tbuckley/cabot-search huggingface dataset:
Variant <i>PNLDC1</i>, Defective piRNA Processing, and Azoospermia
Authors: Liina Nagirnaja, Nina Mørup, John E. Nielsen, Rytis Stakaitis, Ieva Golubickaite, Manon S. Oud, Sofia B. Winge, Filipa Carvalho, Kenneth I. Aston, Francesca Khani, Godfried W. van der Heijden, C. Joana Marques, Niels E. Skakkebaek, Ewa Rajpert–De Meyts, Peter N. Schlegel, Niels Jørgensen, Joris A. Veltman, Alexandra M. Lopes, Donald F. Conrad, Kristian Almstrup
Journal: New England Journal of Medicine (2021)

P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are short (21 to 35 nucleotides in length) and noncoding and are found almost exclusively in germ cells, where they regulate aberrant expression of transposable elements and postmeiotic gene expression. Critical to the processing of piRNAs is the protein poly(A)-specific RNase-like domain containing 1 (PNLDC1), which trims their 3' ends and, when disrupted in mice, causes azoospermia and male infertility.We performed exome sequencing on DNA samples from 924 men who had received a diagnosis of nonobstructive azoospermia. Testicular-biopsy samples were analyzed by means of histologic and immunohistochemical tests, in situ hybridization, reverse-transcriptase-quantitative-polymerase-chain-reaction assay, and small-RNA sequencing.Four unrelated men of Middle Eastern descent who had nonobstructive azoospermia were found to carry mutations in PNLDC1: the first patient had a biallelic stop-gain mutation, p.R452Ter (rs200629089; minor allele frequency, 0.00004); the second, a novel biallelic missense variant, p.P84S; the third, two compound heterozygous mutations consisting of p.M259T (rs141903829; minor allele frequency, 0.0007) and p.L35PfsTer3 (rs754159168; minor allele frequency, 0.00004); and the fourth, a novel biallelic canonical splice acceptor site variant, c.607-2A→T. Testicular histologic findings consistently showed error-prone meiosis and spermatogenic arrest with round spermatids of type Sa as the most advanced population of germ cells. Gene and protein expression of PNLDC1, as well as the piRNA-processing proteins PIWIL1, PIWIL4, MYBL1, and TDRKH, were greatly diminished in cells of the testes. Furthermore, the length distribution of piRNAs and the number of pachytene piRNAs was significantly altered in men carrying PNLDC1 mutations.Our results suggest a direct mechanistic effect of faulty piRNA processing on meiosis and spermatogenesis in men, ultimately leading to male infertility. (Funded by Innovation Fund Denmark and others.).
Covid-19 laboratory leak hypothesis: extraordinary claims demand extraordinary evidence
Authors: Owain Donnelly
Journal: BMJ (2021)

Thacker’s piece on the laboratory leak hypothesis does not provide much clarity for readers on the various arguments in the literature for the virus having a natural origin.1

A quotation notes that “An accident . . . is the opposite of a conspiracy,” but the conspiracy refers to the major effort needed to cover up such an incident, which would most likely involve hundreds of people. Such an extraordinary …
Impaired fertility in men diagnosed with inflammatory arthritis: results of a large multicentre study (iFAME-Fertility)
Authors: Luis Fernando Perez-Garcia, Esther Röder, Robbert J Goekoop, Johanna M W Hazes, Marc R Kok, Hieronymus T W Smeele, Ilja Tchetverikov, Annette H M van der Helm-van Mil, Jos H van der Kaap, Petra Kok, Bouwe P Krijthe, Radboud J E M Dolhain
Journal: Annals of the Rheumatic Diseases (2021)

