bluuebunny/crossref_metadata_2025 huggingface dataset:
Concomitant Drugs Prognostic Score in Patients With Metastatic Renal Cell Carcinoma Receiving Ipilimumab and Nivolumab in the Compassionate Use Program in Italy: Brief Communication
Authors: Buti Sebastiano , Basso Umberto , Giannarelli Diana , De Giorgi Ugo , Maruzzo Marco , Iacovelli Roberto , Galli Luca , Porta Camillo , Carrozza Francesco , Procopio Giuseppe , Fonarini Giuseppe , Lo Re Giovanni , Santoni Matteo , Sabbatini Roberto , Cusmai Antonio , Zucali Paolo Andrea , Aschele Carlo , Baldini Editta , Zafarana Elena , Favaretto Adolfo , Leo Silvana , Hamzaj Alketa , Mirabelli Rosanna , Nole’ Franco , Zai Silvia , Chini Claudio , Masini Cristina , Fatigoni Sonia , Rocchi Andrea , Tamburini Emiliano , Cortellini Alessio , Bersanelli Melissa
Published: December 2022

A concomitant drug-based score was developed by our group and externally validated for prognostic and predictive purposes in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). The model considers the use of three classes of drugs within a month before initiating ICI, assigning score 1 for each between proton pump inhibitor and antibiotic administration until a month before immunotherapy initiation and score 2 in case of corticosteroid intake. In the present analysis, the drug score was validated in a prospective population of 305 patients with metastatic renal cell carcinoma treated with ipilimumab plus nivolumab in the first-line setting. The value of the model in predicting overall survival and progression-free survival was statistically significant and clinically meaningful, with an overall survival rate at 12 months of 73% vs. 44% (P<0.0001), and median progression-free survival of 11.6 (95% CI: 9.1–14.1) months versus 4.8 (95% CI: 2.7–7.0) months (P=0.002), respectively, for patients belonging to the favorable group (score 0–1) versus the unfavorable (score 2–4). Further development will be represented by the gut microbiome analysis according to the drug-based model classification and to the outcome of patients to ICI therapy to demonstrate the link between drug exposure and immune sensitivity.
Heparin-induced thrombocytopenia occurring early after living donor liver transplantation: a case report
Authors: Iwasaki Naoya , Sekino Motohiro , Hara Takanobu , Soyama Akihiko , Hidaka Masaaki , Kasai Yusuke , Suzumura Miki , Araki Hiroshi , Yano Rintaro , Matsumoto Sojiro , Ichinomiya Taiga , Higashijima Ushio , Eguchi Susumu , Hara Tetsuya
Published: December 2022

Background

Thrombocytopenia commonly occurs early after liver transplantation. Heparin, usually administered as anticoagulant therapy for thrombosis, a common complication after liver transplantation, may cause heparin-induced thrombocytopenia. Heparin-induced thrombocytopenia is a rare but life-threatening complication, and its diagnosis after liver transplantation is challenging.

Case presentation

We report a case of heparin-induced thrombocytopenia after living donor liver transplantation with a good outcome because of early diagnosis and discontinuation of heparin. After liver transplantation, the platelet count usually reaches a nadir on postoperative days 3–5 and gradually recovers. In contrast, heparin-induced thrombocytopenia typically occurs 5–10 days after heparin administration; therefore, if heparin is started intraoperatively, then thrombocytopenia will occur on postoperative days 5–10.

Conclusion

Monitoring the trend and timing of thrombocytopenia and detailed examination for thrombosis may help confirm the diagnosis of heparin-induced thrombocytopenia in the early stage after liver transplantation.
Past, Present, and Future Labor Market Participation Among Patients Admitted to Hospital With Concurrent Substance Use and Mental Health Disorder, and What We Can Learn From It
Authors: Sell Lea , Lund Henrik Lambrecht , Johansen Katrine Schepelern
Published: December 2022

Objective

The aim of the study is to investigate the labor market participation of patients with concurrent substance use and mental health disorder before treatment, as well as the strength of the barriers to re-enter the labor market.

Methods

The study population is composed of individuals with concurrent substance use and mental health disorder at a psychiatric unit in 1996, 2001, 2006, 2011, and 2016. The number of self-supported years 20 years back in time, as well as present and subsequent employment, was calculated.

Results

From 1996 to 2016, there was a decrease by 43.8% in self-supported years before treatment and by 36.4% in the fraction of patients working at the time of admission.

Conclusions

The results point to increasing difficulties with regard to labor market attachment among individuals with mental illnesses.
Concussion in Ladies Gaelic Football: Self-reported History, Clinical Profiles, and Management Behavior
Authors: Leahy Róisín , Rochfort Keith D. , Whyte Enda , Kontos Anthony P. , Collins Michael W. , O'Connor Siobhán
Published: December 2022

Objective:

To describe the prevalence, characteristics, and management behavior of self-reported sport-related concussion (SRC) in Ladies Gaelic Football (LGF) players.

Design:

Cross-sectional study.

Setting:

Online survey distributed to LGF clubs throughout Ireland.

Participants:

Elite and nonelite adult LGF players (n = 657).

Interventions:

Participants were recruited by convenience sampling and answered an online survey. Questions on demographic characteristics, SRC history, symptoms, injury characteristics, and management behavior after SRCs that occurred while playing LGF during the previous season were included.

