Miracle-dz/UniFAR-FTUs huggingface dataset:
HIV-1 subtypes and drug resistance mutations among female sex workers varied in different cities and regions of the Democratic Republic of Congo

Background Complex mosaic structures of HIV-1 were found in the Democratic Republic of Congo (DRC). Currently, there is limited information on the circulating HIV-1 strains, the distribution of these strains and antiretroviral (ART) resistant viruses in different regions of the country, and the HIV-1 strains harbored by the high-risk groups like female sex workers (FSW) reported to be the source of recombinant and ART resistant viruses. Methods Dried Blood Spots (DBS), collected from 325 infected FSWs in ten cities from 2012 DRC HIV/STI Integrated Biological and Behavioral Surveillance Survey, were tested for HIV-1 genotypes and antiretroviral resistance mutations. Regional segregation of HIV-1 clades was detected using phylogenetics. The significance for differences in HIV-1 subtype and drug resistance mutations were evaluated using Chi-square tests. Results There were 145 (env) and 93 (pol) sequences analyzed. Based on env sequences, the predominant subtype was A1 (44%), and recombinants as defined pol sequences comprised 35% of the total sample. Paired sequences of pol and env from DRC FSW revealed mosaic recombinant in 54% of the sequences. Distinct geographic distributions of different HIV-1 subtypes and recombinants were observed. Subtype A1 was prevalent (40%) in Goma located in the East and significantly higher than in Mbuji-Mayi (p<0.05) in the South-central region, or in Lubumbashi in the South. Antiretroviral resistance was detected in 21.5% of 93 pol sequences analyzed, with the M184I/V and K103N mutations that confer high-level resistance to NRTI and NNRTI, respectively, being the most frequent mutations. However, the K103N mutant viruses were found only in the East. Conclusion HIV-1 variants found in DRC FSW reflect those reported to circulate in the general population from the corresponding geographical locations. HIV-1 mosaic genetics were readily detected in FSW. Importantly, ART resistance mutations to NNRTI and NRTI were common in the DRC sex workers.
Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta-analysis.

PURPOSE While various studies have highlighted the prognostic significance of pathological complete response (pCR) after neoadjuvant chemotherapy (NAT), the impact of additional adjuvant therapy after pCR is not known. EXPERIMENTAL DESIGN PubMed was searched for studies with NAT for breast cancer and individual patient-level data was extracted for analysis using plot digitizer software. Hazard ratios (HRs), with 95% probability intervals (PIs), measuring the association between pCR and overall survival (OS) or event-free survival (EFS), were estimated using Bayesian piecewise-exponential proportional hazards hierarchical models including pCR as predictor. RESULTS Overall, 52 of 3209 publications met inclusion criteria, totaling 27,895 patients. Patients with a pCR after NAT had significantly better EFS (HR 0.31, 95% PI: 0.24-0.39), particularly for triple negative (HR 0.18, 95% PI: 0.10-0.31) and HER2+ (HR 0.32, 95% PI: 0.21-0.47) disease. Similarly, pCR after NAT was also associated with improved survival (HR 0.22, 95% PI: 0.15-0.30). The association of pCR with improved EFS was similar among patients who received subsequent adjuvant chemotherapy (HR 0.36, 95% PI: 0.19-0.67) and those without adjuvant chemotherapy (HR 0.36, 95% PI: 0.27-0.54), with no significant difference between the two groups (p = 0.60). INTERPRETATION Achieving pCR following NAT is associated with significantly better EFS and OS, particularly for triple negative and HER2+ breast cancer. The similar outcomes with or without adjuvant chemotherapy in patients who attain pCR likely reflects tumor biology and systemic clearance of micrometastatic disease, highlighting the potential of escalation/de-escalation strategies in the adjuvant setting based on neoadjuvant response.
Matrix Metalloproteinases in Diabetic Kidney Disease

