Miracle-dz/UniFAR-FTUs huggingface dataset:
Overexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation

During viremia, the HIV-specific memory response in lymph nodes is mediated by T-bethi B cells that inefficiently participate in affinity selection. Abrogated antibody responses in chronic infection Despite the presence of abundant and persistent antigen, chronic infections such as HIV often do not induce protective antibody responses. Memory B cells from people chronically infected with HIV have previously been reported to express the transcription factor T-bet. Austin et al. observed that T-bethi memory B cells were in the lymph nodes but not localized to germinal centers, where high-affinity antibody responses develop. Although clonally related to germinal center B cells, these T-bethi memory B cells had a lower frequency of somatic hypermutation and reduced capacity to neutralize HIV in vitro. Exclusion of T-bethi memory cells from germinal centers may be one mechanism contributing to the lack of a protective antibody response in most HIV infections. Nearly all chronic human infections are associated with alterations in the memory B cell (MBC) compartment, including a large expansion of CD19hiT-bethi MBC in the peripheral blood of HIV-infected individuals with chronic viremia. Despite their prevalence, it is unclear how these B cells arise and whether they contribute to the inefficiency of antibody-mediated immunity in chronic infectious diseases. We addressed these questions by characterizing T-bet–expressing B cells in lymph nodes (LN) and identifying a strong T-bet signature among HIV-specific MBC associated with poor immunologic outcome. Confocal microscopy and quantitative imaging revealed that T-bethi B cells in LN of HIV-infected chronically viremic individuals distinctly accumulated outside germinal centers (GC), which are critical for optimal antibody responses. In single-cell analyses, LN T-bethi B cells of HIV-infected individuals were almost exclusively found among CD19hi MBC and expressed reduced GC-homing receptors. Furthermore, HIV-specific B cells of infected individuals were enriched among LN CD19hiT-bethi MBC and displayed a distinct transcriptome, with features similar to CD19hiT-bethi MBC in blood and LN GC B cells (GCBC). LN CD19hiT-bethi MBC were also related to GCBC by B cell receptor (BCR)–based phylogenetic linkage but had lower BCR mutation frequencies and reduced HIV-neutralizing capacity, consistent with diminished participation in GC-mediated affinity selection. Thus, in the setting of chronic immune activation associated with HIV viremia, failure of HIV-specific B cells to enter or remain in GC may help explain the rarity of high-affinity protective antibodies.
Risk of Perforation in the Era of Nonemergent Management for Acute Appendicitis

Prompt appendectomy has long been the standard of care for acute appendicitis because of the risk of progression to perforation. Recently, studies have suggested nonemergent management of acute appendicitis. Our study aimed to determine changes in risk of rupture and complications in patients with appendicitis, with increasing time from symptom onset to treatment. Retrospective study of patients aged ≥18 years presenting to the University of North Carolina Hospitals with signs and symptoms of acute appendicitis who subsequently underwent appendectomy from 2011 to 2015 was performed. Demographic, clinical, laboratory, and pathologic data were reviewed. Bivariate analysis was performed to assess variables associated with increased risk of perforation. Poisson regression modeling was completed to evaluate the risk of perforation and postoperative abscess based on time from symptoms to treatment. Within our database of 1007 patients, the mean time from onset of symptoms to operative intervention was 3.24 ± 2.2 days. Modified Poisson regression modeling demonstrated the relative risk for perforation increases by 9% (RR 1.09, P < 0.001) for each day delay. Age (RR 1.03), male gender (RR 1.50), temperature on admission (RR 1.32), and the presence of fecalith (RR 1.89) statistically significantly increased the risk of perforation. Furthermore, for each day delay, there is an 8% increased risk of postoperative abscess (RR 1.08, P = 0.027). The relative risk for appendiceal perforation is 9 per cent per day delay with a resultant 8 per cent increased risk of postoperative abscess. Thus, appendectomy for acute appendicitis should remain an emergent procedure, given that delays in operative management lead to complications and increases in cost of care.
Cellular targets of inhalational anaesthetic- and opioid receptor agonist-induced cardioprotection

