Miracle-dz/UniFAR-FTUs huggingface dataset:
Towards the elimination of cervical cancer in low-income and lower-middle-income countries: modelled evaluation of the effectiveness and cost-effectiveness of point-of-care HPV self-collected screening and treatment in Papua New Guinea

Introduction WHO has launched updated cervical screening guidelines, including provisions for primary HPV screen-and-treat. Papua New Guinea (PNG) has a high burden of cervical cancer, but no national cervical screening programme. We recently completed the first field trials of a screen-and-treat algorithm using point-of-care self-collected HPV and same-day treatment (hereafter self-collected HPV S&T) and showed this had superior clinical performance and acceptability to visual inspection of the cervix with acetic acid (VIA). We, therefore, evaluated the effectiveness, cost-effectiveness and resource implications of a national cervical screening programme using self-collected HPV S&T compared with VIA in PNG. Methods An extensively validated platform (‘Policy1-Cervix’) was calibrated to PNG. A total of 38 strategies were selected for investigation, and these incorporated variations in age ranges and screening frequencies and allowed for the identification of the optimal strategy across a wide range of possibilities. A selection of strategies that were identified as being the most effective and cost-effective were then selected for further investigation for longer-term outcomes and budget impact estimation. In the base case, we assumed primary HPV testing has a sensitivity to cervical intraepithelial neoplasia 2 (CIN2+) + of 91.8% and primary VIA of 51.5% based on our earlier field evaluation combined with evidence from the literature. We conservatively assumed HPV sampling and testing would cost US$18. Costs were estimated from a service provider perspective based on data from local field trials and local consultation. Results Self-collected HPV S&T was more effective and more cost-effective than VIA. Either twice or thrice lifetime self-collected HPV S&T would be cost-effective at 0.5× gross domestic product (GDP) per capita (incremental cost-effectiveness ratio: US$460–US$656/life-years saved; 1GDPper-capita: US$2829 or PGK9446 (year 2019)) and could prevent 33 000–42 000 cases and 23 000–29 000 deaths in PNG over the next 50 years, if scale-up reached 70% coverage from 2023. Conclusion Self-collected HPV S&T was effective and cost-effective in the high-burden, low-resource setting of PNG, and, if scaled-up rapidly, could prevent over 20 000 deaths over the next 50 years. VIA screening was not effective or cost-effective. These findings support, at a country level, WHO updated cervical screening guidelines and indicate that similar approaches could be appropriate for other low-resource settings.
B-Cell NHL Subtype Risk Associated with Autoimmune Conditions and PRS

Abstract Background: A previous International Lymphoma Epidemiology (InterLymph) Consortium evaluation of joint associations between five immune gene variants and autoimmune conditions reported interactions between B-cell response-mediated autoimmune conditions and the rs1800629 genotype on risk of B-cell non–Hodgkin lymphoma (NHL) subtypes. Here, we extend that evaluation using NHL subtype-specific polygenic risk scores (PRS) constructed from loci identified in genome-wide association studies of three common B-cell NHL subtypes. Methods: In a pooled analysis of NHL cases and controls of Caucasian descent from 14 participating InterLymph studies, we evaluated joint associations between B-cell–mediated autoimmune conditions and tertile (T) of PRS for risk of diffuse large B-cell lymphoma (DLBCL; n = 1,914), follicular lymphoma (n = 1,733), and marginal zone lymphoma (MZL; n = 407), using unconditional logistic regression. Results: We demonstrated a positive association of DLBCL PRS with DLBCL risk [T2 vs. T1: OR = 1.24; 95% confidence interval (CI), 1.08–1.43; T3 vs. T1: OR = 1.81; 95% CI, 1.59–2.07; P-trend (Ptrend) < 0.0001]. DLBCL risk also increased with increasing PRS tertile among those with an autoimmune condition, being highest for those with a B-cell–mediated autoimmune condition and a T3 PRS [OR = 6.46 vs. no autoimmune condition and a T1 PRS, Ptrend < 0.0001, P-interaction (Pinteraction) = 0.49]. Follicular lymphoma and MZL risk demonstrated no evidence of joint associations or significant Pinteraction. Conclusions: Our results suggest that PRS constructed from currently known subtype-specific loci may not necessarily capture biological pathways shared with autoimmune conditions. Impact: Targeted genetic (PRS) screening among population subsets with autoimmune conditions may offer opportunities for identifying those at highest risk for (and early detection from) DLBCL.
Tanshinone IIA prevents acetaminophen‐induced nephrotoxicity through the activation of the Nrf2‐Mrp2/4 pathway in mice