Main Outcome Measures:

Overall concussion history, occurrence of an SRC during the previous LGF season, clinical profile scores, characteristics (eg mechanism and setting), and management behavior (eg following a graded RTP program) after SRCs that occurred during the previous season.

Results:

Approximately one-fifth (17.5%) of participants sustained a suspected or diagnosed SRC during the previous season, which was higher among elite (26.1%) than nonelite (15.3%) players (P < 0.01). The highest scoring clinical profiles were the ocular and migraine profiles. Only 3.5% of respondents adhered to all SRC management recommendations. Although players who reported a medically diagnosed versus a suspected SRC more often followed these guidelines, SRC management beyond the initial phase of injury remained inadequate.

Conclusion:

SRC is common in LGF; however, adherence to recommended management guidelines is poor, even among players who receive medical assistance. In particular, few LGF athletes receive clinical concussion care beyond the initial diagnosis and acute management phase. Further research is needed to examine the underlying reasons for poor SRC management in LGF, which will guide the development of future sport-specific interventions.
Lipid-lowering therapies and cardiovascular risk-stratification strategies in adults with type 1 diabetes
Authors: Lan Nick S.R. , Bell Damon A. , Watts Gerald F. , Fegan P. Gerry
Published: December 2022

Purpose of review

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of mortality in adults with type 1 diabetes (T1D). Although dyslipidaemia is a modifiable and prevalent risk factor in individuals with T1D, determining when to initiate lipid-lowering therapy for primary prevention of ASCVD can be challenging. In this article, recommendations for lipid-lowering therapy from updated clinical guidelines over the last 5 years, additional risk-stratification methods, hypertriglyceridaemia management and potential barriers to optimal care in adults with T1D are discussed.

Recent findings

Low-density lipoprotein cholesterol (LDL-C) is the primary target for lipid-lowering. However, international guidelines recommend differing approaches to ASCVD risk-stratification, lipid-lowering, and LDL-C goals in individuals with diabetes, predominantly reflecting evidence from studies in type 2 diabetes. Despite guideline recommendations, several studies have demonstrated that statins are underused, and LDL-C goals are not attained by many individuals with T1D. Additional risk-stratification methods including T1D-specific ASCVD risk calculators, coronary artery calcium scoring, and lipoprotein(a) may provide additional information to define when to initiate lipid-lowering therapy.

Clinical trial evidence for lipid-lowering therapies in T1D is lacking, and further studies are needed to inform best practice. Optimization and harmonization of ASCVD risk-stratification and lipid management in individuals with T1D is required.
Novel therapeutic opportunities for familial lecithin:cholesterol acyltransferase deficiency: promises and challenges
Authors: Vitali Cecilia , Rader Daniel J. , Cuchel Marina
Published: December 2022

Purpose of review

Genetic lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare, inherited, recessive disease, which manifests as two different syndromes: Familial LCAT deficiency (FLD) and Fish-eye disease (FED), characterized by low HDL-C and corneal opacity. FLD patients also develop anaemia and renal disease. There is currently no therapy for FLD, but novel therapeutics are at different stages of development. Here, we summarize the most recent advances and the opportunities for and barriers to the further development of such therapies.

Recent findings

Recent publications highlight the heterogeneous phenotype of FLD and the uncertainty over the natural history of disease and the factors contributing to disease progression. Therapies that restore LCAT function (protein and gene replacement therapies and LCAT activators) showed promising effects on markers of LCAT activity. Although they do not restore LCAT function, HDL mimetics may slow renal disease progression.

The further development of novel therapeutics requires the identification of efficacy endpoints, which include quantitative biomarkers of disease progression. Because of the heterogeneity of renal disease progression among FLD individuals, future treatments for FLD will have to be tailored based on the specific clinical characteristics of the patient. Extensive studies of the natural history and biomarkers of the disease will be required to achieve this goal.
Focused investigations to expedite cancer diagnosis among patients with lymphadenopathy in a tuberculosis and HIV-endemic region
Authors: Antel Katherine , Oosthuizen Jenna , Brown Karryn , Malherbe Francois , Loebenberg Perry , Seaton Cylene , Baloyi Siphiwe , Simba Kudakwashe , Chetty Dharshnee , Louw Vernon J. , Maartens Gary , Verburgh Estelle R.
Published: December 2022

Purpose:

In tuberculosis (TB)-endemic areas, lymphadenopathy is frequently due to TB adenitis, but lymphoma and cancers are important differential diagnoses and critical to diagnose at the earliest opportunity. Key obstacles to lymphoma diagnosis include empiric TB treatment and difficulty accessing a biopsy. We report on a specialized clinic utilizing high-yield investigations for patients with lymphadenopathy.

Methods:

This prospective interventional study investigated the utility of a core biopsy and the Xpert MTB/RIF Ultra (Ultra) on fine-needle aspirate (FNA) and tissue in a newly established lymph node biopsy clinic over 4 years. Electronic referral facilitated patient assessment within a week. Hematology fellows without specialist surgical or radiological expertise performed the biopsy on the first visit.