Several anaesthetics and anaesthetic adjuvants have been shown to limit the extent of myocardial injury due to ischaemia and reperfusion, a protective phenomenon known as anaesthetic-induced cardioprotection. Inhalational anaesthetics and opioid receptor agonists are among the key players in anaesthetic-induced cardioprotection. However, the mechanisms underlying anaesthetic-induced cardioprotection are not fully understood, and as such there are currently no concrete guidelines regarding the choice of anaesthetic protocols designed to enhance cardioprotection. This mini-review provides insights into the mechanisms through which the cardioprotection due to inhalational agents and opioid receptor agonists occurs, and discusses the clinical implications thereof. The mechanisms underlying this cardioprotection are diverse and remain unresolved, but several cellular signaling cascades involve key targets such as receptors, sarcolemmal- and mitochondrial ATP-sensitive K+ channels, the mitochondrial permeability transition pore, glycogen synthase kinase-3 beta, nitric oxide, and anti-apoptotic factors. Such factors represent potential therapeutic targets in promoting anaesthetic-induced cardioprotection. Keywords:anaesthetic,cardiac, cardioprotection, inhalational agents, opioid receptor
Predicting Attrition Among Hospice Volunteers

To explore those factors predicting continued involvement among hospice volunteers, this study collected data from questionnaires distributed among 53 individuals who were hospice volunteers, to include personal demographics and measures of locus of control, burnout, hospice self-efficacy, spirituality, and death anxiety. Participants were then contacted between 6 and 8 months later to assess whether they were still actively volunteering for hospice. Those who remained in hospice reported less burnout when adjusting for previous volunteer experience, age, education, and duration of volunteering and a combination of burnout, spirituality, and hospice self-efficacy accurately predicted group membership (completers vs. dropouts) in 82% of the cases. The implications of these exploratory findings for the retention of hospice volunteers are discussed in the context to carefully screening persons before they enter the hospice volunteer role and providing hospice volunteer training for them.
Tumor Microenvironment following Gemcitabine Treatment Favors Differentiation of Immunosuppressive Ly6Chigh Myeloid Cells

Key Points Hyperexpression of GM-CSF in tumor cells promotes M-MDSC immunosuppression. Efferocytosis enhances immunosuppression of Ly6Chigh myeloid cells. Chemoresistance decreases the sensitivity to CTL-induced cytotoxicity. Regulation of myeloid-derived suppressor cells (MDSC) by ongoing inflammation following repeated chemotherapy remain elusive. In this study, we show that a multidose clinical regimen of gemcitabine (GEM) treatment enhances the immunosuppressive function of monocytic MDSC (M-MDSC), although tumor development is delayed in E0771 tumor-bearing mice. Accordingly, effector IFN-γ–producing CD4 and CD8 T cells are significantly decreased in the tumor microenvironment (TME) of GEM-treated mice. The conditioned medium of GEM-treated tumor cells enhances differentiation of mouse bone marrow cells and human PBMC into immunosuppressive M-MDSC. Cytokine profiling of GEM-treated tumor cells identifies GM-CSF as one of the most differentially expressed cytokines. Blockade or knockdown of GM-CSF can partially reduce immunosuppression of Ly6Chigh cells induced by GEM–conditioned medium. Knockdown of GM-CSF in tumor cells also delays tumor progression with decreased accumulation of M-MDSC in the TME. Mechanistically, enhanced production of reactive oxygen species and activation of NF-κB are observed in GEM-treated tumor cells. Treatment with the mitochondrial-targeted antioxidant and inhibitor of NF-κB signaling can abrogate GEM-induced hyperexpression of GM-CSF in E0771 cells. In addition, the phagocytic clearance of apoptotic tumor cells (efferocytosis) enhances the immunosuppressive function of bone marrow Ly6Chigh myeloid cells. Further, GEM treatment results in metabolic changes in residual tumor cells, leading to the resistance to T cell–mediated killing. Together, our results define an undesired effect of repeated GEM treatment promoting immunosuppression in TME via upregulation of GM-CSF and efferocytosis as well as deregulation of lipid metabolism in residual tumor cells.
Rod Photoreceptors Signal Fast Changes in Daylight Levels Using a Cx36-Independent Retinal Pathway in Mouse