It's known that APAP overdose often leads to hepatotoxicity and nephrotoxicity. In the present study, we investigated the preventative effect of Tan IIA on APAP‐induced nephrotoxicity. Mice were orally administrated with Tan IIA (10 or 30 mg/kg/day) for 1 week and subsequently gavaged with 200 mg/kg of APAP. Tan IIA reduced APAP‐induced nephrotoxicity as evidenced by histopathological evaluation and serum creatinine levels. Tan IIA pretreatment promoted the efflux of the toxic intermediate metabolite N‐acetyl‐p‐benzoquinone imine (NAPQI), thus reduced its injury to mouse kidney. After Tan IIA pretreatment, a remarkable increase in mRNA and protein expression of Nrf2 and its target genes Mrp2 and Mrp4 was observed in Nrf2+/+ mice kidneys, however, no obvious change of Mrp2 and Mrp4 mRNA and protein expression was detected in Nrf2−/− mice kidneys. HK‐2 cells were used for exploring the roles of Tan IIA in the Nrf2‐MRPs pathway in vitro. Consistently, Tan IIA up‐regulated the Nrf2‐MRPs pathway and promoted the nuclear Nrf2 accumulation in HK‐2 cells. Collectively, our findings suggested that Tan IIA facilitated the clearance of toxic intermediate metabolite NAPQI from the kidney through upregulation of the Nrf2‐MRP2/4 pathway, thereby, performing preventive effects against APAP‐induced nephrotoxicity.
Defensive Confidence and Certainty in Unchanged Attitudes: The Role of Affect–Cognition Matching

Despite much prior research on matching appeals to the affective–cognitive orientation of attitudes, little attention has focused on the consequences of affect–cognition (mis)matching when individuals resist persuasion. We propose that unlike a matched attack, an attack that is mismatched to the affective–cognitive orientation of attitudes would result in low defensive confidence individuals holding onto their unchanged attitudes with less certainty than high defensive confidence individuals. As hypothesized, low defensive confidence participants were less certain after an affective than a cognitive attack for a cognitive issue (Study 1), and the opposite was true for an affective issue (Study 2). Both patterns occurred again when the affective–cognitive orientation of attitudes was manipulated (Study 3) or measured as an individual difference (Study 4). Moreover, perceived knowledge mediated the effects on attitude certainty (Study 4). We end by discussing implications for our understanding of affect–cognition matching and attitude certainty.
Acute cellular rejection in liver transplantation recipients following vaccination against coronavirus disease 2019: A case series

To the editor, Vaccination of liver transplantation (LT) recipients is vital to prevent transmissible infections and serious illness in a vulnerable population. The massive toll taken by the coronavirus disease 2019 (COVID19) pandemic has resulted in the development of innovative, effective vaccines in record time. In December 2020, two messenger RNA (mRNA) vaccines (BNT162b2 vaccine from Pfizer– BioNTech and the mRNA1273 vaccine from Moderna) were authorized by the US Food and Drug Administration under an Emergency Use Authorization. [1] Most adverse events related to the COVID19 vaccines are attributed to local adverse effects related to vaccine reactogenicity. However, there are reports of more serious reactions to COVID19 vaccines possibly related to their immunogenicity, including one report describing several cases of newonset autoimmune hepatitis. [2] In LT recipients, there has been one case report to date of biopsyproven acute cellular rejection (ACR) after receiving a COVID19 vaccine, albeit in the context of tapering off corticosteroids in the early posttransplant period. [3] We report a case series of 5 LT recipients who developed biopsyproven ACR following vaccination against COVID19.
“We don’t have the same bodies; we don’t react the same way”: mothers and adolescent girls’ perceptions of the risks and benefits of HPV vaccination in France