The impact of inflammatory arthritis (IA) on male fertility remains unexplored. Our objective was to evaluate the impact of IA on several male fertility outcomes; fertility rate (number of biological children per man), family planning, childlessness and fertility problems.We performed a multicentre cross-sectional study (iFAME-Fertility). Men with IA 40 years or older who indicated that their family size was complete were invited to participate. Participants completed a questionnaire that included demographic, medical and fertility-related questions. To analyse the impact of IA on fertility rate, patients were divided into groups according to the age at the time of their diagnosis: ≤30 years (before the peak of reproductive age), between 31 and 40 years (during the peak) and ≥41 years (after the peak).In total 628 participants diagnosed with IA were included. Men diagnosed ≤30 years had a lower mean number of children (1.32 (SD 1.14)) than men diagnosed between 31 and 40 years (1.60 (SD 1.35)) and men diagnosed ≥41 years (1.88 (SD 1.14)).This was statistically significant (p=0.0004).The percentages of men diagnosed ≤30 and 31-40 years who were involuntary childless (12.03% vs 10.34% vs 3.98%, p=0.001) and who reported having received medical evaluations for fertility problems (20.61%, 20.69% and 11.36%, p=0.027) were statistically significant higher than men diagnosed ≥41 years.This is the first study that shows that IA can impair male fertility. Men diagnosed with IA before and during the peak of reproductive age had a lower fertility rate, higher childlessness rate and more fertility problems. Increased awareness and more research into the causes behind this association are urgently needed.
28620 The impact of the COVID-19 pandemic on perceived hair loss and stress in a cohort of alopecia areata patients: A cross-sectional study
Authors: Chloe J. Walker, Kelly E. Flanagan, James T. Pathoulas, Isabel Pupo Wiss, Abby Ellison, Natasha Mesinkovska, Maryanne M. Senna
Journal: Journal of the American Academy of Dermatology (2021)

Alopecia areata (AA) results in nonscarring hair loss ranging from scalp to full body involvement. Studies have demonstrated increased occurrence of stress-related cutaneous disorders with COVID-19; however, no studies have explored COVID-19–related stress and disease perception among AA patients.This study examines perceived hair loss and stress (scale of 0-100) related to the COVID-19 pandemic stratified by AA subtype. Of 740 respondents from the National Alopecia Areata Foundation and Massachusetts General Hospital hair loss clinic, 672 (90.8%) completed surveys and were included. 460 (69.2%) had AA, 166 (25.0%) had alopecia universalis (AU), and 39 (6.0%) had alopecia totalis (AT). 33.0% AA, 20.5% AT, and 12.05% AU reported increased hair loss due to COVID-19 stress. 20.0% AA, 20.5% AT, and 7.83% AU reported increased hair loss due to COVID-19 interrupting treatment. Compared with other subtypes, patients with AA (P = .00) or AU (P = .00) had significantly higher rates of increased hair loss due to COVID-19 stress and treatment interruption, respectively. These findings suggest the vital role of stress and treatment access on hair loss among AA patients.
Association Between the Physician Quality Score in the Merit-Based Incentive Payment System and Hospital Performance in Hospital Compare in the First Year of the Program
Authors: Laurent G. Glance, Caroline P. Thirukumaran, Changyong Feng, Stewart J. Lustik, Andrew W. Dick
Journal: JAMA Network Open (2021)

The scientific validity of the Merit-Based Incentive Payment System (MIPS) quality score as a measure of hospital-level patient outcomes is unknown.To examine whether better physician performance on the MIPS quality score is associated with better hospital outcomes.This cross-sectional study of 38 830 physicians used data from the Centers for Medicare & Medicaid Services (CMS) Physician Compare (2017) merged with CMS Hospital Compare data. Data analysis was conducted from September to November 2020.Linear regression was used to examine the association between physician MIPS quality scores aggregated at the hospital level and hospitalwide measures of (1) postoperative complications, (2) failure to rescue, (3) individual postoperative complications, and (4) readmissions.The study cohort of 38 830 clinicians (5198 [14.6%] women; 12 103 [31.6%] with 11-20 years in practice) included 6580 (17.2%) general surgeons, 8978 (23.4%) orthopedic surgeons, 1617 (4.2%) vascular surgeons, 582 (1.5%) cardiac surgeons, 904 (2.4%) thoracic surgeons, 18 149 (47.4%) anesthesiologists, and 1520 (4.0%) intensivists at 3055 hospitals. The MIPS quality score was not associated with the hospital composite rate of postoperative complications. MIPS quality scores for vascular surgeons in the 11th to 25th percentile, compared with those in the 51st to 100th percentile, were associated with a 0.55-percentage point higher hospital rate of failure to rescue (95% CI, 0.06-1.04 percentage points; P = .03). MIPS quality scores for cardiac surgeons in the 1st to 10th percentile, compared with those in the 51st to 100th percentile, were associated with a 0.41-percentage point higher hospital coronary artery bypass graft (CABG) mortality rate (95% CI, 0.10-0.71 percentage points; P = .01). MIPS quality scores for cardiac surgeons in the 1st to 10th percentile and 11th to 25th percentile, compared with those in the 51st to 100th percentile, were associated with 0.65-percentage point (95% CI, 0.013-1.16 percentage points; P = .02) and 0.48-percentage point (95% CI, 0.07-0.90 percentage points; P = .02) higher hospital CABG readmission rates, respectively.In this study, better performance on the physician MIPS quality score was associated with better hospital surgical outcomes for some physician specialties during the first year of MIPS.
Adequate Initial Dosage and Tapering Methods of Steroids to Reduce the Total Corticosteroid Dose in Myasthenia Gravis
Authors: Hiroyuki Akamine, Akiyuki Uzawa, Satoshi Kuwabara
Journal: JAMA Neurology (2021)

