bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement in quality of life among Sri Lankan patients with haemorrhoids after invasive treatment: a longitudinal observational study
Authors: Keong S Y J , Tan H K , Lamawansa M D , Allen J C , Low Z L , Østbye T
Published: February 2021

Background

Haemorrhoids is a common chronic disease that can significantly impact patients’ quality of life. Yet, few studies have evaluated health-related quality of life (HRQoL) of patients with haemorrhoids before and after treatment. This study investigated the HRQoL of patients with haemorrhoids before and after treatment and the change in HRQoL from baseline.

Methods

A prospective observational study of patients with haemorrhoids was conducted at two public hospitals in Kandy, Sri Lanka. Two questionnaires assessing symptom severity and haemorrhoid-specific QoL were administered at initial consultation and at 4- and 8-week follow-ups after treatment (sclerotherapy, rubber band ligation (RBL), haemorrhoidectomy or evacuation of haematoma). The primary outcome was the least squares (LS) change of HRQoL score from baseline, measured using the Short Health Scale adapted for Haemorrhoidal Disease (4 domains: symptom load, interference with daily activities, concern, general well-being).

Results

In 48 patients selected for this study, LS mean change from baseline showed significant improvement in HRQoL across all domains and total Short Health Scale adapted for Haemorrhoidal Disease score at 4- and 8-week follow-ups (P < 0.001). Difference in LS mean change from baseline also showed continued improvement of HRQoL from week 4 to week 8 (P < 0.010). ‘Concern’ showed greatest improvement at 4 and 8 weeks (P < 0.001). Averaged LS mean changes from baseline showed RBL had greater improvement of HRQoL compared with sclerotherapy (P = 0.004).

Conclusion

Patients with haemorrhoids had improved HRQoL after invasive treatment. Haemorrhoid-specific QoL is an important component of the extent of disease and can serve as an aid to guide treatment, assess outcomes and monitor disease.
A data-driven approach to post-stroke aphasia classification and lesion-based prediction
Authors: Landrigan Jon-Frederick , Zhang Fengqing , Mirman Daniel
Published: February 2021

Aphasia is an acquired impairment in the production or comprehension of language, typically caused by left hemisphere stroke. The subtyping framework used in clinical aphasiology today is based on the Wernicke-Lichtheim model of aphasia formulated in the late 19th century, which emphasizes the distinction between language production and comprehension. The current study used a data-driven approach that combined modern statistical, machine learning, and neuroimaging tools to examine behavioural deficit profiles and their lesion correlates and predictors in a large cohort of individuals with post-stroke aphasia. First, individuals with aphasia were clustered based on their behavioural deficit profiles using community detection analysis (CDA) and these clusters were compared with the traditional aphasia subtypes. Random forest classifiers were built to evaluate how well individual lesion profiles predict cluster membership. The results of the CDA analyses did not align with the traditional model of aphasia in either behavioural or neuroanatomical patterns. Instead, the results suggested that the primary distinction in aphasia (after severity) is between phonological and semantic processing rather than between production and comprehension. Further, lesion-based classification reached 75% accuracy for the CDA-based categories and only 60% for categories based on the traditional fluent/non-fluent aphasia distinction. The results of this study provide a data-driven basis for a new approach to classification of post-stroke aphasia subtypes in both research and clinical settings.
How understudied populations have contributed to our understanding of Alzheimer’s disease genetics
Authors: Dehghani Nadia , Bras Jose , Guerreiro Rita
Published: February 2021

The majority of genome-wide association studies have been conducted using samples with a broadly European genetic background. As a field, we acknowledge this limitation and the need to increase the diversity of populations studied. A major challenge when designing and conducting such studies is to assimilate large samples sizes so that we attain enough statistical power to detect variants associated with disease, particularly when trying to identify variants with low and rare minor allele frequencies. In this review, we aimed to illustrate the benefits to genetic characterization of Alzheimer’s disease, in researching currently understudied populations. This is important for both fair representation of world populations and the translatability of findings. To that end, we conducted a literature search to understand the contributions of studies, on different populations, to Alzheimer’s disease genetics. Using both PubMed and Alzforum Mutation Database, we systematically quantified the number of studies reporting variants in known disease-causing genes, in a worldwide manner, and discuss the contributions of research in understudied populations to the identification of novel genetic factors in this disease. Additionally, we compared the effects of genome-wide significant single nucleotide polymorphisms across populations by focusing on loci that show different association profiles between populations (a key example being APOE). Reports of variants in APP, PSEN1 and PSEN2 can initially determine whether patients from a country have been studied for Alzheimer’s disease genetics. Most genome-wide significant associations in non-Hispanic white genome-wide association studies do not reach genome-wide significance in such studies of other populations, with some suggesting an opposite effect direction; this is likely due to much smaller sample sizes attained. There are, however, genome-wide significant associations first identified in understudied populations which have yet to be replicated. Familial studies in understudied populations have identified rare, high effect variants, which have been replicated in other populations. This work functions to both highlight how understudied populations have furthered our understanding of Alzheimer’s disease genetics, and to help us gauge our progress in understanding the genetic architecture of this disease in all populations.
Glutathione transferase Omega 1 confers protection against azoxymethane-induced colorectal tumour formation
Authors: Tummala Padmaja , Rooke Melissa , Dahlstrom Jane E , Takahashi Shuhei , Casarotto Marco G , Fernando Nilisha , Hughes Mark M , O’Neill Luke A J , Board Philip G
Published: February 2021