ABSTRACT Human Papillomavirus (HPV) vaccination is one of the most publicly mistrusted vaccines in Europe, with countries such as France struggling with low vaccine uptake due to parental questioning of vaccine risks and benefits. However, limited evidence exists on adolescent girls’ perceptions of the risks and benefits of HPV vaccination. The aim of this qualitative study was to provide an in-depth exploration and comparison of French mothers (n = 21) and adolescent girls’ (n = 36) perceptions of the risks and benefits of HPV vaccination. A thematic analysis showed that adolescent girls and mothers perceived the risks and benefits of HPV vaccination differently, with girls reporting positive and beneficial views and emotions toward vaccination and mothers expressing concerns about possible risks. Adolescent girls also reported that both perceptions and actual risks and benefits may vary from one individual to another. Vaccine safety was also understood differently, with mothers reporting a widespread view that vaccines are unsafe and focusing on controversial side effects and girls discussing short-term consequences of vaccination (e.g. pain, fever) and administration and storage issues. Strategies to improve uptake of HPV vaccination should consider and address both the mothers’ and daughters’ perceptions and understandings of HPV vaccination.
Glutamate levels across deep brain structures in patients with a psychotic disorder and its relation to cognitive functioning

Background: Patients with psychotic disorders often show prominent cognitive impairment. Glutamate seems to play a prominent role, but its role in deep gray matter (DGM) regions is unclear. Aims: To evaluate glutamate levels within deep gray matter structures in patients with a psychotic disorder in relation to cognitive functioning, using advanced spectroscopic acquisition, reconstruction, and post-processing techniques. Methods: A 7-Tesla magnetic resonance imaging scanner combined with a lipid suppression coil and subject-specific water suppression pulses was used to acquire high-resolution magnetic resonance spectroscopic imaging data. Tissue fraction correction and registration to a standard brain were performed for group comparison in specifically delineated DGM regions. The brief assessment of cognition in schizophrenia was used to evaluate cognitive status. Results: Average glutamate levels across DGM structures (i.e. caudate, pallidum, putamen, and thalamus) in mostly medicated patients with a psychotic disorder (n = 16, age = 33, 4 females) were lower compared to healthy controls (n = 23, age = 24, 7 females; p = 0.005, d = 1.06). Stratified analyses showed lower glutamate levels in the caudate (p = 0.046, d = 0.76) and putamen p = 0.013, d = 0.94). These findings were largely explained by age differences between groups. DGM glutamate levels were positively correlated with psychomotor speed (r(30) = 0.49, p = 0.028), but not with other cognitive domains. Conclusions: We find reduced glutamate levels across DGM structures including the caudate and putamen in patients with a psychotic disorder that are linked to psychomotor speed. Despite limitations concerning age differences, these results underscore the potential role of detailed in vivo glutamate assessments to understand cognitive deficits in psychotic disorders.
Transfemoral Versus Subclavian Access for Transcatheter Aortic Valve Replacement

Objective: This study sought to compare outcomes of transcatheter aortic valve replacement (TAVR) performed through subclavian access with those performed through transfemoral access. Methods: This was an observational study utilizing an institutional TAVR database from 2010 to 2018. All patients undergoing a TAVR via a transfemoral (TF-TAVR) or subclavian (SC-TAVR) approach were included in the study. The groups were analyzed for differences in operative mortality and postoperative outcomes. Multivariable Cox analysis was performed to identify variables associated with long-term survival after TAVR. Results: Of the 1,095 patients identified, 133 patients underwent SC-TAVR and 962 patients underwent TF-TAVR. Patients who underwent SC-TAVR were younger, more likely to have chronic lung disease and peripheral vascular disease, had higher Society of Thoracic Surgeons predicted risk of mortality scores, and were more likely to have self-expanding valves placed (P < 0.05). Operative mortality was similar between the TF-TAVR (2.7%) and SC-TAVR (3.8%) groups. There were no significant differences in stroke, length of stay, 30-day readmission, blood transfusions, acute kidney injury, need for permanent pacemaker, paravalvular leak, or major vascular complications between the groups (P > 0.05). The unadjusted Kaplan-Meier survival estimate for TF-TAVR was significantly higher than for SC-TAVR (P = 0.009, log-rank). However, on multivariable Cox analysis, subclavian access was not significantly associated with an increased hazard of death as compared with transfemoral access (P = 0.21). Conclusions: Outcomes of SC-TAVR are comparable to those of TF-TAVR. Subclavian access may be a favorable alternative approach when TF-TAVR is contraindicated.
Placental vascular and inflammatory findings from pregnancies diagnosed with coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis.

