bluuebunny/crossref_metadata_2025 huggingface dataset:
High fibrinogen-prealbumin ratio (FPR) predicts stroke-associated pneumonia
Authors: Qiu Huihua , Luan Xiaoqian , Mei Enci
Published: August 2023

Background

Stroke-associated pneumonia (SAP) is a common complication in acute ischemic stroke patients. Although both single markers of fibrinogen and prealbumin are found to be associated with stroke and pneumonia, fibrinogen-prealbumin ratio (FPR) is a novel and comprehensive indicator that has not been explored in acute ischemic stroke patients. Besides, no study has explored the relationship between SAP and FPR. This study aims to explore whether FPR is higher in acute ischemic stroke patients and whether FPR is associated with SAP.

Methods

A total of 902 acute ischemic stroke patients participated in this study. Meanwhile, 146 healthy controls were also recruited. Fibrinogen and prealbumin were measured within 24 hours on admission. FPR was calculated after dividing fibrinogen (g/L) by prealbumin (mg/L)× 1000. SAP was defined according to the modified Centers for Disease Control criteria.

Results

In this study, 121 patients were diagnosed with SAP. FPR was significantly higher in both non-SAP patients and SAP patients than in healthy controls. In binary logistic regression analysis, we found that FPR was significantly higher in SAP group than non-SAP group (15.97[11.72-24.34] vs. 11.81[9.27-15.64]; P < 0.001) after adjusting for confounders. Besides, FPR (>18.22) was independently associated with SAP (OR3.028; 95% CI:1.607-5.706; P = 0.001). Moreover, diabetes mellitus, NIHSS score, dysphagia, leukocyte count and hs-CRP were independently correlated with SAP.

Conclusion

Higher FPR was observed in acute ischemic stroke patients compared to healthy controls and high FPR significantly increased the risk of SAP. Patients with high FPR should be paid more attention by physicians.
Protocol for a multicentre randomised controlled trial of STeroid Administration Routes For Idiopathic Sudden sensorineural Hearing loss: the STARFISH trial
Authors: Smith Matthew E , Knappet Rachel , Vickers Debi , White David , Schramm Chris J , Mehta Samir , Sun Yongzhong , Watkins Ben , Chadburn Marie , Jarrett Hugh , James Karen , Roberts Tracy , Bance Manohar L ,   INTEGRATE, the UK ENT Trainee Research Network, Tysome James R
Published: August 2023

Idiopathic sudden sensorineural hearing loss (ISSNHL) is the rapid onset of reduced hearing due to loss of function of the inner ear or hearing nerve of unknown aetiology. Evidence supports improved hearing recovery with early steroid treatment, via oral, intravenous, intratympanic or a combination of routes. The STARFISH trial aims to identify the most clinically and cost-effective route of administration of steroids as first-line treatment for ISSNHL.

STARFISH is a pragmatic, multicentre, assessor-blinded, three-arm intervention, superiority randomised controlled trial (1:1:1) with an internal pilot (ISRCTN10535105, IRAS 1004878). 525 participants with ISSNHL will be recruited from approximately 75 UK Ear, Nose and Throat units.

STARFISH will recruit adults with sensorineural hearing loss averaging 30dBHL or greater across three contiguous frequencies (confirmed via pure tone audiogram), with onset over a ≤3-day period, within four weeks of randomisation. Participants will be randomised to 1) oral prednisolone 1mg/Kg/day up to 60mg/day for 7 days; 2) intratympanic dexamethasone: three intratympanic injections 3.3mg/ml or 3.8mg/ml spaced 7±2 days apart; or 3) combined oral and intratympanic steroids.

The primary outcome will be absolute improvement in pure tone audiogram average at 12- weeks following randomisation (0.5, 1.0, 2.0 and 4.0kHz). Secondary outcomes at 6 and 12 weeks will include: Speech, Spatial and Qualities of hearing scale, high frequency pure tone average thresholds (4.0, 6.0 and 8.0kHz), Arthur Boothroyd speech test, Vestibular Rehabilitation Benefit Questionnaire, Tinnitus Functional Index, adverse events and optional weekly online speech and pure tone hearing tests.

A health economic assessment will be performed, and presented in terms of incremental cost effectiveness ratios, and cost per quality-adjusted life-year.

Primary analyses will be by intention-to-treat. Oral prednisolone will be the reference. For the primary outcome, the difference between group means and 97.5% confidence intervals at each time-point will be estimated via a repeated measures mixed-effects linear regression model.
New manual qPCR assay validated on tongue swabs collected and processed in Uganda shows sensitivity that rivals sputum-based molecular TB diagnostics
Authors: Steadman Amy , Andama Alfred , Ball Alexey , Mukwatamundu Job , Khimani Khushboo , Mochizuki Tessa , Asege Lucy , Bukirwa Alice , Kato John Baptist , Katumba David , Kisakye Esther , Mangeni Wilson , Mwebe Sandra , Nakaye Martha , Nasuna Irene , Nyawere Justine , Visente Deryk , Cook Catherine , Nalugwa Talemwa , Bachman Christine M. , Semitalia Fred , Weigl Bernhard H. , Connelly John , Worodria William , Cattamanchi Adithya
Published: August 2023

Background

Reliance on sputum-based testing is a key barrier to increasing access to molecular diagnostics for tuberculosis (TB). Many people with TB are unable to produce and sputum processing increases the complexity and cost of molecular assays. Tongue swabs are emerging as an alternative to sputum, but performance limits are uncertain.