Inflammatory bowel disease (IBD) is characterized by multiple alterations in cytokine expression and is a risk factor for colon cancer. The Omega class glutathione transferase GSTO1-1 regulates the release of the pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) by deglutathionylating NEK7 in the NLRP3 inflammasome. When treated with azoxymethane and dextran sodium sulphate (AOM/DSS) as a model of IBD, Gsto1−/− mice were highly sensitive to colitis and showed a significant increase in the size and number of colon tumours compared with wild-type (WT) mice. Gsto1−/− mice treated with AOM/DSS had significantly lower serum IL-1β and IL-18 levels as well as significantly decreased interferon (IFN)-γ, decreased pSTAT1 and increased pSTAT3 levels in the distal colon compared with similarly treated WT mice. Histologically, AOM/DSS treated Gsto1−/− mice showed increased active chronic inflammation with macrophage infiltration, epithelial dysplasia and invasive adenocarcinoma compared with AOM/DSS treated WT mice. Thus, this study shows that GSTO1-1 regulates IL-1β and IL-18 activation and protects against colorectal cancer formation in the AOM/DSS model of IBD. The data suggest that while GSTO1-1 is a new target for the regulation of the NLRP3 inflammasome-associated cytokines IL-1β and IL-18 by small molecule inhibitors, there is a possibility that anti-inflammatory drugs targeting these cytokines may potentiate colon cancer in some situations.
Elevated White Blood Cell Count Does Not Predict Clostridium difficile Nucleic Acid Testing Results
Authors: Bosch Dustin E , Mathias Patrick C , Krumm Niklas , Bryan Andrew , Fang Ferric C , Greninger Alex L
Published: February 2021

Background

An elevated white blood cell count (WBC; >15 000/μL) is an established prognostic marker in patients with Clostridium difficile infection (CDI). Small observational studies have suggested that a markedly elevated WBC should prompt consideration of CDI. However, there is limited evidence correlating WBC elevation with the results of C. difficile nucleic acid amplification testing (NAAT).

Methods

Retrospective review of laboratory testing, outcomes, and treatment of 16 568 consecutive patients presenting to 4 hospitals over 4 years with NAAT and WBC testing on the same day.

Results

No significant relationship between C. difficile NAAT results and concurrent WBC in the inpatient setting was observed. Although an elevated WBC did predict NAAT results in the outpatient and emergency department populations (P < .001), accuracy was poor, with receiver-operator areas under the curve of 0.59 and 0.56, respectively. An elevated WBC (>15 000/μL) in CDI was associated with a longer median hospital length of stay (15.5 vs 11.0 days; P < .01), consistent with leukocytosis as a prognostic marker in CDI. NAAT-positive inpatients with elevated WBC were more likely to be treated with metronidazole and/or vancomycin (relative ratio, 1.2; 95% confidence interval [CI], 1.1–1.3) and die in the hospital (relative ratio, 2.9; 95% CI, 2.0–4.3).

Conclusions

Although WBC is an important prognostic indicator in patients with CDI, an isolated WBC elevation has low sensitivity and specificity as a predictor of fecal C. difficile NAAT positivity in the inpatient setting. A high or rising WBC in isolation is not a sufficient indication for CDI testing.
The Persistence of Underreporting of Hepatitis C as an Underlying or Contributing Cause of Death, 2011–2017
Authors: Spradling Philip R , Zhong Yuna , Moorman Anne C , Rupp Loralee B , Lu Mei , Teshale Eyasu H , Schmidt Mark A , Daida Yihe G , Boscarino Joseph A , Gordon Stuart C ,   CHeCS Investigators, Teshale Eyasu H , Spradling Philip R , Moorman Anne C , Xing Jian , Zhong Yuna , Gordon Stuart C , Lu Mei , Li Jia , Rupp Loralee B , Akkerman Nonna , Trudeau Sheri , Zhou Yueren , Boscarino Joseph A , Daar Zahra S , Smith Robert E , Daida Yihe G , Trinacty Connie Mah , Lai Jonathan W , Nie Sixiang , Wong Carmen P , Schmidt Mark A , Donald Judy L
Published: February 2021

Using electronic health records, we found that hepatitis C virus (HCV) reporting on death certificates of 2901 HCV-infected decedents from 4 US healthcare organizations during 2011–2017 was documented in only 50% of decedents with hepatocellular carcinoma and less than half with decompensated cirrhosis. National figures likely underestimate the US HCV mortality burden.
Modeling Effectiveness of Testing Strategies to Prevent Coronavirus Disease 2019 (COVID-19) in Nursing Homes—United States, 2020
Authors: See Isaac , Paul Prabasaj , Slayton Rachel B , Steele Molly K , Stuckey Matthew J , Duca Lindsey , Srinivasan Arjun , Stone Nimalie , Jernigan John A , Reddy Sujan C
Published: February 2021

Background

Identifying asymptomatic individuals early through serial testing is recommended to control coronavirus disease 2019 (COVID-19) in nursing homes, both in response to an outbreak (“outbreak testing” of residents and healthcare personnel) and in facilities without outbreaks (“nonoutbreak testing” of healthcare personnel). The effectiveness of outbreak testing and isolation with or without nonoutbreak testing was evaluated.