Results:

In 277 patients, including 43% people with HIV, TB was the most frequent diagnosis (34%), followed by lymphoma (27%) and other cancers (17%). Patients were seen a median of 5 days [interquartile range (IQR) 2–8.5 days] from referral. Core biopsy provided sufficient tissue for diagnosis in 96% of patients with lymphoma (72/75) and 94% of patients with cancer (44/47). FNA Ultra had a sensitivity of 73.9% [34/46; 95% confidence interval (CI) 58.9–85.7], and tissue Ultra 73% (46/63; 95% CI 60.3–83.4). There were six false-positive Ultra tests, highlighting the value of histology to either support TB or make an alternative diagnosis.

Conclusion:

Core biopsies collected under the conditions described are safe and sensitive and can yield a rapid diagnosis. Combining Ultra and a core biopsy can accurately diagnose TB and cancer. This clinic provides an implementation model for resource-constrained and TB-endemic areas.
I did not scream. I could not; I was terrified. I just followed them…I blocked my mind. Then they all raped me: A narrative inquiry on the onset of tonic immobility among women rape victims in Nigeria
Authors: Gbahabo Dooshima Dorothy , Duma Sinegugu Evidence
Published: December 2022

Tonic immobility (TI) is a common uncontrollable autonomic mammalian response to an extremely fearful situation. It is one of the most immediate devastating consequences of rape and remains poorly understood. While controversies over its definition persist among researchers, this also reflects the care for and support to victims. The study aimed to explore and describe the onset of TI and the meaning attached to the experience among women raped victims in Nigeria. The study design was the qualitative narrative inquiry approach. Criterion and purposive sampling were conducted across four post-rape care facilities in Lagos, Nigeria, to recruit 13 participants. In-depth face-to-face interviews were conducted using a semi-structured interview guide to generate data that were thematically analysed. The findings of the study reveal five themes relating to the onset of TI as follows: the first two focused on the experience of TI: (1) the onset of TI prior to rape due to perceived imminent danger, (2) the onset of TI as a self-protection mechanism from further harm) while the last three relate to the meaning-making of the experience of TI (3) self-loathing as a meaning attached to TI, (4) suicidal ideations as a meaning attached to TI, and (5) divine intervention as a meaning attached to TI.

Conclusion

The findings underscore the experiences and meanings that participants attach to TI following rape. There is a strong likelihood that tonic-immobility is not an uncommon experience amongst rape victims, but that in the absence of research, specialized care on the condition, and its associated consequences will haunt many women, affecting their psychological well-being and their entire quality of life. Describing the phenomenon as it is experienced by the participants is critical because understanding the condition is the first step toward effective appropriate management.
Stimulation better targets fast ripple generating networks in super-responders to the responsive neurostimulator system (RNS)
Authors: Weiss Shennan Aibel , Rubinstein Daniel , Stern John , Eliashiv Dawn , Fried Itzhak , Wu Chengyuan , Sharan Ashwini , Engel Jerome , Staba Richard , Sperling Michael R.
Published: December 2022

Objective

How responsive neurostimulation (RNS) decreases seizure frequency is unclear. Stimulation may alter epileptic networks during inter-ictal epochs. Since fast ripples (FR) may be a substrate of the epileptic network, we examined whether stimulation of FR generating networks differed in RNS super- and intermediate-responders.

Methods

In 10 patients, we detected FR during sleep from stereo EEG (SEEG) contacts during the pre-surgical evaluation in patients with subsequent RNS placement. The normalized coordinates of the SEEG contacts were compared with that of the eight RNS contacts, and RNS stimulated SEEG contacts were defined as within 1.5 cm3of the RNS contacts. We compared the post-RNS placement seizure outcome to 1) the ratio of stimulated SEEG contacts in the seizure-onset zone (SOZ SR); 2) the ratio of FR events on stimulated contacts (FR SR); and 3) the global efficiency of the FR temporal correlational network on stimulated contacts (FR SGe).

Results

We found that the SOZ SR (p=0.18) and FR SR (p=0.06) did not differ in the RNS super- and intermediate-responders, but the FR SGe did (p=0.02). In super-responders highly active desynchronous sites of the FR network were stimulated.

Significance

RNS that better targets FR networks, as compared to the SOZ, may reduce epileptogenicity more.

Short summary

Responsive neurostimulation (RNS) may reduce seizures by altering the epileptic network. Fast ripples (FR) may be a substrate of the epileptic network. We investigated, in 10 patients, if RNS stimulation of FR generating brain differed in RNS super-responders and intermediate-responders. The RNS stimulated brain sites were defined as contacts in the pre-surgical stereo EEG implant within 1.5 cm3of the subsequently placed RNS stimulation contacts. FR events were more highly active and temporally desynchronous (p<0.05) on the stimulated contacts in the RNS super-responders. We show RNS that better targets FR networks, as compared to the seizure onset zone, may reduce epileptogenicity more.
Global Parkinson’s Genetics Program (GP2) Monogenic Network Protocol: Elucidating causative gene variants in hereditary Parkinson’s disease
Authors: Lange Lara M. , Avenali Micol , Ellis Melina , Illarionova Anastasia , Keller Sarmiento Ignacio J. , Tan Ai-Huey , Madoev Harutyun , Galandra Caterina , Junker Johanna , Roopnarain Karisha , Solle Justin , Wegel Claire , Fang Zih-Hua , Heutink Peter , Kumar Kishore R. , Lim Shen-Yang , Valente Enza Maria , Nalls Mike , Blauwendraat Cornelis , Singleton Andrew , Mencacci Niccolo , Lohmann Katja , Klein Christine ,   the Global Parkinson’s Genetic Program (GP2)
Published: December 2022