Methods

From June 2022 to July 2023, we enrolled 397 consecutive adults with cough >2 weeks at two health centers in Kampala, Uganda. We collected routine demographic and clinical information, sputum for routine TB testing (one Xpert MTB/RIF Ultra® and two liquid cultures), and up to four tongue swabs for same-day qPCR. We evaluated tongue swab qPCR diagnostic accuracy in reference to sputum TB test results, quantified TB targets per swab, assessed the impact of serial swabbing, and compared two swab types (Copan FLOQSWAB® and Steripack® spun polyester swabs).

Results

Among 397 participants, 43.1% were female, median age was 33 years, 23.5% were living with HIV (PLHIV) and 32.3% had confirmed TB. Sputum Xpert Ultra and tongue swab qPCR results were concordant for 98.2% [96.2-99.1] of participants. Tongue swab qPCR sensitivity was 91.0% [84.6-94.9] and specificity 98.9% [96.2-99.8] vs. microbiological reference standard (MRS). A single tongue swab recovered a seven-log range of TB copies, with a decreasing recovery trend among four serial swabs. We found no difference between swab types.

Conclusions

Tongue swabs show promise as an alternative to sputum for TB diagnosis, with sensitivity approaching sputum-based molecular tests. Our results provide valuable insights for developing successful tongue swab-based TB diagnostics.
Patients’ experience to inform decision-making and clinical follow-up: The example of total hip arthroplasty
Authors: Lübbeke Anne , Cullati Stéphane , Baréa Christophe , Cole Sophie , Fabiano Gianluca , Silman Alan , Gutacker Nils , Agoritsas Thomas , Hannouche Didier , Pinedo-Villanueva Rafael
Published: August 2023

Background

The aim of this project was to enable patients and clinicians to benefit from previous patients’ experiences with total hip arthroplasty (THA) by seeking out patients’ views on what is important for them, leveraging registry data, and providing outcome information that is perceived as relevant, understandable, adapted to a specific patient’s profile, and readily available.

Methods

We created the information tool “Patients like me” in four steps. (1) The knowledge basis was the systematically collected detailed exposure and outcome information from the Geneva Arthroplasty Registry established 1996. (2) From the registry we randomly selected 275 patients about to undergo or having already undergone THA and asked them via interviews and a survey which benefits and harms associated with the operation and daily life with the prosthesis they perceived as most important. (3) The identified relevant data (39 predictor candidates, 15 outcomes) were evaluated using Conditional Inference Trees analysis to construct a classification algorithm for each of the 15 outcomes at three different time points/periods. Internal validity of the results was tested using bootstrapping. (4) The tool was designed by and pre-tested with patients over several iterations.

Results

Data from 6836 primary elective THAs operated between 1996 and 2019 were included. The trajectories for the 15 outcomes from the domains pain relief, activity improvement, complication (infection, dislocation, peri-prosthetic fracture) and what to expect in the future (revision surgery, need for contralateral hip replacement) over up to 20 years after surgery were presented for all patients and for specific patient profiles. The tool was adapted to various purposes including individual use, group sessions, patient-clinician interaction and surgeon information to complement the preoperative planning. The pre-test patients’ feedback to the tool was unanimously positive. They considered it interesting, clear, complete, and complementary to other information received.

Conclusion

The tool basead on a survey of patients’ perceived concerns and interests and the corresponding long-term data from a large institutional registry makes past patients’ experience accessible, understandable, and visible for today’s patients and their clinicians. It is a comprehensive illustration of trajectories of relevant outcomes from previous “Patients like me”. This principle and methodology can be applied in other medical fields.
Published benefits of ivermectin use in Itajaí, Brazil for COVID-19 infection, hospitalisation, and mortality are entirely explained by statistical artefacts
Authors: Mills Robin , Peçanha Antonio Ana Carolina , Tucker-Kellogg Greg
Published: August 2023

Background

Two recent publications by Kerr et al. (Cureus 14(1):e21272; Cureus 14(8): e28624) reported dramatic effects of prophylactic ivermectin use for both prevention of COVID-19 and reduction of COVID-19-related hospitalisation and mortality, including a dose-dependent effect of ivermectin prophylaxis. These papers have gained an unusually large public influence: they were incorporated into debates around COVID-19 policies and may have contributed to decreased trust in vaccine efficacy and public health authorities more broadly. Both studies were based on retrospective observational analysis of city-wide registry data from the city of Itajaí, Brazil from July-December 2020.

Methods

Starting with initially identified sources of error, we conducted a revised statistical analysis of available data, including data made available with the original papers and public data from the Brazil Ministry of Health. We identified additional uncorrected sources of bias and errors from the original analysis, including incorrect subject exclusion and missing subjects, analysis of longitudinal data with cross-sectional design, an enrolment time bias, and multiple sources of immortal time bias. In models assuming no actual effect from ivermectin use, we conducted Monte Carlo simulations to estimate the contribution of these biases to any observed effect.

Results

Untreated statistical artefacts and methodological errors alone lead to dramatic apparent risk reduction associated with ivermectin use in both studies. The magnitude of apparent risk reduction from these artefacts is comparable to the results reported by the studies themselves, including apparent protection from infection, hospitalisation, and death, and including the reported apparent dose-response relationship.

