No Patient Left Behind: A Novel Paradigm to Fulfill Hepatitis C Virus Treatment for Rural Patients.

Background: This study evaluates a novel multidisciplinary program providing expanded access to hepatitis C virus (HCV) treatment for rural Appalachian patients in South Carolina. This program identified patients via an opt-out emergency department screening program, and it aimed to achieve HCV cure by using community paramedics (CPs) to link and monitor patients from treatment initiation through 12-week sustained virologic response (SVR). Methods: Patients aged ≥18 years who were HCV RNA positive were eligible for enrollment if they failed to appear for a scheduled HCV appointment or reported barriers to accessing office-based treatment. CPs provided home visits (initial and 4, 12, and 24 weeks) using a mobile Wi-Fi hotspot to support telemedicine appointments (compliant with the Health Insurance Portability and Accountability Act) and perform focused physical assessments, venipuncture, and coordinated home delivery of medications. Statistics described participant characteristics, prevalence of SVR, and patient satisfaction results at 12 weeks posttreatment. Results: Thirty-four patients were eligible for SVR laboratory tests by 31 August 2023; the majority were male (61.7%) and White (64.7%) with an average age of 56 years (SD, 11.7). Twenty-eight (82.4%) completed treatment and achieved 12-week SVR. Six (17.6%) were lost to follow-up. Two-thirds strongly agreed that they were satisfied with the overall care that they received, and half strongly agreed that their overall health had improved. Conclusions: This CP-augmented treatment program demonstrated success curing HCV for rural patients who lacked access to office-based treatment. Other health care systems may consider this novel delivery model to treat hard-to-reach individuals who are HCV positive.

Underreporting Supplements: A Case of Drug-induced Liver Injury Due to a Testosterone Booster.

Acute liver injuries (ALIs) are caused by a wide range of etiologies, and determining the cause can often be challenging. Detailed history taking is essential in patients with liver injuries to promptly determine the underlying source of injury and for timely treatment and prognosis. A 27-year-old active duty man presented to the emergency department (ED) with jaundice. On medication reconciliation, he only reported taking acetaminophen for a recent upper respiratory infection. The patient had an ALI and was treated with N-acetyl cysteine for presumed acetaminophen toxicity. Initially, his liver-associated enzymes (LAEs) improved, but 2 weeks after discharge, he returned to the ED upon referral from ship medical for jaundice and worsening liver injury. Repeated query into the patient's history revealed that he was using a testosterone booster supplement for 6 months preceding initial hospitalization. After evaluation of other etiologies for liver injury returned negative, drug-induced liver injury from the testosterone booster was determined to be the underlying etiology. With discontinuation of the supplement, his liver injury improved. Hepatotoxicity is a major concern in supplement use; however, it is largely underreported. Supplements are often not recognized or reported as medications by patients, leading to failure to identify them as potential toxicants. This case highlights the importance of including supplement education and questioning in the evaluation of ALI and maintaining a high index of suspicion when other common etiologies of liver disease are negative.

Impact of the COVID-19 pandemic on new parents enrolled in the 'BABY1000' birth cohort study in Sydney, Australia: A mixed-methods study.

OBJECTIVE: The COVID-19 pandemic was, and continues to be, uniquely experienced by women in the perinatal period and their families. Whilst long-term impacts of the pandemic are unknown, exposures in pregnancy and early life have impacts across the life-course and future generations. The objective of this manuscript was to explore how the pregnancy, postpartum and parenting experiences of a subset of participants from the 'BABY1000' cohort in Sydney, Australia, were affected by the COVID-19 pandemic, and explore associations between these experiences and state anxiety. METHODS: Mixed methods were used. Participants were requested to complete an online survey including the State-Trait Anxiety Inventory short form (STAI-6), followed by an invitation to participate in focus group discussions (FGDs). RESULTS: From September to November 2021, 88 parents completed the survey (mean age 33.5 years, 60% born in Australia, 58% primiparous). Twenty-two parents participated in FGDs. Six themes were identified regarding the experience of parents: (1) Maternal support, (2) Family relationships, (3) Stress and mental health, (4) Healthcare, (5) Family lifestyle and routine, and (6) Long-term impacts. The mean STAI-6 score was 40 (SD 12.3), representing high anxiety. High anxiety was significantly associated with concern regarding COVID-19 and feeling overburdened and lonely. CONCLUSIONS: The COVID-19 pandemic and associated public health orders significantly impacted participants' pregnancy, postpartum and parenting experiences. Whilst these experiences included some unexpected positives, for many, these were outweighed by negative impacts on mental health, social support, health behaviours, and family relationships. IMPLICATIONS FOR PUBLIC HEALTH: Ongoing longitudinal research is imperative to identify potential long-term effects of the pandemic across the life-course, better support families in the short and long-term, and plan for public health crises in the future.