The Monogenic Network of the Global Parkinson’s Genetics Program (GP2) aims to create an efficient infrastructure to accelerate the identification of novel genetic causes of Parkinson’s disease (PD) and to improve our understanding of already identified genetic causes, such as reduced penetrance and variable clinical expressivity of known disease-causing variants. We aim to perform short- and long-read whole-genome sequencing for up to 10,000 patients with parkinsonism.
Are we really targeting and stimulating DLPFC by placing transcranial electrical stimulation (tES) electrodes over F3/F4?
Authors: Soleimani Ghazaleh , Kuplicki Rayus , Camchong Jazmin , Opitz Alexander , Paulus Martin P , Lim Kelvin O , Ekhtiari Hamed
Published: December 2022

Background

In many clinical trials involving transcranial electrical stimulation (tES), target electrodes are typically placed over DLPFC with the assumption that this will primarily stimulate the underlying brain region. However, our study aimed to evaluate the electric fields (EF) that are actually delivered and identify prefrontal regions that may be inadvertently targeted in DLPFC tES.

Methods

Head models were generated from Human Connectome Project database’s T1+T2-weighted MRIs of 80 healthy adults. Two common DLPFC montages were simulated; symmetric-F4/F3, and asymmetric-F4/Fp1. Averaged EF was extracted from (1) the center of target electrode (F4), and (2) the top 1% of voxels showing the strongest EF in individualized EF maps. Inter-individual variabilities were quantified with standard deviation of EF peak location/value. Similar steps were repeated with 66 participants with methamphetamine use disorder (MUDs) as an independent clinical population.

Results

In healthy adults, the group-level location of EF peaks was situated in the medial-frontopolar, and the individualized EF peaks were positioned in a cube with a volume of 29cm3/46cm3 (symmetric/asymmetric montages). EFs in frontopolar area were significantly higher than EF “under” the target electrode in both symmetric (peak:0.41±0.06, F4:0.22±0.04) and asymmetric (peak:0.38±0.04, F4:0.2±0.04) montages (Heges’g>0.7). Similar results with slight between-group differences were found in MUDs.

Conclusions

We highlighted that in common DLPFC tES montages, in addition to inter-individual/inter-group variability, the frontopolar received the highest EFs rather than DLPFC as the main target. We specifically recommended considering the potential involvement of the frontopolar area as a mechanism underlying the effectiveness of DLPFC tES protocols.

Highlights

There are many published tES studies assuming targeting DLPFC with DLPFC tES montages

In DLPFC tES montages, electric field peaks are not located under the electrodes

The electric field peak in DLPFC montages is located in the medial frontopolar area

An independent population showed between-group similarities and variations in electric field

There is a large interindividual variation in both location and strength of the electric field peak
A rapid evidence map of what evidence is available on the effectiveness of community diagnostic centres
Authors: Wale Alesha , Okolie Chukwudi , Everitt Jordan , Hookway Amy , Shaw Hannah , Little Kirsty , Lewis Ruth , Cooper Alison , Edwards Adrian
Published: December 2022

The COVID-19 pandemic has resulted in increased demand and delays to diagnostic services. Community diagnostic centres (which are generally referred to as Regional Diagnostic Hubs in Wales) aim to reduce this backlog and the waiting times for patients by providing a broad range of elective diagnostic services in the community, away from acute hospital facilities. As diagnostic services account for over 85% of clinical pathways and cost the National Health Service (NHS) over six billion pounds a year (NHS 2022), community diagnostic centres across a broader range of diagnostic services may be an effective, efficient, and cost-effective introduction to the UK health sector. This Rapid Evidence Map aimed to identify, describe, and map the available evidence on the effectiveness of diagnostic centres. 50 primary studies were identified. Studies were published between 1995 and 2021: A wide range of study designs were used, and studies were conducted in a range of countries including the UK. 30 studies were specific to cancer diagnosis, whilst the remaining 20 studies focused on diagnosis associated with: anaemia, autism, cerebral palsy, intellectual disability, multiple sclerosis, respiratory conditions, shoulder pain, and unexplained fever Eleven studies reported information on multi-condition diagnostic centres, rather than a specific condition.

The majority of studies were conducted within hospital settings. Two studies evaluated diagnostic centres within a community setting. The diagnostic centres offered a wide range of diagnostic tests and incorporated different staff and facilities. Participants were mainly referred by GPs, primary care centres and emergency departments. However, referrals were also made from outpatient clinics located within the same hospital as the diagnostic centre.

Over 100 different outcomes were reported covering: patient data and referral outcomes, clinical outcomes, performance outcomes, economic outcomes, and patient and physician-reported outcomes.