Around the world diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD), which is characterized by mesangial expansion, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. The hallmark of the pathogenesis of DKD is an increased extracellular matrix (ECM) accumulation causing thickening of the glomerular and tubular basement membranes, mesangial expansion, sclerosis, and tubulointerstitial fibrosis. The matrix metalloproteases (MMPs) family are composed of zinc-dependent enzymes involved in the degradation and hydrolysis of ECM components. Several MMPs are expressed in the kidney; nephron compartments, vasculature and connective tissue. Given their important role in DKD, several studies have been performed in patients with DKD proposing that the measurement of their activity in serum or in urine may become in the future markers of early DKD. Studies from diabetic nephropathy experimental models suggest that a balance between MMPs levels and their inhibitors is needed to maintain renal homeostasis. This review focuses in the importance of the MMPs within the kidney and their modifications at the circulation, kidney and urine in patients with DKD. We also cover the most important studies performed in experimental models of diabetes in terms of MMPs levels, renal expression and its down-regulation effect.
Heart Rate During an Exercise Test and Acute High-intensity Interval Training in Type 2 Diabetes

Abstract To describe and compare the acute heart rate changes during an incremental exercise test and high-intensity interval training (HIIT) in subjects of different glucose control. Seventy-five adults were allocated into three groups: Normoglycaemic (NG, n=32), Pre- (PreT2D, n=30) and Type 2 diabetic (T2D, n=13) subjects. Subjects performed an incremental cycling test to determine cardiorespiratory fitness (VO2max), maximum heart rate (HRmax) and HR recovery post maximal effort, as well as a HIIT cycling session. HR variations are reported as HR pre (HR-preINT), and post interval (HR-postINT), percentage of maximum HR (%HRmax), delta of HR increased (∆HRINT), and delta HR recovery after each interval (∆HRR). By groups, there was a significant difference for the %HRmax in 1st and 2nd, but not in intervals 3rd to 10th between Pre-T2D and T2D groups. There were significant differences for the %HRmax in 1st to 2nd intervals between Pre-T2D and T2D groups. Significant (P<0.05) differences at some intervals were found for ΔHRINT, and ΔHRR. These findings suggest that the HR during an incremental exercise test, and from a typical 10-intervals based HIIT protocol could be used as an intensity marker for individuals independent of their glycaemic control.
Effects of Manual Rib Cage Compressions on Mucus Clearance in Mechanically Ventilated Pigs

BACKGROUND: Manual rib cage compression is a chest physiotherapy technique routinely used in clinical practice. However, scientific evidence remains scarce on the effects of manual rib cage compression on airway clearance and oxygenation in mechanically ventilated patients. METHODS: Anesthetized pigs were intubated via the trachea and mechanically ventilated. To create atelectasis, artificial mucus was infused into the airway. Each pig was randomly assigned to 1 of 2 groups: closed suctioning alone (control group, 7 pigs), or manual rib cage compression combined with closed suctioning (manual rib cage compression group, 8 pigs). Hard and brief rib cage compression synchronized with early expiratory phase was tested. Mucus clearance and oxygenation were assessed after the intervention. Sequential changes of hemodynamics were assessed after the intervention. RESULTS: During hard manual rib cage compression, the mean ± SD peak expiratory flow increased to 44 ± 7 L/min compared with 31 ± 7 L/min without treatment (P < .001). Manual rib cage compression combined with endotracheal suctioning increased mucus clearance compared with closed suctioning alone (mucus amounts, 5.5 [3.4–9.4] g vs 0.7 [0.5–2.0] g; P = .004); however, it did not improve gas exchange and radiologic findings. There were no significant differences in hemodynamic variables between the 2 groups. CONCLUSIONS: Our findings indicated that hard and brief manual rib cage compression combined with closed suctioning was safe and led to improvement of mucus clearance; however, no effectiveness was confirmed with regard to oxygenation and ventilation.
Oral administration of the food derived hydrophilic antioxidant ergothioneine enhances object recognition memory in mice.