OBJECTIVE We aimed to perform a meta-analysis of the literature concerning histopathologic findings in the placentas of women with SARS-CoV-2 infection during pregnancy. Methods and material Searches for articles in English included PubMed, Web of Science, Google Scholar and reference lists (up to April 2021). Studies presenting data on placental histopathology according to the Amsterdam consensus group criteria in SARS-CoV-2 positive and negative pregnancies were identified. Lesions were categorized into: maternal (MVM) and fetal (FVM) vascular malperfusion, acute placental inflammation with maternal (MIR) and fetal (FIR) inflammatory response, chronic inflammatory lesions (CILs) and increased perivillous fibrin deposition (PVFD). Results A total of 15 studies reporting on 19,025 placentas, n=699 of which were derived from women who were identified as being infected with SARS-CoV-2 and 18,326 as SARS-CoV-2 negative controls, were eligible for analysis. No significant difference in incidence of MVM (OR: 1.18, 95% CI 0.73-1.90), FVM (OR: 1.23, 95% CI 0.63-2.42), MIR (OR: 0.66, 95% CI 0.29-1.52) nor FIR (OR: 0.85, 95% CI 0.44-1.63), CILs (OR:0.97, 95% CI 0.55-1.72) was found between placentae from gravidae identified as being SARS-CoV-2 infected. However, placenta from gravidae identified as being infected with SARS-CoV-2 were associated with significantly increased occurrence of PVFD (OR: 2.77, 95% CI 1.06-7.27). After subgroup analyses based on clinical severity of COVID-19 infection, no significant difference was observed in terms of reported placental pathology between symptomatic or asymptomatic SARS-CoV-2 gravidae placenta. CONCLUSIONS Current evidence based on the available literature suggest that the only pathologic finding in the placentae of women who are pregnant identified as having been infected with SARS-CoV-2 was an increased prevalence of PVFD.
A Retrospective Study of the Relationship Between Blood Transfusion and 30-Day Postoperative Outcomes in Patients Undergoing Isolated Off-Pump Coronary Artery Bypass Grafting

Introduction The objective of this single-center study it to retrospectively analyze the relationship between transfusion and 30-day postoperative outcomes in patients undergoing isolated off-pump coronary artery bypass grafting. Methods Perioperative data of 2,178 patients who underwent isolated off-pump coronary artery bypass grafting from 2018 to 2019 were collected. A 1:1 propensity score matching was performed to control for potential biases between patients who received blood transfusion and those who did not. After propensity score matching, we analyzed the clinical outcomes of transfusion and non-transfusion patients. Postoperative complications and the survival of patients within 30 days after surgery in both groups were analyzed. Kaplan-Meier survival curve and log-rank test were used for survival analysis. Results The total blood transfusion rate of all patients was 29%, including red blood cell (27.6%), plasma (7.3%), and platelet (1.9%). Four hundred and forty patients in each group were compared after propensity score matching. There were no significant differences in the incidence of stroke, myocardial infarction, atrial fibrillation, acute kidney function injury, and sternal wound infection of both groups (P>0.05). However, higher incidence of postoperative pulmonary infection and more mechanical ventilation time and days of stay in the intensive care unit and postoperative in-hospital stay were associated with blood transfusion (P<0.05). The 30-day cumulative survival rate of the transfusion group was lower than that of the control group (P<0.05). Conclusion Perioperative blood transfusion increases the risks of postoperative pulmonary infection and short-term mortality in off-pump coronary artery bypass grafting patients.
Distinct early life stage gene expression effects of hybridization among European and North American farmed and wild Atlantic salmon populations