The findings of this rapid evidence map were used to select a substantive focus for a subsequent rapid review on community diagnostic centres that can be accessed by primary care teams.
Changes in Children’s Fitness and Health Status Over the Course of the COVID-19 Pandemic: A 34-month Longitudinal Study of 331 Primary School Children (September 2019 to June 2022)
Authors: Jarnig Gerald , Kerbl Reinhold , van Poppel Mireille N.M.
Published: December 2022

Background

Previous studies have shown that coronavirus disease 2019 (COVID-19) mitigation measures lead to reductions in health status and health-related fitness in children, whereas no data are currently available on the development of children after the removal of these mitigation measures. Therefore, we aimed to investigate the influence of different stringent measures, during and after COVID-19, on the longitudinal development of fitness and health status of primary school children.

METHODS

A longitudinal cohort study of 331 primary school children in Austria aged 7.7 ± 0.4 years at the start of the observation period was conducted. Before (Sept 2019), and during (June 2020, Sept 2020) and after (March 2021, June 2021, Sept 2021, and June 2022) the COVID-19 mitigation measures, fitness tests were carried out and anthropometric data of the children were collected. Age- and sex-specific standard deviation scores (SDSs) were calculated for seven individual fitness tests of the AUT FIT [1] test battery, body mass index, and waist-to-height ratio. In addition, children were classified into different fitness categories based on the AUT FIT summary score.

Results

After the implementation of COVID-19 mitigation measures, cardiorespiratory fitness and action speed decreased dramatically, and the number of children with overweight or obesity increased. At the last measurement after the COVID-19 mitigation measures (June 2022), significant improvements in cardiorespiratory fitness and weight status were observed. However, pre-COVID fitness levels were not achieved and BMI was still higher compared to Sept 2019.

Interpretation

Our study showed a trend reversal, in that the negative indirect effects of the COVID-19 measures on fitness and health parameters of children were followed by significant improvements in these parameters after the removal of those mitigation measures. At the end of the observation period, a positive trend in the development of fitness and health status was observed, although pre-COVID levels were not reached. Collaborative efforts are needed to reinforce the observed positive trend, and to continue to improve the level of fitness and health status of primary school children, and to mitigate the long-term negative health consequences of the COVID-19 pandemic.

Funding

Austrian Federal Ministry of Arts, Culture, Public Service and Sports (GZ2021-0.361.671).
Mpox (monkeypox) knowledge, concern, willingness to change behaviour, and seek vaccination: Results of a national cross-sectional survey
Authors: MacGibbon James , Cornelisse Vincent , Smith Anthony K J , Broady Timothy R , Hammoud Mohamed A , Bavinton Benjamin R , Paynter Heath , Vaughan Matthew , Wright Edwina J , Holt Martin
Published: December 2022

Background

We assessed knowledge and concern about mpox, acceptability of behavioural changes to reduce transmission risk, and willingness to be vaccinated among gay, bisexual and queer-identifying men and non-binary people.

Methods

We conducted a national, online cross-sectional survey with a convenience sample between August and September 2022. Participants were recruited through community organisation promotions, online advertising, and direct email invitations. Eligible participants were gay, bisexual or queer; identified as male (cisgender or transgender) or non-binary; aged 16 years or older; and lived in Australia. The main outcome measures were: knowledge and concern about mpox; recognition of mpox symptoms and transmission routes; vaccination history; acceptability of behavioural changes to reduce mpox risk, and willingness to be vaccinated.

Results

Of 2287 participants, most participants were male (2189/2287; 95.71%) and gay (1894/2287; 82.82%). Nearly all had heard about mpox (2255/2287; 98.60%), and the majority were concerned about acquiring it (1461/2287; 64.42%). Most of the 2268 participants not previously diagnosed with mpox identified skin lesions (2087; 92.02%), rash (1977; 87.17%), and fever (1647; 72.62%) as potential symptoms, and prolonged and brief skin-to-skin contact as potential ways to acquire mpox (2124, 93.65%; and 1860, 82.01% respectively). The most acceptable behavioural changes were reducing or avoiding attendance at sex parties (1494; 65.87%) and sex-on-premises venues (1503; 66.40%), and having fewer sexual partners (1466; 64.64%). Most unvaccinated and undiagnosed participants were willing to be vaccinated (1457/1733; 84.07%).

Conclusions

People at risk of mpox should be supported to adopt acceptable risk reduction strategies during outbreaks and seek vaccination.
A machine learning model to explore individual risk factors for tuberculosis treatment non-adherence in Mukono district
Authors: Gichuhi Haron W. , Magumba Mark , Kumar Manish , Mayega Roy William
Published: December 2022

Despite the availability and implementation of well-known efficacious interventions for Tuberculosis (TB) prevention and treatment by the Ministry of Health, Uganda (MoH), treatment non-adherence persists. Moreover, identifying a specific patient at risk of non-adherence is still a challenge. Thus, this study set out to utilize machine learning modeling to explore individual risk factors predictive of tuberculosis treatment non-adherence in the Mukono district.

This was a retrospective study based on a record review of 838 TB patients enrolled in six health facilities (3 government, 3 private-not-for-profit) in the Mukono district. We developed five machine learning algorithms (Logistic regression (LR), artificial neural networks (ANN), support vector machines (SVM), Random Forest (RF), and AdaBoost) to explore the individual risk factors for tuberculosis treatment non-adherence. Also, we evaluated their accuracy by computing the positive predictive value (PPV) and negative predictive value (NPV) through the aid of a confusion matrix.