Conclusions

The inference of ivermectin effect reported in both papers is unsupported, as the observed effects are entirely explained by untreated statistical artefacts and methodological errors. Our re-analysis calls for caution in interpreting highly publicised observational studies and highlights the importance of common sources of bias in clinical research.
A Susceptible Vaccinated Exposed Infected Hospitalized and Removed/Recovered (SVEIHR) Model Framework for COVID-19
Authors: Oyamakin S.O. , Popoola J.I
Published: August 2023

In reaction to the severe socio-economic effects and upheavals that the Covid-19 sickness had on the world within the first few weeks of its introduction, everyone involved had to act quickly to look for possible solutions for preventing the ensuing epidemics. A prompt response is more critical given Nigeria’s subpar social, economic, and healthcare infrastructure. Investigated was the efficacy of various pharmacological, non-pharmaceutical, or a combination of both therapies in flattening the Covid-19 incidence curve. In order to investigate the impact of these interventions, a deterministic SVEIHR model was created and applied. The Nigerian Center for Disease Control (NCDC) portal’s Covid-19 data were used to parametrize the model. For simulations using a system dynamic simulation, estimated parameters were employed. The fundamental reproduction number, R0, was used to evaluate the success of our suggested intervention in effectively managing COVID-19 transmission. The simulation results demonstrated that the use of only non-pharmaceutical interventions, such as the use of face masks, a light lockdown, and hand washing at baseline or high levels, is insufficient, with the R0varying from vaccination at the vaccination rate of 0.5% with non-pharmaceutical interventions at any level of compliance, and a combination of vaccination at 0.05% and high hygiene level were effective in flattening the Covid-19 disease incidence curve in Nigeria, returning a R0less than 0. Furthermore, maintaining a high level of cleanliness, which includes hand washing and the use of a face mask, would be sufficient to stop the spread of Covid-19 disease and eventually flatten Covid-19 disease incidence curve in Nigeria, given a low turnout of 0.05% for vaccination and the easing of lockdown.
Do MOXFQ scores change over time? A retrospective study of podiatric surgery outcomes
Authors: North Victoria , Reilly Ian , Bridgen Andy , Maher Anthony
Published: August 2023

Background

Recording patient-reported outcome measurements six months after surgery using PASCOM-10 is common practice in podiatric surgery in the United Kingdom. This study aims to establish if the health-related quality of life after foot surgery is changed at the 12- month point.

Method

An audit of patient-reported outcomes following foot surgery was undertaken. Electronic case notes were examined, and 236 patients were identified over 1 year. Patients completed the Manchester Oxford Foot/Ankle Questionnaire (MOXFQ) pre-surgery, at six months post-operatively (in person/telephone conversation) and were then invited by letter to complete this again at 12 months post-operatively.

Results

91 participants (39%) completed both post-operative questionnaires (66 females 25 males), 45% completed a six-month questionnaire only and 61% completed a 12-month questionnaire. The results demonstrate a significant score change between the three time points and across the three MOXFQ domains of walking/standing, pain and social interaction (0.353, F [6, 356] = 40.59, p <.001), and a further interaction with gender (0.435, F [6,352] = 30.23, p <.001). An average, positive change in health-related quality of life (HRQOL) across all domains was the greatest from pre-surgery to six months post-surgery at 78% improved, and then decreased to 62% improved at 12 months post-surgery. Females experience lower HRQOL before surgery, at 6 months and at 12-month post-operation time points but gain the greatest improvement over pre-operative scores at 30%.

Conclusion

A patient-centred approach is key in foot surgery, patient-reported health-related quality of life changes significantly at different time points. In this review, the overall health- related quality of life improved with surgery at the six- and 12-month point, but with some deterioration at 12 months. A short period of recovery may not yield genuine long-term patient- reported outcomes, and an increase to a minimum of 12 months is recommended from the more common six months. However, the different methods of collecting post-operative data at various time points may have had an influence on scores.

Level of clinical evidence:4
Risk of Alzheimer’s Disease is Associated with Longitudinal Changes in Plasma Biomarkers in the Multiethnic Washington Heights, Inwood Columbia Aging Project Cohort
Authors: Gu Yian , Honig Lawrence S. , Kang Min Suk , Bahl Aanya , Sanchez Danurys , Reyes-Dumeyer Dolly , Manly Jennifer J. , Lantigua Rafael A. , Dage Jeffrey L. , Brickman Adam M. , Vardarajan Badri N , Mayeux Richard
Published: August 2023

INTRODUCTION

Alzheimer’s disease (AD) biomarkers can help differentiate cognitively unimpaired (CU) individuals from mild cognitive impairment (MCI) and dementia. The role of AD biomarkers in predicting cognitive impairment and AD needs examination.

METHODS

In 628 CU individuals from a multi-ethnic cohort, Aβ42, Aβ40, phosphorylated tau-181 (P-tau181), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL) were measured in plasma.

RESULTS

Higher baseline levels of P-tau181/Aβ42 ratio were associated with increased risk of incident dementia. A biomarker pattern (with elevated Aβ42/Aβ40 but low P-tau181/Aβ42) was associated with decreased dementia risk. Compared to CU, participants who developed MCI or dementia had a rapid decrease in the biomarker pattern reflecting AD-specific pathological change.