Methods

Using published SARS-CoV-2 transmission parameters, the fraction of SARS-CoV-2 transmissions prevented through serial testing (weekly, every 3 days, or daily) and isolation of asymptomatic persons compared with symptom-based testing and isolation was evaluated through mathematical modeling using a Reed-Frost model to estimate the percentage of cases prevented (ie, “effectiveness”) through either outbreak testing alone or outbreak plus nonoutbreak testing. The potential effect of simultaneous decreases (by 10%) in the effectiveness of isolating infected individuals when instituting testing strategies was also evaluated.

Results

Modeling suggests that outbreak testing could prevent 54% (weekly testing with 48-hour test turnaround) to 92% (daily testing with immediate results and 50% relative sensitivity) of SARS-CoV-2 infections. Adding nonoutbreak testing could prevent up to an additional 8% of SARS-CoV-2 infections (depending on test frequency and turnaround time). However, added benefits of nonoutbreak testing were mostly negated if accompanied by decreases in infection control practice.

Conclusions

When combined with high-quality infection control practices, outbreak testing could be an effective approach to preventing COVID-19 in nursing homes, particularly if optimized through increased test frequency and use of tests with rapid turnaround.
Angiotensin II receptor 1 controls profibrotic Wnt/β-catenin signalling in experimental autoimmune myocarditis
Authors: Czepiel Marcin , Diviani Dario , Jaźwa-Kusior Agnieszka , Tkacz Karolina , Rolski Filip , Smolenski Ryszard T , Siedlar Maciej , Eriksson Urs , Kania Gabriela , Błyszczuk Przemysław
Published: February 2021

Aims

Angiotensin (Ang) II signalling has been suggested to promote cardiac fibrosis in inflammatory heart diseases; however, the underlying mechanisms remain obscure. Using Agtr1a-/- mice with genetic deletion of angiotensin receptor type 1 (ATR1) and the experimental autoimmune myocarditis (EAM) model, we aimed to elucidate the role of Ang II-ATR1 pathway in development of heart-specific autoimmunity and post-inflammatory fibrosis.

Methods and results

EAM was induced in wild-type (WT) and Agtr1a-/- mice by subcutaneous injections with alpha myosin heavy chain peptide emulsified in complete Freund’s adjuvant. Agtr1a-/- mice developed myocarditis to a similar extent as WT controls at day 21 but showed reduced fibrosis and better systolic function at day 40. Crisscross bone marrow chimaera experiments proved that ATR1 signalling in the bone marrow compartment was critical for cardiac fibrosis. Heart infiltrating, bone-marrow-derived cells produced Ang II, but lack of ATR1 in these cells reduced transforming growth factor beta (TGF-β)-mediated fibrotic responses. At the molecular level, Agtr1a-/- heart-inflammatory cells showed impaired TGF-β-mediated phosphorylation of Smad2 and TAK1. In WT cells, TGF-β induced formation of RhoA-GTP and RhoA-A-kinase anchoring protein-Lbc (AKAP-Lbc) complex. In Agtr1a-/- cells, stabilization of RhoA-GTP and interaction of RhoA with AKAP-Lbc were largely impaired. Furthermore, in contrast to WT cells, Agtr1a-/- cells stimulated with TGF-β failed to activate canonical Wnt pathway indicated by suppressed activity of glycogen synthase kinase-3 (GSK-3)β and nuclear β-catenin translocation and showed reduced expression of Wnts. In line with these in vitro findings, β-catenin was detected in inflammatory regions of hearts of WT, but not Agtr1a-/- mice and expression of canonical Wnt1 and Wnt10b were lower in Agtr1a-/- hearts.

Conclusion

Ang II-ATR1 signalling is critical for development of post-inflammatory fibrotic remodelling and dilated cardiomyopathy. Our data underpin the importance of Ang II-ATR1 in effective TGF-β downstream signalling response including activation of profibrotic Wnt/β-catenin pathway.
Tbx5 variants disrupt Nav1.5 function differently in patients diagnosed with Brugada or Long QT Syndrome
Authors: Nieto-Marín Paloma , Tinaquero David , Utrilla Raquel G , Cebrián Jorge , González-Guerra Andrés , Crespo-García Teresa , Cámara-Checa Anabel , Rubio-Alarcón Marcos , Dago María , Alfayate Silvia , Filgueiras-Rama David , Peinado Rafael , López-Sendón José Luis , Jalife José , Tamargo Juan , Bernal Juan Antonio , Caballero Ricardo , Delpón Eva ,   the ITACA Consortium Investigators, Arribas F , Pérez-Villacastín J , Alonso-Martín J J , Atienza F , López-Sendón J L , Toquero J , Hernández-Madrid A , Delpón E
Published: February 2021

Aims

The transcription factor Tbx5 controls cardiogenesis and drives Scn5a expression in mice. We have identified two variants in TBX5 encoding p. D111Y and p. F206L Tbx5, respectively, in two unrelated patients with structurally normal hearts diagnosed with long QT (LQTS) and Brugada (BrS) syndrome. Here, we characterized the consequences of each variant to unravel the underlying disease mechanisms.