Cohort profile: the BABY1000 pilot prospective longitudinal birth cohort study based in Sydney, Australia.

PURPOSE: The health of parents prior to conception, a woman's health during pregnancy and the infant's environment across their first months and years collectively have profound effects on the child's health across the lifespan. Since there are very few cohort studies in early pregnancy, gaps remain in our understanding of the mechanisms underpinning these relationships, and how health may be optimised. 'BABY1000', a pilot prospective longitudinal birth cohort study, aims to (1) identify factors before and during pregnancy and early life that impact longer-term health and (2) assess the feasibility and acceptability of study design to inform future research. PARTICIPANTS: Participants were based in Sydney, Australia. Women were recruited at preconception or 12 weeks' gestation, and data were collected from them throughout pregnancy and postpartum, their children until the age of 2 years, and dietary information from a partner (if able) at the last study visit. The pilot aimed to recruit 250 women. However, recruitment ceased earlier than planned secondary to limitations from the COVID-19 pandemic and the final number of subjects was 225. FINDINGS TO DATE: Biosamples, clinical measurements and sociodemographic/psychosocial measures were collected using validated tools and questionnaires. Data analysis and 24-month follow-up assessments for children are ongoing. Key early findings presented include participant demographics and dietary adequacy during pregnancy. The COVID-19 pandemic and associated public health and research restrictions affected recruitment of participants, follow-up assessments and data completeness. FUTURE PLANS: The BABY1000 study will provide further insight into the developmental origins of health and disease and inform design and implementation of future cohort and intervention studies in the field. Since the BABY1000 pilot was conducted across the COVID-19 pandemic, it also provides unique insight into the early impacts of the pandemic on families, which may have effects on health across the lifespan.

SARS-CoV-2 leverages airway epithelial protective mechanism for viral infection.

Despite much concerted effort to better understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection, relatively little is known about the dynamics of early viral entry and infection in the airway. Here we analyzed a single-cell RNA sequencing dataset of early SARS-CoV-2 infection in a humanized in vitro model, to elucidate key mechanisms by which the virus triggers a cell-systems-level response in the bronchial epithelium. We find that SARS-CoV-2 virus preferentially enters the tissue via ciliated cell precursors, giving rise to a population of infected mature ciliated cells, which signal to basal cells, inducing further rapid differentiation. This feedforward loop of infection is mitigated by further cell-cell communication, before interferon signaling begins at three days post-infection. These findings suggest hijacking by the virus of potentially beneficial tissue repair mechanisms, possibly exacerbating the outcome. This work both elucidates the interplay between barrier tissues and viral infections and may suggest alternative therapeutic approaches targeting non-immune response mechanisms.

Reduction in Tamoxifen Metabolites Endoxifen and N-desmethyltamoxifen With Chronic Administration of Low Dose Cannabidiol: A CYP3A4 and CYP2D6 Drug Interaction.