Temporal contrast detected by rod photoreceptors is channeled into multiple retinal rod pathways that ultimately connect to cone photoreceptor pathways via Cx36 gap junctions or via chemical synapses. However, we do not yet understand how the different rod pathways contribute to the perception of temporal contrast (changes in luminance with time) at mesopic light levels, where both rods and cones actively respond to light. Here, we use a forced-choice, operant behavior assay to investigate rod-driven, temporal contrast sensitivity (TCS) in mice of either sex. Transgenic mice with desensitized cones (GNAT2cpfl3 line) were used to identify rod contributions to TCS in mesopic lights. We found that at low mesopic lights (400 photons/s/μm2 at the retina), control and GNAT2cpfl3 mice had similar TCS. Surprisingly, at upper mesopic lights (8000 photons/s/μm2), GNAT2cpfl3 mice exhibited a relative reduction in TCS to low (<12 Hz) while maintaining normal TCS to high (12–36 Hz) temporal frequencies. The rod-driven responses to high temporal frequencies developed gradually over time (>30 min). Furthermore, the TCS of GNAT2cpfl3 and GNAT2cpfl3::Cx36−/− mice matched closely, indicating that transmission of high-frequency signals (1) does not require the rod-cone Cx36 gap junctions as has been proposed in the past; and (2) a Cx36-independent rod pathway(s) (e.g., direct rod to OFF cone bipolar cell synapses and/or glycinergic synapses from AII amacrine cells to OFF ganglion cells) is sufficient for fast, mesopic rod-driven vision. These findings extend our understanding of the link between visual circuits and perception in mouse. SIGNIFICANCE STATEMENT The contributions of specific retinal pathways to visual perception are not well understood. We found that the temporal processing properties of rod-driven vision in mice change significantly with light level. In dim lights, rods relay relatively slow temporal variations. However, in daylight conditions, rod pathways exhibit high sensitivity to fast but not to slow temporal variations, whereas cone-driven responses supplement the loss in rod-driven sensitivity to slow temporal variations. Our findings highlight the dynamic interplay of rod- and cone-driven vision as light levels rise from night to daytime levels. Furthermore, the fast, rod-driven signals do not require the rod-to-cone Cx36 gap junctions as proposed in the past, but rather, can be relayed by alternative Cx36-independent rod pathways.
Chagas Disease in the United States: a Public Health Approach

Trypanosoma cruzi is the etiological agent of Chagas disease, usually transmitted by triatomine vectors. An estimated 20 to 30% of infected individuals develop potentially lethal cardiac or gastrointestinal disease. Sylvatic transmission cycles exist in the southern United States, involving 11 triatomine vector species and infected mammals such as rodents, opossums, and dogs. Nevertheless, imported chronic T. cruzi infections in migrants from Latin America vastly outnumber locally acquired human cases. SUMMARY Trypanosoma cruzi is the etiological agent of Chagas disease, usually transmitted by triatomine vectors. An estimated 20 to 30% of infected individuals develop potentially lethal cardiac or gastrointestinal disease. Sylvatic transmission cycles exist in the southern United States, involving 11 triatomine vector species and infected mammals such as rodents, opossums, and dogs. Nevertheless, imported chronic T. cruzi infections in migrants from Latin America vastly outnumber locally acquired human cases. Benznidazole is now FDA approved, and clinical and public health efforts are under way by researchers and health departments in a number of states. Making progress will require efforts to improve awareness among providers and patients, data on diagnostic test performance and expanded availability of confirmatory testing, and evidence-based strategies to improve access to appropriate management of Chagas disease in the United States.
Prevalence of extended spectrum beta‐lactamase‐producing Klebsiella species at the University of Ilorin Teaching Hospital

Beta lactamases are enzymes that degrade the beta‐lactam ring of the beta‐lactam antibiotic group such as penicillin and cephalosporins. Extended spectrum beta‐lactamase (ESBL) is an acquired class A beta‐lactamase that hydrolyzes and confers resistance to oxyimino second and third generation cephalosporins e.g. cefuroxime (CXM), cefotaxime (CTX), ceftazidime (CAZ), and ceftriaxone (CRO). This is one group of beta‐lactamases that is, found in certain species of Gram negative bacilli, usually Klebsiela spp. , Proteus spp. and Escherichia coli. ESBL, however, are not the sole Address for correspondence: Mr. Faari Babatunde Usman, Departments of Medical Microbiology and Parasitology, University of Ilorin Teaching Hospital, PMB 1459, Ilorin, Nigeria. E-mail: faariusman@gmail.com Original Article
Reducing Child Undernutrition through Dietary Diversification, Reduced Aflatoxin Exposure, and Improved Hygiene Practices: The Immediate Impacts in Central Tanzania