Methods and results

We combined clinical analysis with in vivo and in vitro electrophysiological and molecular techniques in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs), HL-1 cells, and cardiomyocytes from mice trans-expressing human wild-type (WT) or mutant proteins. Tbx5 increased transcription of SCN5A encoding cardiac Nav1.5 channels, while repressing CAMK2D and SPTBN4 genes encoding Ca/calmodulin kinase IIδ (CaMKIIδ) and βIV-spectrin, respectively. These effects significantly increased Na current (INa) in hiPSC-CMs and in cardiomyocytes from mice trans-expressing Tbx5. Consequently, action potential (AP) amplitudes increased and QRS interval narrowed in the mouse electrocardiogram. p. F206L Tbx5 bound to the SCN5A promoter failed to transactivate it, thus precluding the pro-transcriptional effect of WT Tbx5. Therefore, p. F206L markedly decreased INa in hiPSC-CM, HL-1 cells and mouse cardiomyocytes. The INa decrease in p. F206L trans-expressing mice translated into QRS widening and increased flecainide sensitivity. p. D111Y Tbx5 increased SCN5A expression but failed to repress CAMK2D and SPTBN4. The increased CaMKIIδ and βIV-spectrin significantly augmented the late component of INa (INaL) which, in turn, significantly prolonged AP duration in both hiPSC-CMs and mouse cardiomyocytes. Ranolazine, a selective INaL inhibitor, eliminated the QT and QTc intervals prolongation seen in p. D111Y trans-expressing mice.

Conclusions

In addition to peak INa, Tbx5 critically regulates INaL and the duration of repolarization in human cardiomyocytes. Our original results suggest that TBX5 variants associate with and modulate the intensity of the electrical phenotype in LQTS and BrS patients.
Effect of a dedicated mitral heart team compared to a general heart team on survival: a retrospective, comparative, non-randomized interventional cohort study based on prospectively registered data
Authors: Sardari Nia Peyman , Olsthoorn Jules R , Heuts Samuel , van Kuijk Sander M J , Vainer Jindrich , Streukens Sebastian , Schalla Simon , Segers Patrique , Barenbrug Paul , Crijns Harry J G M , Maessen Jos G
Published: February 2021

OBJECTIVES

Although in both the US and European guidelines the ‘heart team approach’ is a class I recommendation, supporting evidence is still lacking. Therefore, we sought to provide comparative survival data of patients with mitral valve disease referred to the general and the dedicated heart team.

METHODS

In this retrospective cohort, patients evaluated for mitral valve disease by a general heart team (2009–2014) and a dedicated mitral valve heart team (2014–2018) were included. Decision-making was recorded prospectively in heart team electronic forms. The end point was overall survival from decision of the heart team.

RESULTS

In total, 1145 patients were included of whom 641 (56%) were discussed by dedicated heart team and 504 (44%) by general heart team. At 5 years, survival probability was 0.74 [95% confidence interval (CI) 0.68–0.79] for the dedicated heart team group compared to 0.70 (95% CI 0.66–0.74, P = 0.040) for the general heart team. Relative risk of mortality adjusted for EuroSCORE II, treatment groups (surgical, transcatheter and non-intervention), mitral valve pathology (degenerative, functional, rheumatic and others) and 13 other baseline characteristics for patients in the dedicated heart team was 29% lower [hazard ratio (HR) 0.71, 95% CI 0.54–0.95; P = 0.019] than for the general heart team. The adjusted relative risk of mortality was 61% lower for patients following the advice of the heart team (HR 0.39, 95% CI 0.25–0.62; P < 0.001) and 43% lower for patients following the advice of the general heart team (HR 0.57, 95% CI 0.37–0.87; P = 0.010) compared to those who did not follow the advice of the heart team.

CONCLUSIONS

In this retrospective cohort, patients treated for mitral valve disease based on a dedicated heart team decision have significantly higher survival independent of the allocated treatment, mitral valve pathology and baseline characteristics.
A call to action for new global approaches to cardiovascular disease drug solutions
Authors: Figtree Gemma A , Broadfoot Keith , Casadei Barbara , Califf Robert , Crea Filippo , Drummond Grant R , Freedman Jane E , Guzik Tomasz J , Harrison David , Hausenloy Derek J , Hill Joseph A , Januzzi James L , Kingwell Bronwyn A , Lam Carolyn S P , MacRae Calum A , Misselwitz Frank , Miura Tetsuji , Ritchie Rebecca H , Tomaszewski Maciej , Wu Joseph C , Xiao Junjie , Zannad Faiez
Published: February 2021

Whilst we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic ‘buckets’. Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased ‘omic’ approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.
Risk stratification of patients undergoing transvenous lead extraction with the ELECTRa Registry Outcome Score (EROS): an ESC EHRA EORP European lead extraction ConTRolled ELECTRa registry analysis
Authors: Sidhu Baldeep S , Ayis Salma , Gould Justin , Elliott Mark K , Mehta Vishal , Kennergren Charles , Butter Christian , Deharo Jean-Claude , Kutarski Andrzej , Maggioni Aldo P , Auricchio Angelo , Kuck Karl-Heinz , Blomström-Lundqvist Carina , Bongiorni Maria Grazia , Rinaldi Christopher A ,   the ELECTRa Investigators Group
Published: February 2021

Aims

Transvenous lead extraction is associated with a significant risk of complications and identifying patients at highest risk pre-procedurally will enable interventions to be planned accordingly. We developed the ELECTRa Registry Outcome Score (EROS) and applied it to the ELECTRa registry to determine if it could appropriately risk-stratify patients.