BACKGROUND: Cannabidiol (CBD) serves as a promising medicine, with few known adverse effects apart from the potential of drug interactions with the cytochrome P450 system. It has been hypothesized drug interactions may occur with chemotherapeutic agents, but no supporting evidence has been published to date. CASE: A 58-year-old female with a history of bilateral breast carcinoma in remission, was treated with tamoxifen for breast cancer prevention for over 6 years. CBD was instituted to treat persistent postsurgical pain, inadequately managed by alternate analgesics. It was postulated that CBD may diminish tamoxifen metabolism by CYP3A4 and 2D6 to form active metabolite endoxifen, which exerts the anticancer benefits. Endoxifen, tamoxifen, N-desmetyltamoxifen and 4-hydroxytamoxifen levels were collected while the patient chronically received CBD 40 mg/day, and after a 60-day washout. Upon discontinuation of CBD 40 mg/day, it was observed that endoxifen levels increased by 18.75% and N-desmethyltamoxifen by 9.24%, while 4-hydroxytamoxifen remained unchanged. CONCLUSION: CBD at a low dose of 40 mg/day resulted in the potential inhibition of CYP3A4 and/or CYP2D6. Patients receiving CBD and interacting chemotherapeutic drugs, such as tamoxifen, require monitoring to identify possible subtherapeutic response to treatment. Further pharmacokinetic studies are required to ascertain the dynamics of this drug interaction.

Quantifying Proximal Collecting Tubule Deficiency in Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Fetopathy.

INTRODUCTION: Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers (AAs) are used for several indications, with cessation recommended in pregnancy due to toxic effects. AA fetopathy phenotype is similar to renal tubular dysgenesis including reduced proximal convoluted tubules (PCTs). Our study aimed to quantify the reduction of PCTs in fetuses and infants with prenatal exposure to AAs. MATERIALS AND METHODS: We identified 5 fetal AA exposure cases that underwent autopsy at our institution between 2011 and 2018 and compared with 5 gestational age-matched controls. Immunohistochemistry with CD10 and epithelial membrane antigen (EMA) was utilized. RESULTS: CD10 and EMA identified a median PCT density of 19.0% ± 12.3% in AA fetopathy patients, significantly less than controls (52.8% ± 4.4%; p < 0.0001). One case with in utero cessation had a PCT density of 34.2% ± 0.2%. Among other AA fetopathy findings, 1 case demonstrated unilateral renal vein thrombosis and 4 had hypocalvaria. CONCLUSIONS: We have quantified the reduction in AA fetopathy PCT density, and demonstrated in utero cessation may recover PCT differentiation. Future studies may benefit from calculating PCT percentage as a potential biomarker to correlate with post-natal renal function and maternal factors including medication type, dosage, duration, and time from medication cessation.

Simultaneous evaluation of multiple microarray surface chemistries through real-time interferometric imaging.

Surface chemistry is a crucial aspect for microarray modality biosensor development. The immobilization capability of the functionalized surface is indeed a limiting factor for the final yield of the binding reaction. In this work, we were able to simultaneously compare the functionality of protein ligands that were locally immobilized on different polymers, while on the same solid support, therefore demonstrating a new way of multiplexing. Our goal was to investigate, in a single experiment, both the immobilization efficiency of a group of reactive polymers and the resulting affinity of the tethered molecules. This idea was demonstrated by spotting many reactive polymers on a Si/SiO2 chip and depositing the molecular probes on the spots immediately after. As a proof of concept, we focused on which polymers would better immobilize a model protein (α-Lactalbumin) and a peptide (LAC-1). We successfully showed that this protocol is applicable to proteins and peptides with a good efficiency. By means of real-time binding measurements performed with the interferometric reflectance imaging sensor (IRIS), local functionalization proved to be comparable to the classical flat coating solution. The final outcome highlights the multiplexing power of this method: first, it allows to characterize dozens of polymers at once. Secondly, it removes the limitation, related to coated surfaces, that only molecules with the same functional groups can be tethered to the same solid support. By applying this protocol, many types of molecules can be studied simultaneously and immobilization for each probe can be individually optimized.

Levator ani muscle (LAM) anatomical volume compared to age and body mass index (BMI) of patients.

