM1 exposure and heart rate variability using wearable low-cost sensing devices.

Few studies have investigated the effect of personal PM2.5 and PM1 exposures on heart rate variability (HRV) for a community-based population, especially in Asia. This study evaluates the effects of personal PM2.5 and PM1 exposure on HRV during two seasons for 35 healthy adults living in an urban community in Taiwan. The low-cost sensing (LCS) devices were used to monitor the PM levels and HRV, respectively, for two consecutive days. The mean PM2.5 and PM1 concentrations were 13.7 ± 11.4 and 12.7 ± 10.5 µg/m3 (mean ± standard deviation), respectively. Incense burning was the source that contributed most to the PM2.5 and PM1 concentrations, around 9.2 µg/m3, while environmental tobacco smoke exposure had the greatest impacts on HRV indices, being associated with the highest decrease of 20.2% for high-frequency power (HF). The results indicate that an increase in PM2.5 concentrations of one interquartile range (8.7 µg/m3) was associated with a change of -1.92% in HF and 1.60% in ratio of LF to HF power (LF/HF). Impacts on HRV for PM1 were similar to those for PM2.5. An increase in PM1 concentrations of one interquartile range (8.7 µg/m3) was associated with a change of -0.645% in SDNN, -1.82% in HF and 1.54% in LF/HF. Stronger immediate and lag effects of PM2.5 exposure on HRV were observed in overweight/obese subjects (body mass index (BMI) ≥24 kg/m2) compared to the normal-weight group (BMI <24 kg/m2). These results indicate that even low-level PM concentrations can still cause changes in HRV, especially for the overweight/obese population.

Effects of low-frequency noise from wind turbines on heart rate variability in healthy individuals.

Wind turbines generate low-frequency noise (LFN, 20-200 Hz), which poses health risks to nearby residents. This study aimed to assess heart rate variability (HRV) responses to LFN exposure and to evaluate the LFN exposure (dB, LAeq) inside households located near wind turbines. Thirty subjects living within a 500 m radius of wind turbines were recruited. The field campaigns for LFN (LAeq) and HRV monitoring were carried out in July and December 2018. A generalized additive mixed model was employed to evaluate the relationship between HRV changes and LFN. The results suggested that the standard deviations of all the normal to normal R-R intervals were reduced significantly, by 3.39%, with a 95% CI = (0.15%, 6.52%) per 7.86 dB (LAeq) of LFN in the exposure range of 38.2-57.1 dB (LAeq). The indoor LFN exposure (LAeq) ranged between 30.7 and 43.4 dB (LAeq) at a distance of 124-330 m from wind turbines. Moreover, households built with concrete and equipped with airtight windows showed the highest LFN difference of 13.7 dB between indoors and outdoors. In view of the adverse health impacts of LFN exposure, there should be regulations on the requisite distances of wind turbines from residential communities for health protection.

Correction: Panel study using novel sensing devices to assess associations of PM2.5 with heart rate variability and exposure sources.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A ferrobotic system for automated microfluidic logistics.

Automated technologies that can perform massively parallelized and sequential fluidic operations at small length scales can resolve major bottlenecks encountered in various fields, including medical diagnostics, -omics, drug development, and chemical/material synthesis. Inspired by the transformational impact of automated guided vehicle systems on manufacturing, warehousing, and distribution industries, we devised a ferrobotic system that uses a network of individually addressable robots, each performing designated micro-/nanofluid manipulation-based tasks in cooperation with other robots toward a shared objective. The underlying robotic mechanism facilitating fluidic operations was realized by addressable electromagnetic actuation of miniature mobile magnets that exert localized magnetic body forces on aqueous droplets filled with biocompatible magnetic nanoparticles. The contactless and high-strength nature of the actuation mechanism inherently renders it rapid (~10 centimeters/second), repeatable (>10,000 cycles), and robust (>24 hours). The robustness and individual addressability of ferrobots provide a foundation for the deployment of a network of ferrobots to carry out cross-collaborative logistics efficiently. These traits, together with the reconfigurability of the system, were exploited to devise and integrate passive/active advanced functional components (e.g., droplet dispensing, generation, filtering, and merging), enabling versatile system-level functionalities. By applying this ferrobotic system within the framework of a microfluidic architecture, the ferrobots were tasked to work cross-collaboratively toward the quantification of active matrix metallopeptidases (a biomarker for cancer malignancy and inflammation) in human plasma, where various functionalities converged to achieve a fully automated assay.

Panel study using novel sensing devices to assess associations of PM2.5 with heart rate variability and exposure sources.