Methods and results

EROS was devised to risk-stratify patients into low risk (EROS 1), intermediate risk (EROS 2), and high risk (EROS 3). This was applied to the ESC EORP European Lead Extraction ConTRolled ELECTRa registry; 57.5% EROS 1, 31.8% EROS 2, and 10.7% EROS 3. Patients with EROS 3 or 2 were significantly more likely to require powered sheaths and a femoral approach to complete procedures. Patients with EROS 3 were more likely to suffer procedure-related major complications including deaths (5.1 vs. 1.3%; P < 0.0001), both intra-procedural (3.5 vs. 0.8%; P = 0.0001) and post-procedural (1.6 vs. 0.5%; P = 0.0192). They were more likely to suffer post-procedural deaths (0.8 vs. 0.2%; P 0.0449), cardiac avulsion or tear (3.8 vs. 0.5%; P < 0.0001), and cardiovascular lesions requiring pericardiocentesis, chest tube, or surgical repair (4.6 vs. 1.0%; P < 0.0001). EROS 3 was associated with procedure-related major complications including deaths [odds ratio (OR) 3.333, 95% confidence interval (CI) 1.879–5.914; P < 0.0001] and all-cause in-hospital major complications including deaths (OR 2.339, 95% CI 1.439–3.803; P = 0.0006).

Conclusion

EROS successfully identified patients who were at increased risk of significant procedural complications that require urgent surgical intervention.
Self-reported symptoms in French primary care SARS-CoV-2 patients: association with gender and age group
Authors: Sebo Paul , Maisonneuve Hubert , Lourdaux Julie , Cuzin Clara , Floquet Martin , Tudrej Benoit , Haller Dagmar M
Published: February 2021

Introduction

The early identification of COVID-19 patients is of outmost importance in the current pandemic. As with other pathogens, presenting symptoms of SARS-CoV-2 may vary, depending on sociodemographic factors. We aimed to describe the clinical characteristics of COVID-19 patients by age/gender and to assess whether the diagnostic performance of these symptoms varied according to these variables.

Methods

We analysed data from a cross-sectional study involving primary care patients undergoing RT-PCR testing in Lyon, France. Among patients who tested positive, we examined whether there was an association between age/gender and various symptoms. In addition, we calculated the diagnostic performance of the most specific symptoms (smell/taste disorder).

Results

Among 1543 consecutive patients, 253 tested positive (16%). There were significant age/gender-related differences in symptoms. In middle-aged women, the diagnostic performance of smell/taste disorders were AUC = 0.65 [95%CI 0.59–0.71] and PPV = 72% [95%CI 53–87%], that is higher than in the entire sample (smell/taste disorders: AUC = 0.59 [95%CI 0.57–0.62] and PPV = 57% [95%CI 47–67%]. In contrast, the negative predictive values of smell/taste disorders were similar in both groups (85% [95%CI 81–89%] for middle-age women and 86% [95%CI 85–88%] for the entire sample).

Conclusion

We found significant age/gender-related differences in the clinical characteristics of COVID-19 patients. Screening strategies based on smell/taste disorders performed better in middle-aged women, but could not ensure a diagnosis of COVID-19 in any subgroup of patients. Future diagnostic strategies should use age/gender differentiated approaches.
Soil depth matters: shift in composition and inter-kingdom co-occurrence patterns of microorganisms in forest soils
Authors: Mundra Sunil , Kjønaas O Janne , Morgado Luis N , Krabberød Anders Kristian , Ransedokken Yngvild , Kauserud Håvard
Published: February 2021

Soil depth represents a strong physiochemical gradient that greatly affects soil-dwelling microorganisms. Fungal communities are typically structured by soil depth, but how other microorganisms are structured is less known. Here, we tested whether depth-dependent variation in soil chemistry affects the distribution and co-occurrence patterns of soil microbial communities. This was investigated by DNA metabarcoding in conjunction with network analyses of bacteria, fungi, as well as other micro-eukaryotes, sampled in four different soil depths in Norwegian birch forests. Strong compositional turnover in microbial assemblages with soil depth was detected for all organismal groups. Significantly greater microbial diversity and fungal biomass appeared in the nutrient-rich organic layer, with sharp decrease towards the less nutrient-rich mineral zones. The proportions of copiotrophic bacteria, Arthropoda and Apicomplexa were markedly higher in the organic layer, while patterns were opposite for oligotrophic bacteria, Cercozoa, Ascomycota and ectomycorrhizal fungi. Network analyses indicated more intensive inter-kingdom co-occurrence patterns in the upper mineral layer (0–5 cm) compared to the above organic and the lower mineral soil, signifying substantial influence of soil depth on biotic interactions. This study supports the view that different microbial groups are adapted to different forest soil strata, with varying level of interactions along the depth gradient.
Genome stability is guarded by yeast Rtt105 through multiple mechanisms
Authors: Corda Yves , Maestroni Laetitia , Luciano Pierre , Najem Maria Y , Géli Vincent
Published: February 2021

Ty1 mobile DNA element is the most abundant and mutagenic retrotransposon present in the genome of the budding yeast Saccharomyces cerevisiae. Protein regulator of Ty1 transposition 105 (Rtt105) associates with large subunit of RPA and facilitates its loading onto a single-stranded DNA at replication forks. Here, we dissect the role of RTT105 in the maintenance of genome stability under normal conditions and upon various replication stresses through multiple genetic analyses. RTT105 is essential for viability in cells experiencing replication problems and in cells lacking functional S-phase checkpoints and DNA repair pathways involving homologous recombination. Our genetic analyses also indicate that RTT105 is crucial when cohesion is affected and is required for the establishment of normal heterochromatic structures. Moreover, RTT105 plays a role in telomere maintenance as its function is important for the telomere elongation phenotype resulting from the Est1 tethering to telomeres. Genetic analyses indicate that rtt105Δ affects the growth of several rfa1 mutants but does not aggravate their telomere length defects. Analysis of the phenotypes of rtt105Δ cells expressing NLS-Rfa1 fusion protein reveals that RTT105 safeguards genome stability through its role in RPA nuclear import but also by directly affecting RPA function in genome stability maintenance during replication.
Racial/Ethnic Differences in Women’s Life Event Exposure Across Midlife
Authors: Koffer R E , Thurston R C , Bromberger J T , Matthews K A
Published: February 2021

Objective

Stressful life events are associated with poorer physical, cognitive, and mental health. Examining life events trends across midlife illustrates normative experiences of stress in a critical life period for intervention and disease prevention. Further, there is a critical need for research with racially/ethnically diverse samples to identify differences in life event exposure, as they may relate to later health disparities.