INTRODUCTION AND HYPOTHESIS: The levator ani muscle (LAM) plays an important role in pelvic support. Estimated levator ani subtended volume (eLASV) is an objective measurement of the anatomical volume of the LAM obtained from pelvic MRIs. The aim of this study was to assess the relationship between the anatomical volume of LAM to the age and body mass index (BMI) of a surgical patient based on our previous published cutoff value of increased LAM volume as measured by pelvic MRIs (eLASV > 38.5). We hypothesize that increasing age and BMI will both be correlated with the increasing volumes of LAM. METHODS: We conducted a secondary analysis of an Institutional Review Board-approved retrospective cohort study. Standard protocol pelvic MRI measurements, including the pubococcygeal line, H-line, and M-line, were collected along with the calculated width of the levator ani hiatus (eLASV = - 72.838 + 0.598H-line + 1.217 M-line + 1.136WLH). Comparison to patients' age and BMI was assessed using the Wilcoxon-Mann-Whitney (continuous) and chi-square test (group). Spearman's correlation analysis was used to explore the relationship between age and BMI to eLASV. RESULTS: Patients with elevated LAM volumes of eLASV were more likely to be older than patients with low volume of LAM, with median age 65 (37, 83) vs. 49.5 (28, 72), respectively (p < 0.001). We observed no difference in median BMI between patients with elevated volumes of eLASV compared with patients with low volumes of eLASV. CONCLUSIONS: Increasing age of women appears to be directly related to elevated volumes for levator ani muscle morphology when measured with eLASV.

Single-cell connectomic analysis of adult mammalian lungs.

Efforts to decipher chronic lung disease and to reconstitute functional lung tissue through regenerative medicine have been hampered by an incomplete understanding of cell-cell interactions governing tissue homeostasis. Because the structure of mammalian lungs is highly conserved at the histologic level, we hypothesized that there are evolutionarily conserved homeostatic mechanisms that keep the fine architecture of the lung in balance. We have leveraged single-cell RNA sequencing techniques to identify conserved patterns of cell-cell cross-talk in adult mammalian lungs, analyzing mouse, rat, pig, and human pulmonary tissues. Specific stereotyped functional roles for each cell type in the distal lung are observed, with alveolar type I cells having a major role in the regulation of tissue homeostasis. This paper provides a systems-level portrait of signaling between alveolar cell populations. These methods may be applicable to other organs, providing a roadmap for identifying key pathways governing pathophysiology and informing regenerative efforts.

Overall user satisfaction with family planning services and associated quality care factors: a cross-sectional analysis.

BACKGROUND: Studies of user satisfaction with family planning services (FPSs) have been conducted in different countries, and have been employed to identify ways of improving health, reducing costs and implementing reforms. The present work is the first-ever study undertaken in Mexico on the subject. Our objective was to identify how overall user satisfaction with FPSs in Mexico was related to: healthcare logistics, the functional value of services and the quality of interpersonal relations. METHODS: Users of 18 public clinics were surveyed in 2015. Data collected referred to their past and present use of FPSs, as well as to their perceptions of the services provided. We built a logistic regression model with potentially influential variables in order to assess their association with overall satisfaction. RESULTS: According to the self-reports of the 722 users interviewed, the following factors were decisive in their overall satisfaction with services: receiving sufficient information during visits (OR = 3.38; 95% CI:1.88-6.06), feeling that their opinions were taken into consideration by clinic staff (OR = 2.58; 95% CI:1.14-5.85), feeling that the motives for their visits were addressed (OR = 2.71; 95% CI:1.29-5.71), being assigned enough time for consultation (OR = 2.35; 95% CI:1.26-4.37), having the opportunity to ask questions and clarify doubts (OR = 2.31; 95% CI:1.21-4.43), experiencing no or few interruptions during their medical consultations (OR = 1.97;95% CI:1.10-3.51), and feeling satisfied with the contraceptive method provided (OR = 1.79; 95% CI:1.03-3.11). CONCLUSIONS: Service providers must be kept well informed on the perspective of users concerning user expectations. Taking into account the cultural context and perceived needs of users while providing service would improve the quality of care and, hence, the overall satisfaction of users.

Arsenic and cigarette smoke synergistically increase DNA oxidation in the lung.