BACKGROUND The enhancement of learning and memory through food-derived ingredients is of great interest to healthy individuals as well as those with diseases. Ergothioneine (ERGO) is a hydrophilic antioxidant highly contained in edible golden oyster mushrooms (Pleurotus cornucopiae var. citrinopileatus), and systemically absorbed by its specific transporter, carnitine/organic cation transporter OCTN1/SLC22A4. OBJECTIVE This study aims to examine the possible enhancement of object recognition memory by oral administration of ERGO in normal mice. METHOD Novel object recognition test, spatial recognition test, LC-MS/MS, Golgi staining, neuronal culture, western blotting, immunocytochemistry, and quantitative RT-PCR were utilized. RESULT After oral administration of ERGO (at a dose of 1-50 mg/kg) three times per week for two weeks in ICR mice, the novel object recognition test revealed a longer exploration time for the novel object than for the familiar object. Oral administration of ERGO also revealed a longer exploration time for the moved object in the spatial recognition test in mice fed ERGO-free diet. The discrimination index was significantly higher in the ERGO-treated group than the control in both behavioral tests. ERGO administration led to an increase in its concentration in the plasma and hippocampus. The systemic concentration reached was relevant to those found in humans after oral ERGO administration. Golgi staining revealed that ERGO administration increased the number of matured spines in the hippocampus. Exposure of cultured hippocampal neurons to ERGO elevated the expression of the synapse formation marker, synapsin I. This elevation of synapsin I was inhibited by the tropomyosin receptor kinase inhibitor, K252a. Treatment with ERGO also increased the expression of neurotrophin-3 and -5, and phosphorylated mammalian target of rapamycin in hippocampal neurons. CONCLUSION Oral intake of ERGO which provides its plasma concentration achievable in humans may enhance object recognition memory, and this enhancement effect could occur, at least in part, through the promotion of neuronal maturation in the hippocampus.
Circulating Tumor DNA Analysis to Assess Risk of Progression after Long-term Response to PD-(L)1 Blockade in NSCLC

Purpose: Treatment with PD-(L)1 blockade can produce remarkably durable responses in patients with non–small cell lung cancer (NSCLC). However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression. Experimental Design: In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (progression-free survival ≥ 12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing. Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing (n = 18) or by targeted sequencing (n = 6). Results: Thirty-one patients with NSCLC with long-term benefit to PD-(L)1 blockade were identified, and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; in contrast, all 4 patients with detectable ctDNA eventually progressed [Fisher P < 0.0001; positive predictive value = 1, 95% confidence interval (CI), 0.51–1; negative predictive value = 0.93 (95% CI, 0.80–0.99)]. Conclusions: ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 blockade and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression.
Effect of Workplace Violence and Psychological Stress Responses on Medical-Surgical Nurses’ Medication Intake

Background Workplace violence is a prevalent phenomenon in the health-care sector globally, but few studies have examined its impact on nurses’ use of prescribed and/or over-the-counter medications to manage signs and symptoms. Purpose The purpose of this study was to examine the direct and indirect effect of workplace violence, through the pathway of psychological stress responses, on nurses’ frequencies of medication intake. An occupational stress and health outcomes model was tested in this study. Methods A secondary analysis of cross-sectional survey data from 551 medical-surgical nurses in British Columbia was conducted. Both emotional and physical workplace violence were examined. Emotional exhaustion and posttraumatic stress disorder were psychological stress responses to workplace violence. Results Emotional and physical violence from patients and/or families were the most prevalent sources of workplace violence. Physical violence and psychological stress responses increased the frequency of medication intake after controlling for nurse characteristics. Emotional violence was not related to medication intake over and above the effect of psychological stress responses. Physical and emotional violence elicited psychological stress responses resulting in increased medication use. Conclusion Workplace violence triggers psychological stress responses with adverse outcomes on nurses’ health and well-being.
Utility of Nuclear Grading System in Epithelioid Malignant Pleural Mesothelioma in Biopsy-heavy Setting