Method

Annual life event reports were analyzed from 3,066 White, Black, Hispanic, Chinese, and Japanese women in the Study of Women’s Health Across the Nation. Across ages 43–65, longitudinal trajectories were fit to annual number of life events and 9 subcategories of life events (i.e., work problems, economic problems, partner unemployment, illness/accident of loved one, caregiving, bereavement, relationship problems, family legal/police problems, and violent events that happened to the self or family). Racial/ethnic differences were examined, controlling for education.

Results

Number of annual life events declined with age and plateaued in later midlife. This pattern was largely consistent across types of life events, though family health and bereavement-related life events increased in later midlife. Compared to White women, Black women experienced more life events, while Chinese, Hispanic, and Japanese women experienced fewer life events. Racial/ethnic differences were amplified in specific subtypes of life events.

Discussion

Racial/ethnic differences in exposure to life events across midlife may contribute to racial/ethnic health disparities in later life.
Dementia-Friendly Neighborhood and the Built Environment: A Scoping Review
Authors: Gan Daniel R Y , Chaudhury Habib , Mann Jim , Wister Andrew V
Published: February 2021

Background and Objectives

There has been a proliferation of research on dementia-friendly communities in recent years, particularly on interpersonal and social aspects. Nonetheless, the neighborhood built environment remains a co-constituent of the lived experience of people living with dementia (PLWD) that is amenable to interventions for health and well-being in the community. This scoping review presents a narrative synthesis of empirical research on dementia-friendly neighborhoods, with a focus on the built environment and its associated sociobehavioral aspects. Planning and design principles are distilled to identify research and policy implications.

Research Design and Methods

We reviewed 29 articles identified through a systematic search of AgeLine, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Global Health, Medical Literature Analysis and Retrieval System Online, and Scopus. Peer-reviewed articles that employed quantitative and/or qualitative methods in community settings were included.

Results

An equal number of studies focused on behavioral/psychosocial aspects of the built environment and assessment of specific environmental features. The former often used qualitative methods, whereas statistical methods were common in studies on discrete features of the neighborhood built environment. Few studies focused on rural contexts. Emerging research areas include interactions between dementia risk factors and neighborhood environments to support primary and secondary prevention.

Discussion and Implications

The body of literature needs expansion into planning and design fields to foster community participation of PLWD by optimizing environmental stimuli, minimizing environmental barriers, and engaging PLWD in dementia-friendly community initiatives. While evidence has accumulated on landmarks and social participation at the individual level, research at the community and policy levels is limited. This requires advanced mixed methods.
The interplay of fast waves and slow convection in geodynamo simulations nearing Earth’s core conditions
Authors: Aubert Julien , Gillet Nicolas
Published: February 2021

Ground observatory and satellite-based determinations of temporal variations in the geomagnetic field probe a decadal to annual timescale range where Earth’s core slow, inertialess convective motions and rapidly propagating, inertia-bearing hydromagnetic waves are in interplay. Here we numerically model and jointly investigate these two important features with the help of a geodynamo simulation that (to date) is the closest to the dynamical regime of Earth’s core. This model also considerably enlarges the scope of a previous asymptotic scaling analysis, which in turn strengthens the relevance of the approach to describe Earth’s core dynamics. Three classes of hydrodynamic and hydromagnetic waves are identified in the model output, all with propagation velocity largely exceeding that of convective advection: axisymmetric, geostrophic Alfvén torsional waves, and non-axisymmetric, quasi-geostrophic Alfvén and Rossby waves. The contribution of these waves to the geomagnetic acceleration amounts to an enrichment and flattening of its energy density spectral profile at decadal timescales, thereby providing a constraint on the extent of the $f^{-4}$ range observed in the geomagnetic frequency power spectrum. As the model approaches Earth’s core conditions, this spectral broadening arises because the decreasing inertia allows for waves at increasing frequencies. Through non-linear energy transfers with convection underlain by Lorentz stresses, these waves also extract an increasing amount of energy from the underlying convection as their key timescale decreases towards a realistic value. The flow and magnetic acceleration energies carried by waves both linearly increase with the ratio of the magnetic diffusion timescale to the Alfvén timescale, highlighting the dominance of Alfvén waves in the signal and the stabilizing control of magnetic dissipation at non-axisymmetric scales. Extrapolation of the results to Earth’s core conditions supports the detectability of Alfvén waves in geomagnetic observations, either as axisymmetric torsional oscillations or through the geomagnetic jerks caused by non-axisymmetric waves. In contrast, Rossby waves appear to be too fast and carry too little magnetic energy to be detectable in geomagnetic acceleration signals of limited spatio-temporal resolution.
ADAM10 hyperactivation acts on piccolo to deplete synaptic vesicle stores in Huntington’s disease
Authors: Cozzolino Flora , Vezzoli Elena , Cheroni Cristina , Besusso Dario , Conforti Paola , Valenza Marta , Iacobucci Ilaria , Monaco Vittoria , Birolini Giulia , Bombaci Mauro , Falqui Andrea , Saftig Paul , Rossi Riccardo L , Monti Maria , Cattaneo Elena , Zuccato Chiara
Published: February 2021