DISCUSSION

Elevated levels of AD biomarker P-tau181/Aβ42, by itself or combined with a low Aβ42/Aβ40 level, predicts clinically diagnosed AD. Individuals with a rapid change in these biomarkers may need close monitoring for the potential downward trajectory of cognition.

Research in Context

Systematic Review: Few studies have evaluated the clinical application of AD blood-based biomarkers longitudinally as antecedent risk predictors. Data from multiethnic populations are even more limited. How preclinical trajectories of blood-based biomarkers are related with the risk of developing clinically diagnosed MCI or AD is largely unknown.

Interpretation: High circulating level of P-tau181/Aβ42, by itself or combined with a low level of Aβ42/Aβ40, may predict development of incident clinical AD. Biomarkers levels of P-tau181, P-tau181/Aβ42, and NfL increase with age even among individuals who remain cognitively healthy. A rapid change in biomarkers may indicate the individuals in the active trajectory to develop clinically diagnosed MCI or AD.

Future Directions: Larger studies or meta-analyses are needed to examine whether the predictive utility of blood-based biomarkers for AD differs across racial/ethnic groups. Well-designed studies are needed to evaluate the optimal duration between repeated measures of biomarkers.
Assessing community factors associated with Antiretroviral Therapy (ART) defaulting among youth accessing HIV care in Mzimba District, Malawi
Authors: Kasalu Isaac Paul , Lazaro Mathews , Chilinda Idesi
Published: August 2023

Introduction/Background

ART defaulting has been associated with increased morbidity and mortality of HIV positive youth. Youth that default tend to develop drug resistance and resurgence of opportunistic infections. They can also transmit drug resistant strains of HIV to others through unprotected sexual intercourse. This study, therefore, aims at assessing community factors influencing ART defaulting amongst HIV positive youth enrolled on ART in Mzimba District.

Material and Methods

This study utilized a quantitative, case control design. A sample of 411 HIV positive youth (n=137 cases and n=274 controls) attending an HIV care clinic was recruited. Both ART defaulters and non-defaulters were enrolled using random sampling technique. Data were collected using a structured questionnaire and analyzed using the Statistical Package for Social Scientists (SPSS) version 20.0. Descriptive statistics were used to provide count, frequencies, proportions and ranges while inferential statistics were used to establish association between dependent variable with independent variables.

Results

Results from this study indicate that lack of community social support (p< 0.001, OR: 11.257, 95% CL: 6.782-18.686), long distance to ART clinics (p: 0.002, OR: 2.454, 95% CL: 1.511-3.985) and migration of the youth other countries (p:0.001, OR: 35.661, 95% CL: 4.675-272.049) are statistically significant factors to ART defaulting among the study participants who are youth in Mzimba District in Malawi.

Conclusion

The study conclusively proved that lack of community social support, forgetfulness and going to RSA for employment influenced defaulting to antiretroviral therapy among the youth in Mzimba, Malawi. The researcher recommends introduction of community ART outreach programs to help in reducing defaulting among the youth. Further, policy review to provide for technology that enables free ARVs regardless of national identity (ID) documents requirements and cross-border collaboration in managing HIV among the youth on ART between countries to ensure continuity of care.
WITHDRAWN: Early estimation of life expectancy using weekly deaths data
Authors: Lanzieri Giampaolo
Published: August 2023

Withdrawal Statement

The author has withdrawn this manuscript owing to the results changing in the final published version, which is now available from Eurostat (see DOI: 10.2785/655566). Therefore, the author does not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Impact of Significant Hemoglobin Drop without Bleeding in Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Reddy Pavan , Merdler Ilan , Zhang Cheng , Cellamare Matteo , Ben-Dor Itsik , Satler Lowell F. , Rogers Toby , Garcia-Garcia Hector M. , Waksman Ron
Published: August 2023

Background

Hemoglobin (Hgb) drop without bleeding is common among patients undergoing transcatheter aortic valve replacement (TAVR); however, the clinical implications of significant Hgb drop have not been fully evaluated. We sought to describe clinical phenotype and outcomes of patients with significant Hgb drop without bleeding.

Methods

Consecutive patients undergoing TAVR at our institution from 2011-2021 were retrospectively reviewed. Three groups were assessed: No Hgb Drop and No Bleed (NoD-NoB – reference group), Hgb Drop with Bleed (D-wB), and Hgb Drop and No Bleed (D-NoB). Hgb drop was defined as ≥3 g/dL decrease from pre-to post-TAVR. Outcomes of interest were in-hospital death and 1-year all-cause mortality.

Results

A total of 1,851 cases with complete Hgb data were included: NoD-NoB: n=1,579 (85.3%); NoD-NoB: n=49 (2.6%); D-wB n=223 (12.6%). Compared to NoD-NoB, D-NoB were older (81.1 vs. 78.9 years) with higher pre-procedure Hgb (12.9 vs. 11.7 g/dL). In-hospital death rate was higher among patients with D-NoB vs. NoD-NoB (4.5% vs. 0.8%, p<0.001) and similar to D-wB (4.5% vs. 4.1%, p=0.999). Predictors of in-hospital death were D-NoB (odds ratio [OR]: 3.45; 95% confidence interval [CI]: 1.32-8.69) and transfusion (OR: 10.6; 95% CI 4.25-28.2). Landmark survival analysis found that D-NoB experienced one-year mortality rate comparable to NoD-NoB, while D-wB had higher mid-term mortality (HR: 3.2; 95% CI: 1.83-5.73), and transfusion continued to impact mortality (HR: 2.5; 95% CI 1.79-3.63).