Of the five developed and evaluated models, SVM performed the best with an accuracy of 91.28 % compared to RF (89.97%), LR (88.30%), ANN (88.30%), and AdaBoost (91.05%) respectively. Individual risk factors predictive of non-adherence included; TB type, GeneXpert results, sub-country, ART status, contacts below 5 years, health facility ownership, sputum test results at 2 months, treatment supporter, CPT Dapson status, risk group, patient age, gender, middle and upper arm circumference, referral, positive sputum test at 5 months and 6 months.

This study shows that classification machine learning techniques can identify patient factors predictive of treatment non-adherence and accurately differentiate between adherent and non-adherent patients. Thus, TB program management should consider adopting the machine learning techniques evaluated in this study as a screening tool for both identity and target-suited interventions for these patients.
Role ofSTING/TMEM173mutation in systemic lupus erythematosus: from animal model to intrinsic human genetics
Authors: Vejvisithsakul Pichpisith Pierre , Wanachate Satima , Ngamjanyaporn Pintip , Thumarat Chisanu , Suangtamai Thanitta , Leelahavanichkul Asada , Hirankan Nattiya , Pisitkun Trairak , Paludan Soren Riis , Pisitkun Prapaporn
Published: December 2022

Objective

We aim to confirm the function ofSting/Tmem173in pristane-induced lupus and identify the role ofSTING/TMEM173variants in SLE susceptibility.

Methods

Pristane-induced lupus model was introduced in theSting-deficient mice (ENU-induced Goldenticket mutant mice). Autoantibody, histopathology, and immunophenotypes were analyzed after pristane injection for six months. Isolated DNA from 302 SLE patients and 173 healthy donors were tested for STING genotyping. We calculated the Odd Ratios of each STING variant and the inheritance patterns that significantly increased SLE susceptibility. Then, we analyzed the associations between STING genotypes and lupus phenotypes.

Results

The absence of STING signaling in the Goldenticket mutant mice reduced the autoantibody production and severity of glomerulonephritis in pristane-induced lupus. The humanSTINGmutation at p.R284S (gain-of-function) significantly increased the SLE risk in autosomal dominant pattern [OR = 64.0860 (95%CI = 22.8605-179.6555), p < 0.0001], while the mutation at p.R232H (loss of function) reduced the SLE risk in autosomal recessive pattern [OR = 0.2515 (95%CI = 0.1648-0.3836), p < 0.0001]. The combination of STING variants in a specific inheritance pattern increased the higher OR than a single variant. The patient who had p.R284S with p.R232H showed milder disease activity than those who had p.R284S alone at the time of diagnosis.

Conclusion

The inhibition of STING rescued autoimmune phenotypes in pristane-induced lupus. Gain-of-function STING mutation increased SLE susceptibility and severity of the disease. These data suggested the critical function via STING-mediated signaling in SLE. Targeted at STING may provide a favorable outcome in SLE patients.
Impact of COVID-19 Vaccinations in India - A Statewise Analysis
Authors: Adhikary Abhigayan , Pal Manoranjan , Maiti Raju , Ghosh Palash
Published: December 2022

Objective

The COVID-19 vaccination program in India started after the first wave of infections had almost subsided. In this work, the objective is to perform a statewise analysis to assess the impact of vaccination during the second COVID-19 wave in India. A total of 21 states are chosen for the analysis encompassing 97% of the Indian population.

Methods

We use the generalized Gompertz curve to study the COVID-19 outbreak. The generalized Gompertz model is then modified to study the impact of vaccination. The modified model considers the cumulative daily number of individuals having the first and second shots of the vaccine in each state as explanatory variables.

Results

We observe that, out of 21 states, 16 states show the effectiveness of vaccines in curbing the spread of COVID-19. However, in states like Telangana, West Bengal, Tamil Nadu, Rajasthan, and Kerala, we do not conclusively observe the impact of vaccination during the study period.

Conclusions

The effectiveness of COVID-19 vaccine depends on many factors. Some of them are not directly measurable. Using only COVID-19 infection cases and the vaccination data, we conclude that overall the vaccination program was effective in curbing the spread of COVID-19 in India.
Computational simulation of virtual patients reduces dataset bias and improves machine learning-based detection of ARDS from noisy heterogeneous ICU datasets
Authors: Sharafutdinov Konstantin , Fritsch Sebastian Johannes , Iravani Mina , Ghalati Pejman Farhadi , Saffaran Sina , Bates Declan G. , Hardman Jonathan G. , Polzin Richard , Mayer Hannah , Marx Gernot , Bickenbach Johannes , Schuppert Andreas
Published: December 2022

Goal

Machine learning (ML) technologies that leverage large-scale patient data are promising tools predicting disease evolution in individual patients. However, the limited generalizability of ML models developed on single-center datasets, and their unproven performance in real-world settings, remain significant constraints to their widespread adoption in clinical practice. One approach to tackle this issue is to base learning on large multi-center datasets. However, such heterogeneous datasets can introduce further biases driven by data origin, as data structures and patient cohorts may differ between hospitals.