ABSTRACT The study aimed to quantify the immediate effects of dietary diversification, food safety, and hygiene interventions on child undernutrition in four rural villages in Kongwa district of central Tanzania. One hundred mothers with their children of less than 24 months old were recruited for this study. The difference-in-difference (DID) method was used to assess the effects of intensive intervention through a learning-by-doing process on the topic of aflatoxin free diversified food utilization and improved hygiene practices. Periodic anthropometric measurements were conducted on the 0th, 7th, 14th, and 21st days, and DID estimator showed the significant and positive average marginal effects of the intervention on Z-Scores being 0.459, 0.252, and 0.493 for wasting, stunting, and underweight, respectively. Notably, at the end of the study, the mean aflatoxin M1 level in urine samples decreased by 64% in the intervention group, while it decreased by 11% in the control group. The study provides quantitative evidence on intensive 21-day training for mothers incorporating integrated technologies yielded positive impacts on their children’s nutritional outcomes.
Perinatal Mental Health in Women with Polycystic Ovary Syndrome: A Cross-Sectional Analysis of an Australian Population-Based Cohort

Women with polycystic ovary syndrome (PCOS) have many risk factors associated with perinatal mental disorders, but research in this area is scarce. This study aims to compare the prevalence of common perinatal mental disorders in women with and without PCOS, and examine the relationship between PCOS and common perinatal mental disorders. We performed a cross-sectional study on self-reported data of 5239 women born between 1973 to 1978 in the Australian Longitudinal Study on Women’s Health. Compared with women not reporting PCOS, women reporting PCOS had higher prevalence of antenatal depression (8.9% vs. 4.4%, p < 0.001), antenatal anxiety (11.7% vs. 5.6%, p < 0.001), postnatal depression (26.8% vs. 18.6%, p < 0.001) and postnatal anxiety (18.4% vs. 12.0%, p < 0.001). PCOS was positively associated with antenatal depression and/or anxiety (adjusted odds ratio 1.8, 95% confidence interval 1.2–2.6) but not postnatal depression and/or anxiety after controlling for sociodemographic and lifestyle factors, reproductive history, obstetric complications and pre-existing depression and anxiety. General perinatal guidelines currently do not recognize PCOS as a risk factor and the international evidence based PCOS guideline noted inadequate evidence in this area. This paper addresses the gap in literature and highlights the need to screen for common perinatal mental disorders in women with PCOS.
Improved endothelial-dependent and endothelial-independent skin vasodilator responses following remote ischemic preconditioning.

INTRODUCTION One week of daily remote ischemic preconditioning (RIPC) improves cutaneous vasodilatory (VD) function. However, the underlying mechanisms and the number of sessions needed to optimize this adaptive response remain unclear. We hypothesized that the responses to localized heating of the skin will be greater after 2 weeks as opposed to 1 week of RIPC. Furthermore, 2 weeks of repeated RIPC will augment cutaneous VD responses to thermal and pharmacological stimuli. METHODS Twenty-four participants (24±2 years; 13 males, 11 females) performed repeated RIPC (7 daily sessions over 1 week, n=11; 12 sessions over 2 weeks, n=13) consisting of 4 repetitions of 5 min of arm blood flow occlusion separated by 5 min reperfusion. Laser speckle contrast imaging was used to measure skin blood flow responses, as perfusion units (PU), to local heating (Tloc=42 oC), acetylcholine (ACh), and sodium nitroprusside (SNP) before and after repeated RIPC. Data were expressed as cutaneous vascular conductance (CVC=PU∙mmHg-1). RESULTS The VD response to local heating increased after RIPC (∆CVC from baseline; 1 week: 0.94 ± 0.11 to 1.19 ± 0.15, 2 week: 1.18 ± 0.07 to 1.33 ± 0.10 PU∙mmHg-1; p<0.05) but the ∆CVC did not differ between weeks. SNP-induced VD increased after 2 weeks of RIPC (∆CVC; 0.34 ± 0.07 to 0.63 ± 0.11 PU∙mmHg-1; p<0.05) but ACh-induced VD did not. CONCLUSION Repeated RIPC improves local heating- and SNP-mediated cutaneous VD. Compared to 1 week of RIPC, 2 weeks of RIPC does not induce further improvements in cutaneous VD function.
Reduction of Inflammation Drives Lipid Changes in Ankylosing Spondylitis