Conclusion

Hemoglobin drop without bleeding is common among patients undergoing TAVR and may represent a higher risk of peri-procedural death. Blood transfusion increases short-and mid-term mortality risk in patients with and without bleeding, supporting a restrictive transfusion strategy.

What Is Known; What the Study Adds

What is Known

- Hemoglobin drop without overt bleeding may be seen after transcatheter aortic valve replacement (TAVR); however, its incidence and impact on clinical outcomes is unknown.

What the Study Adds

- Hemoglobin drop without a source of bleeding is not uncommon among patients undergoing TAVR.

- Patients more likely to have hemoglobin drop without bleeding include those with lower body surface area, older age, and higher pre-procedural hemoglobin level.

- Compared to patients without bleeding or hemoglobin drop, patients with hemoglobin drop without bleeding had higher inpatient mortality.

- Blood transfusion increased short-and long-term mortality in patients with or without bleeding.

Visual Abstract
Performance of RAPID noncontrast CT stroke platform in large vessel occlusion and intracranial hemorrhage detection
Authors: Yedavalli Vivek , Heit Jeremy J , Dehkharghani Seena , Haerian Hafez , Mcmenamy John M. , Honce Justin , Timpone Vincent M , Harnain Christopher , Kesselman Andrew , Filly Anthony , Beardsley Adam , Sakamoto Brian , Song Christopher , Montuori James L , Navot Benjamin , Mena Francisco Villar , Giurgiutiu Dan-Victor , Kitamura Felipe , Lima Fabricio Oliveira , Silva Henrique Coelho , Mont’Alverne Francisco José Arruda , Albers Gregory W
Published: August 2023

Background

Noncontrast CT (NCCT) is used to evaluate for intracerebral hemorrhage (ICH) and ischemia in acute ischemic stroke (AIS). Large vessel occlusions (LVOs) are a major cause of AIS, but challenging to detect on NCCT.

Aims

The purpose of this study is to evaluate an AI software called RAPID NCCT Stroke (RAPID, iSchemaView, Menlo Park, CA) for ICH and LVO detection compared to expert readers.

Methods

In this IRB approved retrospective, multicenter study, stand-alone performance of the software was assessed based on the consensus of 3 neuroradiologists and sensitivity and specificity were determined. The platform’s performance was then compared to interpretation by readers comprised of eight general radiologists (GR) and three neuroradiologists (NR) in detecting ICH and hyperdense vessel sign (HVS) indicating LVO. Receiver operating characteristics (ROC) curve was used to evaluate the performance of each reader. P < 0.05 was considered significant.

Results

A total of 244 cases were included. Of the 244, 115 were LVOs and 26 were ICHs. One hundred three cases did not have LVO nor ICH. Stand-alone performance of the software demonstrated sensitivities and specificities of 96.2% and 99.5% for ICH and 63.5% and 95.1% for LVO detection.

Compared to all 11 readers and eight GR readers only respectively, the software demonstrated superiority, achieving significantly higher sensitivities (63.5% versus 43.6%, p < 0.0001 and 63.5% versus 40.9%, p =0.001).

Conclusion

The RAPID NCCT Stroke platform demonstrates superior performance to radiologists for detecting LVO from a NCCT. Use of this software platform could lead to earlier LVO detection and expedited transfer of these patients to a thrombectomy capable center.
Gambling in Connecticut Adolescents: Prevalence, Socio-demographic Characteristics, Trauma Exposure, Suicidality, and Other Risk Behaviors
Authors: Stefanovics Elina A. , Zhai Zu Wei , Potenza Marc N.
Published: August 2023

Adolescent gambling is a public health concern and has been linked to suicidality and other risk behaviors and poor health correlates. This study examines relationships between adolescents reporting gambling in the past-year and a range of health risk behaviors, traumatic experiences, school performance, and receipt of social support. Data from the 2019 Youth Risk Behavior Survey in Connecticut high-school students stratified by gambling status were examined in bivariate and multivariate analyses. Among 1,807 adolescents, past-year gambling was reported by 453 or 25.4% (95% confidence interval [CI]=22.7-28.1%). Gambling prevalence was higher among older males and lower in adolescents of Asian origin. Gambling was further associated with suicidality and risk behaviors including substance use, smoking (traditional tobacco and electronic vapor use), risky use of digital technologies, unsafe sex, and aggressive behaviors. Gambling was also associated with traumatic experiences, depression/dysphoria, poor academic performance, and less social support from the family and teachers. The results of this study provide an up-to-date estimate of the current prevalence and correlates of gambling among Connecticut adolescents and underscores the importance of routine screening and monitoring of gambling behaviors, as well as interventions for other risk behaviors in this population.
Association between cannabis use and brain imaging phenotypes in UK Biobank: an observational and Mendelian randomization study
Authors: Ishrat Saba , Levey Daniel F. , Gelernter Joel , Ebmeier Klaus P. , Topiwala Anya
Published: August 2023