Synaptic dysfunction and cognitive decline in Huntington’s disease (HD) involve hyperactive A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10). To identify the molecular mechanisms through which ADAM10 is associated with synaptic dysfunction in HD, we performed an immunoaffinity purification–mass spectrometry (IP–MS) study of endogenous ADAM10 in the brains of wild-type and HD mice. We found that proteins implicated in synapse organization, synaptic plasticity, and vesicle and organelles trafficking interact with ADAM10, suggesting that it may act as hub protein at the excitatory synapse. Importantly, the ADAM10 interactome is enriched in presynaptic proteins and ADAM10 co-immunoprecipitates with piccolo (PCLO), a key player in the recycling and maintenance of synaptic vesicles. In contrast, reduced ADAM10/PCLO immunoprecipitation occurs in the HD brain, with decreased density of synaptic vesicles in the reserve and docked pools at the HD presynaptic terminal. Conditional heterozygous deletion of ADAM10 in the forebrain of HD mice reduces active ADAM10 to wild-type level and normalizes ADAM10/PCLO complex formation and synaptic vesicle density and distribution. The results indicate that presynaptic ADAM10 and PCLO are a relevant component of HD pathogenesis.
Regulating Infrastructure: Human Rights and the Sustainable Development Goals in Myanmar
Authors: Palmer Emma
Published: February 2021

Infrastructure projects, including roads, railways, power, telecommunications and water facilities, are considered necessary to promote many different human rights and the Sustainable Development Goals (SDGs). Infrastructure development has been a central feature of the Myanmar government’s policies, including the Myanmar Sustainable Development Plan 2018–2030, to sustain economic growth and achieve the SDGs. As in many countries, public–private partnerships are promoted to help implement these policies. Yet, infrastructure projects have been associated with serious human rights violations, including in Myanmar. This article explores the links between infrastructure, international human rights law and the SDGs. It analyses how this relationship is governed by international, domestic, ‘soft’ law and self-regulatory mechanisms. It then assesses Myanmar’s legal and policy framework for promoting infrastructure investment and implementing the SDGs. It concludes that there is scope to further clarify responsibilities and accountability mechanisms for the human rights impacts of infrastructure investment.
Pituitary response to GnRH stimulation tests in different FSHB-211 G/T genotypes
Authors: Sansone Andrea , Schubert Maria , Tüttelmann Frank , Krallmann Claudia , Zitzmann Michael , Kliesch Sabine , Gromoll Jörg
Published: February 2021

STUDY QUESTION

Does pituitary response to a GnRH stimulation test differ according to the different FSHB-211 G/T genotypes?

SUMMARY ANSWER

The promoter polymorphism FSHB-211 G > T affects the pituitary response to exogenous GnRH stimulation by reducing FSH and increasing LH outputs.

WHAT IS KNOWN ALREADY

The FSHB-211 G > T single nucleotide polymorphism (SNP) is known to affect pituitary FSH output by impairing the transcriptional activity of FSHB.

STUDY DESIGN, SIZE, DURATION

This was a cross-sectional, retrospective study on 67 male subjects (mean age: 24.6 ± 10.3 years) undergoing a GnRH stimulation test for diagnostic purposes in cases of secondary hypogonadism.

PARTICIPANTS/MATERIALS, SETTING, METHODS

A GnRH stimulation test was performed by administering an i.v. bolus of 100 µg of the GnRH-analogue gonadorelin acetate to all patients, with blood samples drawn from the cubital vein immediately prior to injection (T0) and 30 (T1) and 45 minutes (T2) after. Clinical and genetic data were retrieved from a computerized database. Linear longitudinal mixed-effect models were used to assess the effects of SNP genotype on FSH and LH levels over time via additive and recessive models.

MAIN RESULTS AND THE ROLE OF CHANCE

An overall marked increase in serum FSH and LH following administration i.v. of 100 µg of an LHRH-analogue was found (P < 0.0001 for linear trend, both models). Peak levels of LH were significantly higher in TT carriers than in GT and GG carriers (P = 0.012); no significant between-groups difference was found concerning stimulated FSH levels. In both the additive and recessive model, the main effect of T allele(s) did not reach statistical significance concerning FSH levels (P = 0.9502 and P = 0.8576, respectively), yet interaction effects over time demonstrated an attenuated response in T-allele carriers compared to the GG-allele carriers (P = 0.0219 and P = 0.0276). Main and interaction effects for LH were significant in both the additive (P = 0.0022 and P = 0.0013, respectively) and recessive model (P = 0.0025 and P = 0.0016, respectively).

LIMITATIONS, REASONS FOR CAUTION

Given the retrospective nature of the study and the small number of TT carriers, results should be interpreted with caution.

WIDER IMPLICATIONS OF THE FINDINGS

The FSHB c.-211G>T polymorphism might result in an impaired response to endogenous, as well as exogenous, GnRH stimulation. This finding might contribute to the clinical phenotype of reduced testicular volume and sperm count for patients carrying one or two T alleles.