Due to multigeneration domestication selection, farmed and wild Atlantic salmon diverge genetically, which raises concerns about potential genetic interactions among escaped farmed and wild populations and disruption of local adaptation through introgression. When farmed strains of distant geographic origin are used, it is unknown whether the genetic consequences posed by escaped farmed fish will be greater than if more locally derived strains are used. Quantifying gene transcript expression differences among divergent farmed, wild and F1 hybrids under controlled conditions is one of the ways to explore the consequences of hybridization. We compared the transcriptomes of fry at the end of yolk sac absorption of a European (EO) farmed (“StofnFiskur”, Norwegian strain), a North American (NA) farmed (Saint John River, NB strain), a Newfoundland (NF) wild population with EO ancestry, and related F1 hybrids using 44 K microarrays. Our findings indicate that the wild population showed greater transcriptome differences from the EO farmed strain than that of the NA farmed strain. We also found the largest differences in global gene expression between the two farmed strains. We detected the fewest differentially expressed transcripts between F1 hybrids and domesticated/wild maternal strains. We also found that the differentially expressed genes between cross types over‐represented GO terms associated with metabolism, development, growth, immune response, and redox homeostasis processes. These findings suggest that the interbreeding of escaped EO/NA farmed and NF wild population would alter gene transcription, and the consequences of hybridization would be greater from escaped EO farmed than NA farmed salmon, resulting in potential effects on the wild populations.
Delineating the epilepsy phenotype of NGLY1 deficiency

We delineated the phenotypic spectrum of epilepsy in individuals with NGLY1 deficiency from an international cohort. We collected detailed clinical and electroencephalographic data from 29 individuals with bi‐allelic (likely) pathogenic variants in NGLY1 as part of an ongoing prospective natural history study. Participants were evaluated in‐person at a single center and/or remotely. Historical medical records were reviewed. Published cases were included for comprehensive phenotyping. Of 29 individuals (mean 11.4 years, range 3–27 years), 17 (58.6%) participants had a history of epilepsy. Seizure onset was in early childhood (mean 43 months, range 2 months to 19 years). The most common seizure types were myoclonic and atonic. Epilepsy course was variable, but 35.2% (6/17) of participants with epilepsy achieved seizure freedom. The most common medications included levetiracetam, valproate, lamotrigine, and clobazam. Electroencephalogram (EEGs) were abnormal in 80% (12/15) of participants with or without epilepsy, although encephalopathy was uncommon. There was a trend in neurodevelopmental outcomes that participants with epilepsy had more developmental delays. In summary, epilepsy is common in NGLY1 deficiency. Over half of the participants had a history of epilepsy and nearly all had EEG abnormalities indicating an increased risk of epilepsy. This work expands the electroclinical phenotype of NGLY1 deficiency and supports a high clinical suspicion for seizures. Some of the more common seizure types (epileptic spasms, myoclonic, and atonic seizures) can be subtle and require counseling to ensure early recognition and treatment to ensure the best possible outcomes. Despite transient liver enzyme abnormalities in this disorder, hepatically metabolized medications were well tolerated.
Quantifying the mutational process

Theoretical work has shown that deleterious mutations may explain many evolutionary phenomena, but the role they play depends on their specific properties, including the overall rate at which they occur in the genome and the distribution of their selection ( s) and dominance ( h) coefficients. However, accurate estimates for these parameters from a range of species are still lacking. In this thesis, two distinct approaches were used to quantify the mutational process. In Chapter 3, a novel DNA-based method was used to infer levels of evolutionary constraints in theDrosophilagenome by comparing rates of nucleotide substitution in noncoding and putatively neutrally evolving DNA. Introns were found to have a significantly higher rate of substitution than synonymous sites, and, when introns were used as a neutrally evolving standard, constraint in the 500bp of intergenic DNA upstream and downstream of coding regions was found to be about 44%. Selection against mutations in intergenic DNA should therefore make a substantial contribution to the mutational load in Drosophila. Secondly, a fitness-based approach was used to estimate mutational parameters in lines ofCaenorhabditis elegans containing large numbers of deleterious homozygous EMSinduced mutations. In Chapter 4, replicated inbred sublines were produced for eight mutant lines, and the performance of the sublines, the mutant lines and the wild-type strain was measured for three fitness-related traits. The number of mutations per line was then estimated for each trait by applying a modified version of the Castle-Wright estimator and a maximum likelihood (ML) method. Both the Castle-Wright and the ML analyses suggest that most of the variation among sublines was due to a small number ( ∼1.5–2.5) of largeeffect mutations. Given that each line is expected to have a large number of mutations, this supports the hypothesis that many have very small (but still deleterious) effects. In Chapter 5, the average dominance coefficient of mildly deleterious mutations ( h) was estimated from a selection of 19 relatively high fitness mutant lines by comparing the performance of heterozygotes and homozygotes to the wild-type for three fitness-related traits (viability, productivity, and relative fitness). There was very little net heterozygous or