Cannabis use during adolescence and young adulthood has been associated with brain structure and functional connectivity, yet despite a rapid increase in cannabis use among older adults in the past decade, the impact on brain structure and function in this population remains understudied. We examined 3,641 lifetime cannabis users (mean age = 61.00 years, standard deviation (SD) = 7.07) and 12,255 controls (mean age = 64.49 years, SD = 7.51) from the UK Biobank. Insufficient data were available on cannabis use disorders in the UK Biobank to perform an analysis. Brain structure and functional connectivity were measured using multiple imaging-derived phenotypes. Associations with cannabis use were assessed using multiple linear regression while controlling for potential confounders. Additionally, we conducted a two-sample Mendelian randomization analysis to investigate the potential causal relationship. After correcting for false discovery rate for multiple testing, participants with lifetime cannabis use had significantly lower fractional anisotropy and higher mean diffusivity in the genu of the corpus callosum. A weaker resting-state functional connectivity was observed in brain regions underlying the default mode and central executive networks. Furthermore, bidirectional two-sample Mendelian randomization analyses found no support for a causal relationship between either cannabis use or cannabis dependence and brain structure or function. Our findings indicate that associations between lifetime cannabis use and later life brain structure and function are not likely causal in nature and may represent residual confounding.
Spatial transcriptomic patterns underlying regional vulnerability to amyloid-β and tau pathologies and their relationships to cognitive dysfunction in Alzheimer’s disease
Authors: Yu Meichen , Risacher Shannon L. , Nho Kwangsik T. , Wen Qiuting , Oblak Adrian L. , Unverzagt Frederick W. , Apostolova Liana G. , Farlow Martin R. , Brosch Jared R. , Clark David G. , Wang Sophia , Deardorff Rachael , Wu Yu-Chien , Gao Sujuan , Sporns Olaf , Saykin Andrew J. ,   the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: August 2023

Amyloid-β (Aβ) and tau proteins accumulate within distinct neuronal systems in Alzheimer’s disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aβ and tau pathologies than others, gene expression may play a role. We studied the association between brain-wide gene expression profiles and regional vulnerability to Aβ (gene-to-Aβ associations) and tau (gene-to-tau associations) pathologies leveraging two large independent cohorts (n = 715) of participants along the AD continuum. We identified several AD susceptibility genes and gene modules in a gene co-expression network with expression profiles related to regional vulnerability to Aβ and tau pathologies in AD. In particular, we found that the positiveAPOE-to-tau association was only seen in the AD cohort, whereas patients with AD and frontotemporal dementia shared similar positiveMAPT-to-tau association. Some AD candidate genes showed sex-dependent negative gene-to-Aβ and gene-to-tau associations. In addition, we identified distinct biochemical pathways associated with the gene-to-Aβ and the gene-to-tau associations. Finally, we proposed a novel analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations. Taken together, our study identified distinct gene expression profiles and biochemical pathways that may explain the discordance between regional Aβ and tau pathologies, and filled the gap between gene-to-pathology associations and cognitive dysfunction in individual AD patients that may ultimately help identify novel personalized pathogenetic biomarkers and therapeutic targets.

One Sentence Summary

We identified replicable cognition-related associations between regional gene expression profiles and selectively regional vulnerability to amyloid-β and tau pathologies in AD.
Improving estimates of epidemiological quantities by combining reported cases with wastewater data: a statistical framework with applications to COVID-19 in Aotearoa New Zealand
Authors: Watson Leighton M. , Plank Michael J. , Armstrong Bridget A. , Chapman Joanne R. , Hewitt Joanne , Morris Helen , Orsi Alvaro , Bunce Michael , Donnelly Christl A. , Steyn Nicholas
Published: August 2023

Background

Timely and informed public health responses to infectious diseases such as COVID-19 necessitate reliable information about infection dynamics. The case ascertainment rate (CAR), the proportion of infections that are reported as cases, is typically much less than one and varies with testing practices and behaviours, making reported cases unreliable as the sole source of data. The concentration of viral RNA in wastewater samples provides an alternate measure of infection prevalence that is not affected by clinical testing, healthcare-seeking behaviour or access to care.

Methods

We constructed a state-space model with observed data of levels of SARS-CoV-2 in wastewater and reported case incidence and estimated the hidden states ofRand CAR using sequential Monte Carlo methods.

Results

Here, we analysed data from 1 January 2022 to 31 March 2023 from Aotearoa New Zealand. Our model estimates thatRpeaked at 2.76 (95% CrI 2.20, 3.83) around 18 February 2022 and the CAR peaked around 12 March 2022. We calculate that New Zealand’s second Omicron wave in July 2022 was similar in size to the first, despite fewer reported cases. We estimate that the CAR in the BA.5 Omicron wave in July 2022 was approximately 50% lower than in the BA.1/BA.2 Omicron wave in March 2022.

Conclusions

EstimatingR, CAR, and cumulative number of infections provides useful information for planning public health responses and understanding the state of immunity in the population. This model is a useful disease surveillance tool, improving situational awareness of infectious disease dynamics in real-time.

Plain Language Summary

To make informed public health decisions about infectious diseases, it is important to understand the number of infections in the community. Reported cases, however, underestimate the number of infections and the degree of underestimation likely changes with time. Wastewater data provides an alternative data source that does not depend on testing practices. Here, we combined wastewater observations of SARS-CoV-2 with reported cases to estimate the reproduction number (how quickly infections are increasing or decreasing) and the case ascertainment rate (the fraction of infections reported as cases). We apply the model to Aotearoa New Zealand and demonstrate that the second wave of infections in July 2022 had approximately the same number of infections as the first wave in March 2022 despite reported cases being 50% lower.
Application of self-reporting, clinicians’ assessment, and tacrolimus trough levels in evaluating adherence to immunosuppressive therapy in kidney transplant recipients. A cohort study
Authors: Dorji Choki , Tobgay Tashi , Na-Bangchang Kesara
Published: August 2023

Introduction

Immunosuppressants are drugs with narrow therapeutic indices and pharmacokinetic variation. Nonadherence to the therapy will cause over or underexposure leading to graft rejection.