STUDY FUNDING/COMPETING INTEREST(S)

Parts of the study were supported by the German Research Foundation (CRU326 Male Germ Cells). On behalf of all authors, the corresponding author states that there is no conflict of interest.

TRIAL REGISTRATION NUMBER

NA.
Is there still a rationale for non-invasive PGT-A by analysis of cell-free DNA released by human embryos into culture medium?
Authors: Orvieto Raoul , Aizer Adva , Gleicher Norbert
Published: February 2021

Human embryos utilise an array of processes to eliminate the very high prevalence of aneuploid cells in early embryo stages. Human embryo self-correction was recently demonstrated by their ability to eliminate/expel abnormal blastomeres as cell debris/fragments. A whole genome amplification study has demonstrated that 63.6% of blastocysts expelled cell debris with abnormal chromosomal rearrangements. Moreover, 55.5% of euploid blastocysts expel aneuploid debris, strongly suggesting that the primary source of cell free DNA in culture media is expelled aneuploid blastomeres and/or their fragments. Such a substantial ability to self-correct downstream from the blastocyststage, therefore, renders any chromosomal diagnosis at the blastocyststage potentially useless, and this, unfortunately, also must particularly include non-invasive PGT-A based on cell-free DNA in spent medium. High rates of false-positive diagnoses of human embryos often lead to non-use and/or disposal of embryos with entirely normal pregnancy potential. Before adopting yet another round of unvalidated PGT-A as a routine adjunct to IVF, we here present facts that deserve to be considered.
Ulcerative Colitis Narrative Global Survey Findings: The Impact of Living With Ulcerative Colitis—Patients’ and Physicians’ View
Authors: Dubinsky Marla C , Watanabe Kenji , Molander Pauliina , Peyrin-Biroulet Laurent , Rubin Michele , Melmed Gil Y , Deuring J Jasper , Woolcott John , Cappelleri Joseph C , Steinberg Kathy , Connor Susan
Published: February 2021

Background

The Ulcerative Colitis (UC) Narrative is a global patient and physician survey aimed at identifying the impact of UC and comparing and contrasting perceptions of UC burden and management approaches.

Methods

Surveys of patients with UC (self-reported diagnosis; n = 2100) and physicians (n = 1254) were completed across 10 countries by The Harris Poll between August 2017 and February 2018. Questionnaires covered multiple aspects of UC, including diagnosis, treatment, and impact on patient quality of life, in addition to standard demographic information. Descriptive statistics are reported.

Results

The majority of patients (82%) had moderate to severe UC (based on medication history; those who had only ever taken 5-aminosalicylates were excluded); 67% described their UC as controlled with few to no symptoms. On average, patients experienced 4.3 flares (standard deviation, 7.4) in the past year. Diagnostic delay was on average 2.0 years (standard deviation, 5.4); 42% of patients waited ≥1 year. Most patients (65%) felt that UC controlled their life rather than them controlling their disease. Because of the fear of repercussions, many patients had not disclosed their UC to their employer. Discussion of the emotional impact of UC during routine appointments was less of a priority for physicians, compared with patients.

Conclusions

The data from this global survey highlight that patients with UC experience diagnostic delay, poor disease control, and adverse impact on their quality of life. Patients report UC to be a mentally exhausting condition; however, emotional and mental health issues are infrequently discussed at routine appointments.
Eleven-year outcomes of U-clips in totally robotic coronary artery bypass grafting versus standard hand-sewn running suture in robotic-assisted coronary artery bypass grafting
Authors: Cheng Nan , Zhang Huajun , Yang Ming , Liu Guopeng , Guo Yi , Kang Wenbin , Gao Changqing , Wang Rong
Published: February 2021

OBJECTIVES

The aim of this study was to evaluate the clinical outcomes of patients undergoing off-pump robotic coronary artery bypass grafting (CABG) with either interrupted nitinol U-Clips in totally endoscopic coronary artery bypass (TECAB) or standard running suture anastomosis in robotically assisted direct coronary artery bypass (RADCAB) over a decade.

METHODS

From January 2007 to December 2017, 280 patients underwent robotic off-pump CABG using the da Vinci S/Si Surgical System in our centre. TECAB with interrupted nitinol U-Clips anastomosis was performed in the left internal mammary artery (LIMA) to LAD grafting in 126 patients and RADCAB (n = 154) of the LIMA to LAD was completed with standard running suture. After discharge, patients were contacted through telephone interview and were invited to attend the outpatient clinic every 6 months or 1 year. The graft patency was assessed by coronary angiography or computed tomography angiography.

RESULTS

All cases were completed without conversion to median sternotomy or cardiopulmonary bypass. A total of 275 single internal mammary artery (IMA) grafts (271 LIMAs, 4 right internal mammary arteries) and 5 bilateral IMA grafts were used as single graft or composite grafts. All the patients were discharged without in-hospital mortality or adverse outcomes. The average follow-up was 89.7 ± 30.4 months (range, 14–143 months). The cumulative survival rates (P = 0.53), the cumulative IMA patency rates (P = 0.83), and the rates of freedom from major adverse cerebrovascular and cardiovascular events (P = 0.41) between TECAB and RADCAB all showed no significant difference in the follow-up.

CONCLUSIONS

Robotic off-pump CABG using IMA grafts is safe and can provide reliable long-term outcomes. Compared with the standard hand-sewn running suture technique in RADCAB, interrupted suture with the nitinol U-Clips in TECAB showed similar long-term clinical results and graft patency in LIMA to LAD bypass grafting.