Objective. To investigate the effects of changing inflammation on lipid levels in ankylosing spondylitis. Methods. In a cohort of 230 patients, lipid levels were measured at baseline and after 52 weeks of treatment with tumor necrosis factor-α–blocking agents (anti-TNF). Results. Total cholesterol (TC; +4.6%), low-density lipoprotein cholesterol (+4.3%), and high-density lipoprotein cholesterol (HDL-C; +3.7%) increased upon treatment. Changes were most evident in patients with substantial reduction in inflammatory levels (TC +8.2% vs +1.6% and HDL-C +8.3% vs +2.2% in patients with C-reactive protein ≥ 10 mg/l normalizing upon treatment vs CRP < 10 mg/l throughout treatment period). Conclusion. Anti-TNF therapy results in lipid changes mostly when inflammation is appreciably modified.
Assessment for varicella zoster virus in patients newly suspected of having giant cell arteritis.

OBJECTIVES There is uncertainty if varicella zoster virus (VZV) triggers GCA. This is based on discordant reports of VZV detection in GCA temporal artery biopsies. We conducted a multimodal evaluation for VZV in the inception Giant Cell Arteritis and PET Scan (GAPS) cohort. METHODS Consecutive patients who underwent temporal artery biopsy for suspected GCA were clinically reviewed for active and past VZV infection and followed for 6 months. Serum was tested for VZV IgM and IgG. Temporal artery biopsy (TAB) sections were stained for VZV antigen using the VZV Mouse Cocktail Antibody (Cell Marque, Rocklin, CA, USA). A selection of GCA and control tissues were stained with the VZV gE antibody (Santa Cruz Biotechnology, Dallas, TX, USA), which was used in previous studies. RESULTS A total of 58 patients met inclusion criteria, 12 (21%) had biopsy-positive GCA and 20 had clinically positive GCA. None had herpes zoster at enrolment and only one patient developed a VZV clinical syndrome (zoster ophthalmicus) on follow-up. There was no difference in VZV exposure between GCA and non-GCA patients. None of the 53 patients who had VZV serology collected had positive VZV IgM antibodies. VZV antigen was not convincingly demonstrated in any of the TAB specimens; 57 TABs stained negative and 1 stained equivocally positive. The Santa Cruz Biotechnology VZV antibody exhibited positive staining in a range of negative control tissues, questioning its specificity for VZV antigen. CONCLUSION The absence of active infection markers argues against VZV reactivation being the trigger for GCA. Non-specific immunohistochemistry staining may account for positive findings in previous studies.
Post-pandemic influenza A/H1N1pdm09 is associated with more severe outcomes than A/H3N2 and other respiratory viruses in adult hospitalisations

Abstract This study compares the frequency and severity of influenza A/H1N1pdm09 (A/H1), influenza A/H3N2 (A/H3) and other respiratory virus infections in hospitalised patients. Data from 17 332 adult hospitalised patients admitted to Sir Charles Gairdner Hospital, Perth, Western Australia, with a respiratory illness between 2012 and 2015 were linked with data containing reverse transcription polymerase chain reaction results for respiratory viruses including A/H1, A/H3, influenza B, human metapneumovirus, respiratory syncytial virus and parainfluenza. Of these, 1753 (10.1%) had test results. Multivariable regression analyses were conducted to compare the viruses for clinical outcomes including ICU admission, ventilation, pneumonia, length of stay and death. Patients with A/H1 were more likely to experience severe outcomes such as ICU admission (OR 2.5, 95% CI 1.2–5.5, P = 0.016), pneumonia (OR 3.0, 95% CI 1.6–5.7, P < 0.001) and lower risk of discharge from hospital (indicating longer lengths of hospitalisation; HR 0.64 95% CI 0.47–0.88, P = 0.005), than patients with A/H3. Patients with a non-influenza respiratory virus were less likely to experience severe clinical outcomes than patients with A/H1, however, had similar likelihood when compared to patients with A/H3. Patients hospitalised with A/H1 had higher odds of severe outcomes than patients with A/H3 or other respiratory viruses. Knowledge of circulating influenza strains is important for healthcare preparedness.