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Iron status, fibroblast growth factor 23 and cardiovascular and kidney outcomes in chronic kidney disease
Authors: Rupal C. Mehta, Monique E. Cho, Xuan Cai, Jungwha Lee, Jing Chen, Jiang He, John Flack, Tariq Shafi, Santosh L. Saraf, Valentin David, Harold I. Feldman, Tamara Isakova, Myles Wolf, Lawrence J. Appel, Alan S. Go, James P. Lash, Robert G. Nelson, Mahboob Rahman, Panduranga S. Rao, Vallabh O. Shah, Raymond R. Townsend, Mark L. Unruh
Journal: Kidney International (2021)
Pt/CNT Micro-Nanorobots Driven by Glucose Catalytic Decomposition
Authors: Hao Wang, Jiacheng Kan, Xin Zhang, Chenyi Gu, Zhan Yang
Journal: Cyborg and Bionic Systems (2021)

Swimming micro-nanorobots have attracted researchers' interest in potential medical applications on target therapy, biosensor, drug carrier, and others. At present, the experimental setting of the swimming micro-nanorobots was mainly studied in pure water or H2O2 solution. This paper presents a micro-nanorobot that applied glucose in human body fluid as driving fuel. Based on the catalytic properties of the anode and cathode materials of the glucose fuel cell, platinum (Pt) and carbon nanotube (CNT) were selected as the anode and cathode materials, respectively, for the micro-nanorobot. The innovative design adopted the method of template electrochemical and chemical vapor deposition to manufacture the Pt/CNT micro-nanorobot structure. Both the scanning electron microscope (SEM) and transmission electron microscope (TEM) were employed to observe the morphology of the sample, and its elements were analyzed by energy-dispersive X-ray spectroscopy (EDX). Through a large number of experiments in a glucose solution and according to Stoker's law of viscous force and Newton's second law, we calculated the driving force of the fabricated micro-nanorobot. It was concluded that the structure of the Pt/CNT micro-nanorobot satisfied the required characteristics of both biocompatibility and motion.
28354 Delayed admission to a specialist referral center: Impact on clinical outcomes in Stevens-Johnson syndrome and toxic epidermal necrolysis
Authors: Abigail E. Clark, Stephanie Fook-Chong, Karen Choo, Choon Chiat Oh, Yi Wei Yeo, Shiu Ming Pang, Haur Yueh Lee
Journal: Journal of the American Academy of Dermatology (2021)
Where There’s Smoke, There’s a Joint: Passive Smoking and Rheumatoid Arthritis
Authors: Milena A. Gianfrancesco, Cynthia S. Crowson
Journal: Arthritis & Rheumatology (2021)

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Correspondence on “SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response” by Bonelli <i>et al</i>
Authors: Sarah H Chung, Mark Wener, Alison M Bays, Habib Rahbar, Chihiro Morishima, Andrew B Bryan, Susan L Fink, Seth Cohen, Nandita S Mani, Anu Chaudhary, Gregory C Gardner
Journal: Annals of the Rheumatic Diseases (2021)

Bonelli et al recently reported reduced humoral responses to the BNT162b2 mRNA vaccine in five patients on rituximab therapy; in two patients with repopulated B cells, a low-level Spike protein antibody response occurred, but three patients with no detectable B-cells had no measurable antibody response to the vaccine.1 Of great interest, they reported that interferon-γ T-cell responses to SARS-CoV-2 Spike peptides were present in all five patients, irrespective of the antibody response to the vaccine.