Supplemental Digital Content is available in the text. Nuclear grading systems for epithelioid malignant pleural mesothelioma (MPM) have been proposed but it remains uncertain if they could be applied in a biopsy-heavy setting. Using the proposed system, we conducted an independent, external validation study using 563 consecutive cases of epithelioid MPM diagnosed at our institution between 2003 and 2017, of which 87% of patients underwent biopsies only. The median number of sites sampled was 1, with a median maximum tissue dimension of 17 mm (biopsy) and 150 mm (resection). The median overall survival (OS) was 14.7 months. The frequencies of grade I, II, and III tumors were 31% (132/563), 52% (292/563), and 17% (94/563). Grade I tumors were associated with the most favorable median OS (24.7 mo) followed by grades II (12.7 mo) and III (7.2 mo). The 2-tier nuclear grade separated tumors into low grade (19.3 mo) and high grade (8.9 mo). In multivariate analysis, 3-tier nuclear grade, 2-tier nuclear grade, and mitosis-necrosis score predicted OS independent of age, procedural type, solid-predominant growth pattern, necrosis, and atypical mitosis (all P<0.001 except 2-tier nuclear grade, P=0.001). In the scenario of a single- site biopsy with tissue dimension ≤10 mm, none but age (P=0.002) were independently predictive. Our data also suggested sampling 3 sites or a maximum tissue dimension of at least 20 mm from a single site is optimal for nuclear grade assessment. In conclusion our study confirmed the utility of nuclear grade in epithelioid MPM using a biopsy-heavy cohort provided the tissue sample met minimum dimensional criteria.
Checkpoint Defects Elicit a WRNIP1-Mediated Response to Counteract R-Loop-Associated Genomic Instability

Conflicts between replication and transcription are a common source of genomic instability, a characteristic of almost all human cancers. Aberrant R-loops can cause a block to replication fork progression. A growing number of factors are involved in the resolution of these harmful structures and many perhaps are still unknown. Here, we reveal that the Werner interacting protein 1 (WRNIP1)-mediated response is implicated in counteracting aberrant R-loop accumulation. Using human cellular models with compromised Ataxia-Telangiectasia and Rad3-Related (ATR)-dependent checkpoint activation, we show that WRNIP1 is stabilized in chromatin and is needed for maintaining genome integrity by mediating the Ataxia Telangiectasia Mutated (ATM)-dependent phosphorylation of Checkpoint kinase 1 (CHK1). Furthermore, we demonstrated that loss of Werner Syndrome protein (WRN) or ATR signaling leads to formation of R-loop-dependent parental ssDNA upon mild replication stress, which is covered by Radiorestistance protein 51 (RAD51). We prove that Werner helicase-interacting protein 1 (WRNIP1) chromatin retention is also required to stabilize the association of RAD51 with ssDNA in proximity of R-loops. Therefore, in these pathological contexts, ATM inhibition or WRNIP1 abrogation is accompanied by increased levels of genomic instability. Overall, our findings suggest a novel function for WRNIP1 in preventing R-loop-driven genome instability, providing new clues to understand the way replication–transcription conflicts are handled.
The impact of tumor regression grade on long-term survival in locally advanced rectal cancer treated with preoperative chemoradiotherapy