Methods

In this paper, we demonstrate how mechanistic virtual patient (VP) modeling can be used to capture specific features of patients’ states and dynamics, while reducing biases introduced by heterogeneous datasets. We show how VP modeling can be used to extract relevant medical information on individual patients with suspected acute respiratory distress syndrome (ARDS) from observational data of mixed origin. We compare the results of an unsupervised learning method (clustering) in two cases: where the learning is based on original patient data and on data ‘filtered’ through a VP model.

Results

More robust cluster configurations were observed in clustering using the VP model-based filtered data. VP model-based clustering also reduced biases introduced by the inclusion of data from different hospitals and was able to discover an additional cluster with significant ARDS enrichment.

Conclusions

Our results indicate that mechanistic VP modeling can be used as a filter to significantly reduce biases introduced by learning from heterogeneous datasets and to allow improved discovery of patient cohorts driven exclusively by medical conditions.

IMPACT STATEMENT

Mechanistic virtual patient modeling can be used as a filter to extract relevant medical information on individual patients, significantly reducing biases introduced by learning from heterogeneous datasets and allowing improved discovery of patient cohorts driven exclusively by medical conditions.
ythdf2(ch200)and its role in development of the early zebrafish embryo
Authors: Beadell Alana V.
Published: December 2022

We appreciate the well-presented data and focus on mechanism in the paper titled, “Ythdf m6A Readers Function Redundantly during Zebrafish Development” by Konturet al. December 29, 20201[DOI:https://doi.org/10.1016/j.celrep.2020.108598]. However, we would like to suggest several alternative conclusions regarding the role of Ythdf2 in maternal RNA clearance and the phenotypic consequences of theythdf2(ch200)mutation as described in Zhaoet al. 2017, “m6A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition”2[DOI:https://doi.org/10.1038/nature21355], along with caveats regarding the interpretation of Ythdf2’s roles in mRNA metabolism in the early embryo.
New insights into the structure of Comirnaty Covid-19 vaccine: A theory on soft nanoparticles with mRNA-lipid supercoils stabilized by hydrogen bonds
Authors: Szebeni János , Kiss Bálint , Bozó Tamás , Turjeman Keren , Levi-Kalisman Yael , Barenholz Yechezkel , Kellermayer Miklós
Published: December 2022

Despite the worldwide success of mRNA-LNP Covid-19 vaccines, the nanoscale structure of these formulations is still poorly understood. To fill this gap, we used a combination of atomic force microscopy (AFM), dynamic light scattering (DLS), transmission electron microscopy (TEM), cryogenic transmission electron microscopy (cryo-TEM) and the determination of LNP pH gradient to analyze the nanoparticles (NPs) in BNT162b2 (Comirnaty), comparing it with the well characterized pegylated liposomal doxorubicin (Doxil). Comirnaty NPs had similar size to Doxil, however, unlike Doxil liposomes, wherein the stable ammonium and pH gradient enables accumulation of14C-methylamine in the intraliposomal aqueous phase, Comirnaty LNPs lack such pH gradient in spite of the fact that the pH 4, at which LNPs are prepared, is raised to pH 7.2 after loading of the mRNA. Mechanical manipulation of Comirnaty NPs with AFM revealed soft, compliant structures. The sawtooth-like force transitions seen during cantilever retraction implies that molecular strands, corresponding to mRNA, can be pulled out of NPs, and the process is accompanied by stepwise rupture of mRNA-lipid bonds. Unlike Doxil, cryo-TEM of Comirnaty NPs revealed a granular, solid core enclosed by mono- and bilayers. Negative staining TEM shows 2-5 nm electron-dense spots in the liposom’s interior that are aligned into strings, semicircles, or labyrinth-like networks, which may imply crosslink-stabilized supercoils. The neutral intra-LNP core questions the dominance of ionic interactions holding together this scaffold, raising the alternative possibility of hydrogen bonding between the mRNA and the lipids. Such interaction, described previously for another mRNA/lipid complex, is consistent with the steric structure of ionizable lipid in Comirnaty, ALC-0315, displaying free =O and -OH groups. It is hypothesized that the latter groups can get into steric positions that enable hydrogen bonding with the nitrogenous bases in the mRNA. These newly recognized structural features of mRNA-LNP may be important for the vaccine’s efficacy.
A knowledge-based system for personalised lifestyle recommendations: Design and simulation of potential effectiveness on the UK Biobank data
Authors: Cavallo Francesca Romana , Toumazou Christofer
Published: December 2022

Mobile health applications, which employ wireless technology for healthcare, can aid behaviour change and subsequently improve health outcomes. Mobile health applications have been developed to increase physical activity, but are rarely grounded on behavioural theory and employ simple techniques for personalisation, which has been proven effective in promoting behaviour change. In this work, we propose a theoretically driven and personalised behavioural intervention delivered through an adaptive knowledge-based system. The behavioural system design is guided by the Behavioural Change Wheel and the Capability-Opportunity-Motivation behavioural model. The system exploits the ever-increasing availability of health data from wearable devices, point-of-care tests and consumer genetic tests to issue highly personalised physical activity and sedentary behaviour recommendations. To provide the personalised recommendations, the system firstly classifies the user into one of four diabetes clusters based on their cardiometabolic profile. Secondly, it recommends activity levels based on their genotype and past activity history, and finally, it presents the user with their current risk of developing cardiovascular disease. In addition, leptin, a hormone involved in metabolism, is included as a feedback biosignal to personalise the recommendations further. As a case study, we designed and demonstrated the system on people with type 2 diabetes, since it is a chronic condition often managed through lifestyle changes, such as physical activity increase and sedentary behaviour reduction. We trained and simulated the system using data from diabetic participants of the UK Biobank, a large-scale clinical database, and demonstrate that the system could help increase activity over time. These results warrant a real-life implementation of the system, which we aim to evaluate through human intervention.
Growth Signaling Autonomy in Circulating Tumor Cells Aids Metastatic Seeding
Authors: Sinha Saptarshi , Farfel Alex , Luker Kathryn E. , Parker Barbara A. , Yeung Kay , Luker Gary D. , Ghosh Pradipta
Published: December 2022