Methods

A cohort study was conducted on kidney transplant recipients from the nephrology clinic and therapeutic drug monitoring unit. Patients were asked to self-report their medication adherence using a self-assessment tool. Assessment by clinicians and variation of tacrolimus levels were evaluated. Tacrolimus concentration and kidney function were measured prospectively to correlate with patients’ adherence. The variation of tacrolimus levels between 20-43 % was classified as medium and above 43 % as poor adherence.

Results

Among 58 participants, 33 (56.7%) were females. The maximum number of years attained after transplantation was 17, with a median duration of 5 years. On the self-reporting scale, 47.0% of adherence was due to fear of graft rejection. Among nonadherences, 77.4% had their immunosuppressive therapy two hours before or after the prescribed time. Based on the clinician score, 39 (67.2%) and 42 (72.4%) cases were identified as nonadherence and having tacrolimus Ctroughlevel above 20 % respectively. The median (95% CI) serum creatine and blood urea nitrogen levels in the medium category were 1.23 mg/dL (1.2-1.4) (P = 0.009) and 28.3 mg/dL (26.4-36.4) (P = 0.021) respectively. The corresponding values for poor adherence were 2.5 mg/dL (1.6-3.5) (P = 0.03) and 43.0 mg/dL (35.5-78.0) (P = 0.01).

Conclusions

The fear of allograft rejection is linked to a better adherence rate. Nonadherent transplant recipients required close observation and frequent monitoring of immunosuppressant levels for graft survival.
Comparative Genomic and Transcriptomic Analysis of Avirulent and Virulent Strains ofFusarium oxysporumf. sp.carthami: Insights into Pathogenesis and Virulence Determinants in Safflower Infections
Authors: Aabha  , Laxmi Vijay , Singh Babita , Mehta Samriddhi , Gupta Ashish Kumar , Srivastava Alok , Sawant Samir , Katiyar-Agarwal Surekha , Paritosh Kumar , Agarwal Manu
Published: August 2023

Vascular wilt disease incited byFusarium oxysporumf. sp.carthami(Foc) in Safflower poses a significant threat to its production in India. A comprehensive understanding of the molecular underpinning of compatible and incompatible interaction is of extreme economic importance. In the present study, the genome of a virulent (IARI-5175) and a avirulent (F-00845) Foc strain were sequenced and assembled using data generated from Illumina in combination with Nanopore technologies and HiC. Foc genomes were assembled into 88 and 23 scaffolds with an estimated total size of 46 Mb and 42 Mb respectively for IARI-5175 and F-00845 strains. Reference based mapping of Foc genome withF. oxysporumf. sp.lycopersici(Fol) resulted in chromosomal level ordering of genome and simultaneous identification of accessory genome. Additionally, two lineage specific chromosomes were also identified for virulent Foc strain IARI-5175. Genomic comparisons were made on the basis of effectors, CAZymes, secondary metabolites and mycotoxins to understand the global view pathogenicity in Foc. Moreover, the transcriptome of Foc during compatible and incompatible interaction was sequenced and analyzed leading to the identification of differentially regulated genes. Taken together our study laid a solid foundation to explore novel effector genes that play a crucial role in the establishment of disease and can further be used as targets to devise new strategies to curb wilt disease in safflower.
Epithelial Ca2+waves triggered by enteric neurons heal the gut
Authors: Petsakou Afroditi , Liu Yifang , Liu Ying , Comjean Aram , Hu Yanhui , Perrimon Norbert
Published: August 2023

A fundamental and unresolved question in regenerative biology is how tissues return to homeostasis after injury. Answering this question is essential for understanding the etiology of chronic disorders such as inflammatory bowel diseases and cancer. We used theDrosophilamidgut to investigate this question and discovered that during regeneration a subpopulation of cholinergic enteric neurons triggers Ca2+currents among enterocytes to promote return of the epithelium to homeostasis. Specifically, we found that down-regulation of the cholinergic enzyme Acetylcholinesterase in the epithelium enables acetylcholine from defined enteric neurons, referred as ARCENs, to activate nicotinic receptors in enterocytes found near ARCEN- innervations. This activation triggers high Ca2+influx that spreads in the epithelium through Inx2/Inx7 gap junctions promoting enterocyte maturation followed by reduction of proliferation and inflammation. Disrupting this process causes chronic injury consisting of ion imbalance, Yki activation and increase of inflammatory cytokines together with hyperplasia, reminiscent of inflammatory bowel diseases. Altogether, we found that during gut regeneration the conserved cholinergic pathway facilitates epithelial Ca2+waves that heal the intestinal epithelium. Our findings demonstrate nerve- and bioelectric-dependent intestinal regeneration which advance the current understanding of how a tissue returns to its homeostatic state after injury and could ultimately help existing therapeutics.
Simultaneous targeting of AMPK and mTOR is a novel therapeutic strategy against prostate cancer
Authors: Zhao Gangyin , Forn-Cuní Gabriel , Scheers Marvin , Lindenbergh Pier Pieterszoon , Yin Jie , van Loosen Quint , Passarini Leonardo , Chen Lanpeng , Snaar-Jagalska B. Ewa
Published: August 2023