It has been reported that patients on B-cell depleting therapy are at increased risk for hospitalisation and death from SARS-CoV-2 infection.2 In February 2021, the American College of Rheumatology (ACR) COVID-19 Taskforce published consensus guidelines regarding vaccine timing in immunosuppressed patients, despite the paucity of data available at that time on vaccine efficacy in patients on targeted B cell therapy.3 Moreover, the guidelines specifically …
A prospective longitudinal study of chronic pulmonary aspergillosis in pulmonary tuberculosis in Indonesia (APICAL)
Authors: Findra Setianingrum, Anna Rozaliyani, Robiatul Adawiyah, Ridhawati Syam, Mulyati Tugiran, Cut Yulia Indah Sari, Finny Nandipinto, Johannes Ramnath, Arief Riadi Arifin, Diah Handayani, Erlina Burhan, Martin Rumende, Retno Wahyuningsih, Riina Rautemaa-Richardson, David W Denning
Journal: Thorax (2021)

Chronic pulmonary aspergillosis (CPA) can complicate recovery from pulmonary TB. CPA may also be misdiagnosed as bacteriologically negative TB. This study aimed to determine the incidence of CPA in patients treated for TB in Indonesia, a country with a high incidence of TB.In this prospective, longitudinal cohort study in patients treated for pulmonary TB, clinical, radiological and laboratory findings were analysed. Sputum was collected for fungal culture and TB PCR. Patients were assessed at baseline (0-8 weeks) and at the end (5-6 months) of TB therapy. CPA diagnosis was based on symptoms (≥3 months), characteristic radiological features and positive Aspergillus serology, and categorised as proven, probable and possible.Of the 216 patients recruited, 128 (59%) were followed up until end of TB therapy. At baseline, 91 (42%) had microbiological evidence for TB. Aspergillus-specific IgG was positive in 64 (30%) patients and went from negative to positive in 16 (13%) patients during TB therapy. The incidence rates of proven and probable CPA at baseline were 6% (n=12) and 2% (n=5) and end of TB therapy 8% (n=10) and 5% (n=7), respectively. Six patients (two with confirmed TB) developed an aspergilloma. Diabetes mellitus was a significant risk factor for CPA (p=0.040). Persistent cough (n=5, 50%; p=0.005) and fatigue (n=6, 60%; p=0.001) were the most common symptoms in CPA.CPA should be considered a relatively frequent differential diagnosis in patients with possible or proven TB in Indonesia. Lack of awareness and limited access to Aspergillus-specific IgG tests and CT imaging are obstacles in establishing a CPA diagnosis.
Vascular characteristics of port wine birthmarks as measured by dynamic optical coherence tomography
Authors: Joseph N. Mehrabi, Jon Holmes, Michael Abrouk, Jordan V. Wang, Hyemin Pomerantz, Anton M. Palma, Christopher B. Zachary, Roy G. Geronemus, Jill S. Waibel, Kristen M. Kelly
Journal: Journal of the American Academy of Dermatology (2021)

Port wine birthmarks (PWBs) are congenital capillary malformations. Vessel characteristics, such as diameter and depth, may impact presentation and outcomes. They can be imaged using dynamic optical coherence tomography, a high-resolution, noninvasive imaging method.We conducted a cross-sectional observational study to measure in vivo vascular characteristics as a function of PWB color.Patients undergoing treatment for PWB were recruited from 3 sites. PWBs were classified by color. Dynamic optical coherence tomography images with calculations were obtained.One hundred eight patients were enrolled. Mean age correlated with PWB color, with birthmarks being lighter in younger patients and darker in older patients (P < .01). Mean superficial plexus depth was significantly shallower in purple PWBs than in pink PWBs. Color was not associated with significant differences in mean superficial vessel density or diameter. Among pink PWBs, each 10-year increase in age was associated with a 10.6-μm increase in superficial plexus depth. Among purple PWBs, each 10-year increase in age was associated with a 16.2-μm reduction in superficial plexus depth. In lesions without prior treatment, vessel density was 12.7% lower in purple PWBs than in pink PWBs.Superficial vessels of purple PWBs were significantly closer to the epidermis than those of pink PWBs, which might impact optimal laser parameters.
MTAP Deficiency–Induced Metabolic Reprogramming Creates a Vulnerability to Cotargeting <i>De Novo</i> Purine Synthesis and Glycolysis in Pancreatic Cancer
Authors: Qiangsheng Hu, Yi Qin, Shunrong Ji, Xiuhui Shi, Weixing Dai, Guixiong Fan, Shuo Li, Wenyan Xu, Wensheng Liu, Mengqi Liu, Zheng Zhang, Zeng Ye, Zhijun Zhou, Jingxuan Yang, Qifeng Zhuo, Xianjun Yu, Min Li, Xiaowu Xu
Journal: Cancer Research (2021)