Epidemiological evidence has indicated that arsenic and cigarette smoking exposure act synergistically to increase the incidence of lung cancer. Since oxidative damage of DNA has been linked to cancer, our hypothesis is that aerosolized arsenic and cigarette smoke work synergistically to increase oxidative stress and increase DNA oxidation in the lung. To test this hypothesis male Syrian golden hamsters were exposed to room air (control), aerosolized arsenic compounds (3.2 mg/m3 for 30 minutes), cigarette smoke (5 mg/m3 for 30 minutes), or both smoke and arsenic. Exposures were for 5 days/week for 5 or 28-days. Animals were sacrificed one day after the last exposure. In the 28-day group, glutathione levels and DNA oxidation (8-oxo-2'-deoxyguanosine (8-oxo-dG)) were determined. Our results show that in the 28-day arsenic/smoke group there was a significant decrease in both the reduced and total glutathione levels compared with arsenic or smoke alone. This correlated with a 5-fold increase in DNA oxidation as shown by HPLC. Immunohistochemical localization of 8-oxo-dG showed increase staining in nuclei of airway epithelium and subadjacent interstitial cells. These results show that dual exposure of arsenic and cigarette smoke at environmentally relevant levels can act synergistically to cause DNA damage.

Bilateral organization of unilaterally generated activity in lumbar spinal motoneurons of the rat.

The spinal nucleus of the bulbocavernosus (SNB) is a medially located, bilaterally organized sexually dimorphic motor nucleus in the lumbar spinal cord of the male rat. To begin to assess the potential functional significance of this bilateral organization, we recorded ipsi- and contralateral SNB motor nerve activity following unilateral spinal stimulation and examined the timing, pattern, and recruitment of population motoneuron activity. A possible mechanism for bilateral communication, gap junctional intercellular communication, was also investigated because dye coupling experiments indicate an extensive syncytium in which SNB motoneurons are coupled with each other and neighboring interneurons. An in vivo peripheral nerve recording paradigm was used: a bipolar stimulating electrode was placed on dorsal root L6, and bipolar recording electrodes were placed bilaterally on the SNB motor nerves. All processes were severed distal to electrode placement to isolate the central preparation; recruitment curves of motoneuronal activity were then generated. Amplitude of peak to peak recruitment was greater in the contralateral motor nerve than in the ipsilateral nerve. Response latency, Fourier transform and spike counts showed no evidence of ipsi/contralateral asymmetry. Recruitment was attenuated both ipsi- and contralaterally after pharmacological gap junction blockade, but antidromic stimulation could not drive activity in contralateral motor axons. These results indicate that unilateral input to the SNB may be differentially modulated to produce functionally distinct output in the two separate halves of the nucleus. We also discuss the potential modulatory role of gap junctions in the activity of the SNB.

Patterns of dye coupling in lumbar motor nuclei of the rat.

Gap junctions exist on motoneurons of the spinal nucleus of the bulbocavernosus (SNB) and the dorsolateral nucleus (DLN), both sexually dimorphic motor nuclei in the lumbar spinal cord of the rat. In addition, messenger RNA for gap junction proteins is expressed in motoneurons of the retrodorsolateral nucleus (RDLN), a nondimorphic spinal motor nucleus that innervates a muscle of the foot. Gap junctions on SNB and DLN motoneurons are androgen sensitive; the number and size of gap junctions decrease following castration, a change that can be reversed with exogenous testosterone replacement. In contrast, RDLN gap junction mRNA levels remain constant throughout hormone manipulation. In this study, dye coupling was used to examine patterns of gap junction-mediated connectivity in these three lumbar spinal motor nuclei. Injection of dye into single motoneurons resulted in spatially extensive labeling of neighboring cells in all three nuclei; significantly more coupling was observed in the sexually dimorphic nuclei than in the RDLN. Dye-coupled clusters of cells included motoneurons and interneurons; coupling was bilateral in the SNB. Treatment with oleamide, a gap junction blocker, completely attenuated labeling. In all nuclei, androgen manipulation did not alter the number, identity, or distribution of coupled cells. Thus, sexually dimorphic nuclei in the spinal cord exhibit greater dye coupling than do nondimorphic populations, and the patterns of connectivity are insensitive to androgen despite modification of their number and size.