Metastatic colonization by circulating cancer cells is a highly inefficient process. To colonize distant organs, disseminating cancer cells must overcome many obstacles in foreign microenvironments, and only a small fraction of them survives this process. How these disseminating cancer cells cope with stress and initiate metastatic process is not fully understood. In this study, we report that the metastatic onset of prostate cancer cells is associated with the dynamic conversion of metabolism signaling pathways governed by the energy sensors AMPK and mTOR. While in circulation in blood flow, the disseminating cancer cells display decreased mTOR and increased AMPK activities that protect them from stress-induced death. However, after metastatic onset, the mTOR-AMPK activities are reversed, enabling mTOR-dependent tumor growth. Suppression of this dynamic conversion by co-targeting of AMPK and mTOR signaling significantly suppresses prostate cancer cell and tumor organoid growthin vitroand experimental metastasisin vivo, suggesting that this can be a therapeutic approach against metastasizing prostate cancer.
(De)composing sociality: disentangling individual-specific from dyad-specific propensities to interact
Authors: Neumann Christof , Fischer Julia
Published: August 2023

In socially living animals, relationships between group members are typically highly differentiated. Some dyads maintain strong and long-lasting relationships, while others are only connected by weak ties. There is growing evidence that the number and strength of social bonds are related to reproductive success and survival. Yet, few of these analyses have considered that frequent or prolonged affiliative interactions between two individuals are driven by two different processes: namely, the overall gregariousness of the individuals involved and their dyadic affinity, i.e., the preference the members of the dyad have to inter-act specifically with one another. Crucially, these two axes of sociality cannot be observed directly, although distinguishing them is essential for many research questions, for example, when estimating kin bias or when studying the link between sociality and fitness.

We present a principled statistical framework to estimate the two underlying sociality axes using dyadic interaction data. We provide the R package bamoso, which builds on Stan code to implement models based on the proposed framework and allows visual and numerical evaluation of the estimated sociality axes.

We demonstrate the application and some of the critical advantages of our proposed modeling framework with simulated and empirical data: (1) the possibility of checking model fit against observed data, (2) the assessment of uncertainty in the estimated sociality parameters, and (3) the possibility to extend it to more complex models that use interaction data to estimate the relationship between individual-level sociality and individual-level outcomes in a unified model.

Our model will help to understand how and why individuals interact with each other and will help address questions about the relationship between variation in sociality and other features of interest, both within and across species.
Palaeoproteomic investigation of an ancient human skeleton with abnormal deposition of dental calculus
Authors: Uchida-Fukuhara Yoko , Shimamura Shigeru , Sawafuji Rikai , Nishiuchi Takumi , Yoneda Minoru , Ishida Hajime , Matsumura Hirofumi , Tsutaya Takumi
Published: August 2023

Detailed investigation of extremely severe pathological conditions in ancient human skeletons is important as it could shed light on the breadth of potential interactions between humans and disease etiologies in the past. Here, we applied palaeoproteomics to investigate an ancient human skeletal individual with severe oral pathology, focusing our research on bacterial pathogenic factors and host defense response. This female skeleton, from the Okhotsk period (i.e., 5th–13th century) of Northern Japan, poses relevant amounts of abnormal dental calculus deposition and exhibits oral dysfunction due to severe periodontal disease. A shotgun mass-spectrometry analysis identified 81 human proteins and 15 bacterial proteins from the calculus of the subject. We identified two pathogenic or bioinvasive proteins originating from two of the three “red complex” bacteria, the core species associated with severe periodontal disease in modern humans, as well as two additional bioinvasive proteins of periodontal-associated bacteria. Moreover, we discovered defense response system-associated human proteins, although their proportion was mostly similar to those reported in ancient and modern human individuals with lower calculus deposition. These results suggest that the bacterial etiology was similar and the host defense response was not necessarily more intense in ancient individuals with significant amounts of abnormal dental calculus deposition.
HDAC6/aggresome processing pathway importance for inflammasome formation is context dependent
Authors: Wang Longlong , Unterreiner Adeline , Kapetanovic Ronan , Aslani Selma , Xiong Yuan , Donovan Katherine A. , Farady Christopher J. , Fischer Eric S. , Bornancin Frédéric , Matthias Patrick
Published: August 2023

The inflammasome is a large multiprotein complex that assembles in the cell cytoplasm in response to stress or pathogenic infection. Its primary function is to defend the cell and promote the secretion of pro-inflammatory cytokines, including IL-1β and IL-18. It was shown that in immortalized bone marrow derived macrophages (iBMDMs) inflammasome assembly is dependent on the deacetylase HDAC6 and the aggresome processing pathway (APP), a cellular pathway involved in the disposal of misfolded proteins. Here we used primary BMDMs from mice in which HDAC6 is ablated or impaired and found that inflammasome activation was largely normal. We also used human peripheral blood mononuclear cells and monocytes cell lines expressing a synthetic protein blocking HDAC6-ubiquitin interaction and impairing the APP and found that inflammasome activation was moderately affected. Finally, we used a novel HDAC6 degrader and showed that inflammasome activation was partially impaired in human macrophage cell lines with depleted HDAC6. Our results therefore show that HDAC6 importance in inflammasome activation is context dependent.