Methylthioadenosine phosphorylase (MTAP) is a key enzyme associated with the salvage of methionine and adenine that is deficient in 20% to 30% of pancreatic cancer. Our previous study revealed that MTAP deficiency indicates a poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). In this study, bioinformatics analysis of The Cancer Genome Atlas (TCGA) data indicated that PDACs with MTAP deficiency display a signature of elevated glycolysis. Metabolomics studies showed that that MTAP deletion-mediated metabolic reprogramming enhanced glycolysis and de novo purine synthesis in pancreatic cancer cells. Western blot analysis revealed that MTAP knockout stabilized hypoxia-inducible factor 1α (HIF1α) protein via posttranslational phosphorylation. RIO kinase 1 (RIOK1), a downstream kinase upregulated in MTAP-deficient cells, interacted with and phosphorylated HIF1α to regulate its stability. In vitro experiments demonstrated that the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) and the de novo purine synthesis inhibitor l-alanosine synergized to kill MTAP-deficient pancreatic cancer cells. Collectively, these results reveal that MTAP deficiency drives pancreatic cancer progression by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for treating MTAP-deficient disease. SIGNIFICANCE: This study demonstrates that MTAP status impacts glucose and purine metabolism, thus identifying multiple novel treatment options against MTAP-deficient pancreatic cancer.
Correspondence on “Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: results from the COVID-19 global rheumatology alliance physician registry”
Authors: Ronald F van Vollenhoven, Sander W Tas, Michael T Nurmohamed
Journal: Annals of the Rheumatic Diseases (2021)

Correspondence on "Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: results from the COVID-19 global rheumatology alliance physician registry" by Sparks et al Sparks et al 1 are to be congratulated on an important and timely study.They found that the use of JAKi was associated with worse outcome of COVID-19 infection, and they interpret this as a harmful effect of the treatment in that particular setting.But this question deserves further consideration.Assuming that the observation is correct, what could the mechanism be?As the authors correctly point out, some JAKi's did show benefits for patients with severe COVID-19 infection. 2 3We, therefore, propose an alternative explanation of the observed data.Some guidance documents, 4 5 and certainly medical practice traditions, frequently have patients discontinue immunomodulatory treatments when a potentially severe infection is diagnosed, and it seems safe to assume that the vast majority of patients in the study did, in fact, stop their treatment when they became aware of the infection.While this would of course apply to all antirheumatic therapies, there are important differences in the impact this might have.Biologicals have half-lives in the order of weeks, and the effect of stopping the treatment is, therefore, limited in the acute setting.For methotrexate, pharmacodynamic aspects also lead to a long latency in the impact of discontinuing the drug.In contrast, JAKi have short half-lives and discontinuing the treatment will almost immediately lead to the reactivation of the relevant signalling pathways.We therefore propose, as an alternative possible explanation of the findings by Sparks et al, that it is the discontinuation of JAKi when SARS-CoV-2 infection is diagnosed, rather than the treatment itself, that is harmful.Needless to say, this possibility needs to be tested in clinical studies before leading to changes in practice, and would most likely only be addressed sufficiently in a prospective, randomised trial.
What are the obligations of pharmaceutical companies in a global health emergency?
Authors: Ezekiel J Emanuel, Allen Buchanan, Shuk Ying Chan, Cécile Fabre, Daniel Halliday, Joseph Heath, Lisa Herzog, R J Leland, Matthew S McCoy, Ole F Norheim, Carla Saenz, G Owen Schaefer, Kok-Chor Tan, Christopher Heath Wellman, Jonathan Wolff, Govind Persad
Journal: The Lancet (2021)