BACKGROUND/OBJECTIVE: This work applied a newly developed low-cost sensing (LCS) device (AS-LUNG-P) and a certified medical LCS device (Rooti RX) to assessing PM2.5 impacts on heart rate variability (HRV) and determining important exposure sources, with less inconvenience to subjects. METHODS: Observations using AS-LUNG-P were corrected by side-by-side comparison with GRIMM instruments. Thirty-six nonsmoking healthy subjects aged 20-65 years were wearing AS-LUNG-P and Rooti RX for 2-4 days in both Summer and Winter in Taiwan. RESULTS: PM2.5 exposures were 12.6 ± 8.9 µg/m3. After adjusting for confounding factors using the general additive mixed model, the standard deviations of all normal to normal intervals reduced by 3.68% (95% confidence level (CI) = 3.06-4.29%) and the ratios of low-frequency power to high-frequency power increased by 3.86% (CI = 2.74-4.99%) for an IQR of 10.7 µg/m3 PM2.5, with impacts lasting for 4.5-5 h. The top three exposure sources were environmental tobacco smoke, incense burning, and cooking, contributing PM2.5 increase of 8.53, 5.85, and 3.52 µg/m3, respectively, during 30-min intervals. SIGNIFICANCE: This is a pioneer in demonstrating application of novel LCS devices to assessing close-to-reality PM2.5 exposure and exposure-health relationships. Significant HRV changes were observed in healthy adults even at low PM2.5 levels.

Genetic pathway of major depressive disorder in shortening telomeric length.

CONTEXT: Shortened telomeric length has been associated with aging and monoamine oxidase A gene activity. The pathways of genetic activity and mental disorder in shortening telomeric length, however, remain unclear. OBJECTIVE: The purpose of this study was to explore the possible pathways of the monoamine oxidase A promoter, ApoE polymorphisms and telomeric length in major depressive disorder. METHODS: This study enrolled 253 unrelated patients with major depression in southern Taiwan, and was carried out between March 2001 and September 2004. In addition, 411 controls were randomly selected from the general population in southern Taiwan. RESULTS: Hierarchical regression showed that the influence of the monoamine oxidase A promoter and ApoE2 polymorphisms was not statistically significant to telomeric length, when additionally adjusting for major depressive disorder. A final robust structural equation model showed that aging and major depressive disorder both have a statistically significant shortening effect on telomeric length. Moreover, sex, the Apoepsilon2 allele, and the monoamine oxidase A promoter polymorphism have indirect effects on telomeric length. CONCLUSION: Major depressive disorder is a mediating factor between the monoamine oxidase A promoter polymorphism and telomeric length.

Source apportionment of urban air pollutants using constrained receptor models with a priori profile information.

Exposure to air pollutants such as volatile organic compounds (VOCs) and fine particulate matter (PM2.5) are associated with adverse health effects. This study applied multiple time resolution data of hourly VOCs and 24-h PM2.5 to a constrained Positive Matrix Factorization (PMF) model for source apportionment in Taipei, Taiwan. Ninety-two daily PM2.5 samples and 2208 hourly VOC measurements were collected during four seasons in 2014 and 2015. With some a priori information, we used different procedures to constrain retrieved factors toward realistic sources. A total of nine source factors were identified as: natural gas/liquefied petroleum gas (LPG) leakage, solvent use/industrial process, contaminated marine aerosol, secondary aerosol/long-range transport, oil combustion, traffic related, evaporative gasoline emission, gasoline exhaust, and soil dust. Results showed that solvent use/industrial process was the largest contributor (19%) to VOCs while the largest contributor to PM2.5 mass was secondary aerosol/long-range transport (57%). A robust regression analysis showed that secondary aerosol was mostly contributed by regional transport related factor (25%).

Dopamine D4 receptor gene and the -521C>T polymorphism of the upstream region of the dopamine D4 receptor gene in schizophrenia.

OBJECTIVE: The dopamine D4 receptor (DRD4) is a candidate gene for increasing genetic susceptibility to schizophrenia. A recent study found that a -521C>T promoter base pair change affects transcriptional regulation of the DRD4 gene. The present study was designed to investigate the role of both the -521C>T single nucleotide polymorphism and the DRD4 variable number tandem repeat (VNTR) polymorphism. METHODS: A case-control study of 630 Chinese schizophrenic patients and 428 Chinese controls was conducted to test for allelic association with schizophrenia. RESULTS: The number of DRD4 VNTR fragments was associated with schizophrenia. Long DRD4 VNTR fragments as opposed to short fragments were commoner in schizophrenia. No evidence was found for allelic association between the -521C>T DRD4 polymorphism and schizophrenia. CONCLUSIONS: This study provides preliminary and unconfirmed evidence for the involvement of the DRD4 repeat VNTR in the pathogenesis of schizophrenia.

Formaldehyde Stress Responses in Bacterial Pathogens.

Formaldehyde is the simplest of all aldehydes and is highly cytotoxic. Its use and associated dangers from environmental exposure have been well documented. Detoxification systems for formaldehyde are found throughout the biological world and they are especially important in methylotrophic bacteria, which generate this compound as part of their metabolism of methanol. Formaldehyde metabolizing systems can be divided into those dependent upon pterin cofactors, sugar phosphates and those dependent upon glutathione. The more prevalent thiol-dependent formaldehyde detoxification system is found in many bacterial pathogens, almost all of which do not metabolize methane or methanol. This review describes the endogenous and exogenous sources of formaldehyde, its toxic effects and mechanisms of detoxification. The methods of formaldehyde sensing are also described with a focus on the formaldehyde responsive transcription factors HxlR, FrmR, and NmlR. Finally, the physiological relevance of detoxification systems for formaldehyde in bacterial pathogens is discussed.