Purpose The aim of this study is to investigate the prognostic effect of tumor regression grade (TRG) on long-term survival in locally advanced rectal cancer treated with preoperative chemoradiotherapy. Methods Medical records of 182 patients with locally advanced rectal cancer, who were treated with preoperative chemoradiotherapy followed by surgery between 2002 and 2016, were retrospectively reviewed. TRG was classified into five categories based on the pathological response as follows – TRG1: no viable cancer cell, TRG2: single cancer cell or small groups of cancer cells, TRG3: residual tumor outgrown by fibrosis, TRG4: residual tumor outgrowing fibrosis, TRG5: diffuse residual tumor without regression. TRG1, (TRG2+TRG3), and (TRG4+TRG5) were grouped as complete response, intermediate response, and no response, respectively. Results Of the 182 patients with locally advanced rectal cancer, 112 (61.5%) were male. The mean age was 54.4 (range, 25–87) years. The total number of patients in complete response, intermediate response, and no response group was 24 (13.2%), 105 (57.7%), and 53 (29.1%), respectively. The corresponding five-year relapse-free survival and overall survival rates were 79.8%–92.3%, 74.7%–79.4%, and 55.7%–55.8%, respectively (p < 0.05 for relapse-free survival, p < 0.05 for overall survival). According to ypTNM stage, there was no significant difference in relapse-free survival among TRG groups in ypStage I and II patients (p > 0.05). In ypStage III patients, relapse-free survival was 62 months in no response group vs. not reached in intermediate response group (p < 0.05). According to the ypTNM, there was no significant difference in overall survival among TRG groups in ypStage I, II, and III patients (p > 0.05). In the multivariate analysis, pathological complete response was found to be an independent variable for relapse-free survival and overall survival (hazard ratio (95% confidence interval), 0.34 (0.17–6.77), 0.39 (0.18–0.83), respectively). Conclusion This study showed that patients with pathological complete response to preoperative chemoradiotherapy had longer relapse-free survival and overall survival rates than those with residual disease.
Socioeconomic Status and Ovarian Cancer Stage at Diagnosis: A Study Nested Within UKCTOCS

Background: Tubo-ovarian cancer (OC) continues to be the most lethal of all gynaecological cancers. Over half of women are diagnosed with late stage (III/IV) disease, which has a five-year survival rate of 11%. Socioeconomic status (SES) has been shown to have an impact on outcomes of several cancer types, including OC. This study aims to investigate any potential association between SES and stage at diagnosis of OC. Methods: Women from the non-screening arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) with a confirmed diagnosis of OC prior to 01 January 2015 and an English index of multiple deprivation (IMD) score were eligible for the study. The association between IMD and OC stage (FIGO) was analysed using an ordinal logistic regression model adjusted for age at diagnosis and BMI. Results: Four-hundred and fifty seven women were eligible for inclusion in the primary analysis. The odds of being diagnosed with the higher dichotomization of stage (I vs. II/III/IV; I/II vs. III/IV; I/II/III vs. IV) was 1.29 (p = 0.017; 95% CI: 1.048–1.592) per unit SD (standard deviation) increase in IMD. This translates to a 29% increase in odds of being diagnosed at the higher stage per each unit SD increase in IMD. Conclusion: Increased deprivation is consistently associated with a higher probability of being diagnosed with later stage OC.
Associations Between Screen Exposure in Early Life and Myopia amongst Chinese Preschoolers

This study aimed to explore the association between screen exposure in early life and preschool myopia. During the baseline survey of the Longhua Child Cohort Study (LCCS), data of 29,595 preschoolers were collected via a caregiver-reported questionnaire regarding children’s socio-demographic characteristics, visual status, screen exposure and relevant parental information. Data of 26,433 preschoolers with normal eyesight or myopia were included in the analysis and cox regression modelling was employed to assess the associations. Results suggested the hypothesis that screen exposure in early life could be significantly and positively associated with preschool myopia, and in agreement with this hypothesis was the association being strengthened with the increasing daily exposure duration and total years of exposure; in the stratification analysis based on the presence of parental myopia, these associations still existed, and the strength of associations was stronger in preschoolers with myopic parents than those without. Moreover, a statistically significant association was only observed between initial screen exposure that occurred during 0–1-years old and myopia for preschoolers without myopic parents, while the significant associations were observed between initial screen exposure that occurred during 0–1, 1–2, 2–3, and after 3 years old and myopia for preschoolers who had myopic parents, with the strongest association found in the group of children initially exposed to electronic screens during 0–1 year old. Thus our findings indicated the hypothesis that screen exposure in early life might be associated with the occurrence of preschool myopia, and that the postnatal first year might be the sensitive period for the association. However, it is premature to conclude that early screen time leads to myopia with current data. Further longitudinal studies performed with cycloplegia are necessary to verify the hypothesis and shed light on the more urgent question whether early screen exposure contributes to the later myopia epidemic of school-aged children.