Self-sufficiency (autonomy) in growth signaling, the earliest recognized hallmark of cancer, is fueled by the tumor cell’s ability to ‘secrete-and-sense’ growth factors; this translates into cell survival and proliferation that is self-sustained by auto-/paracrine secretion. A Golgi-localized circuitry comprised of two GTPase switches has recently been implicated in the orchestration of growth signaling autonomy. Using breast cancer cells that are either endowed or impaired (by gene editing) in their ability to assemble the circuitry for growth signaling autonomy, here we define the transcriptome, proteome, and phenome of such autonomous state, and unravel its role during cancer progression. We show that autonomy is associated with enhanced molecular programs for stemness, proliferation, and epithelial-mesenchymal plasticity (EMP). Autonomy is both necessary and sufficient for anchorage-independent growth factor-restricted proliferation and resistance to anti-cancer drugs and is required for metastatic progression. Transcriptomic and proteomic studies show that autonomy is associated, with a surprising degree of specificity, to self-sustained EGFR/ErbB signaling. Derivation of a gene expression signature for autonomy revealed that growth signaling autonomy is uniquely induced in circulating tumor cells (CTCs), the harshest phase in the life of tumor cells when it is deprived of biologically available EGF. We also show that autonomy in CTCs tracks therapeutic response and prognosticates outcome. These data support a role for growth signaling autonomy in multiple processes essential for the blood-borne dissemination of human breast cancer.

GRAPHIC ABSTRACT:

Significance Statement

A Golgi-localized molecular circuitry has been recently implicated in the orchestration of secrete-and-sense auto-/paracrine loops that impart self-sufficiency in growth signaling, a.k.a., growth signaling autonomy. Using a transdisciplinary approach, this work shows that growth signaling autonomy is uniquely induced in tumor cells that are in circulation. Circulating tumor cells (CTCs) represent a brutish and risky phase in the lifetime of tumor cells when they are exposed to the immune system and hemodynamic sheer forces, all in the setting of growth factor starvation. Cancer cells appear to rely on the autonomy circuit to survive and enhance their fitness to seed metastases. Autonomy generates the kind of ‘eat-what-you-kill’ entrepreneurial spirit which minimizes the risk of CTCs dying on an otherwise risky journey.
Isobaric crosslinking mass spectrometry technology for studying conformational and structural changes in proteins and complexes
Authors: Luo Jie , Ranish Jeff
Published: December 2022

Dynamic conformational and structural changes in proteins and protein complexes play a central and ubiquitous role in the regulation of protein function, yet it is very challenging to study these changes, especially for large protein complexes, under physiological conditions. Here we introduce a novel isobaric crosslinker, Qlinker, for studying conformational and structural changes in proteins and protein complexes using quantitative crosslinking mass spectrometry (qCLMS). Qlinkers are small and simple, amine-reactive molecules with an optimal extended distance of ∼10 Å which use MS2 reporter ions for relative quantification of Qlinker-modified peptides derived from different samples. We synthesized the 2-plex Q2linker and showed that the Q2linker can provide quantitative crosslinking data that pinpoints key conformational and structural changes in biosensors, binary and ternary complexes composed of the general transcription factors TBP, TFIIA, and TFIIB, and RNA polymerase II (pol II) complexes.
Drosophilid cuticle pigmentation impacts body temperature
Authors: Freoa Laurent , Chevin Luis-Miguel , Christol Philippe , Méléard Sylvie , Rera Michael , Véber Amandine , Gibert Jean-Michel
Published: December 2022

Cuticle pigmentation has been clearly demonstrated to impact body temperature for several relatively large species of insects, but it was questioned for small insects. Here we used a thermal camera to assess the impact of drosophilid cuticle pigmentation on body temperature when individuals are exposed to light. We compared mutants of large effects within species (Drosophila melanogaster ebonyandyellowmutants). Then we analyzed the impact of naturally occurring pigmentation variation within species complexes (Drosophila americana/Drosophila novamexicanaandDrosophila yakuba/Drosophila santomea). Finally we analyzed lines ofD. melanogasterwith moderate differences in pigmentation. We found significant differences in temperatures for each of the four pairs we analyzed. The temperature differences appeared to be proportional to the differently pigmented area: betweenDrosophila melanogaster ebonyandyellowmutants or betweenDrosophila americanaandDrosophila novamexicana, for which the whole body is differently pigmented, the difference in temperatures was around 0.6°C ±0.2°C. By contrast, betweenD. yakubaandD. santomeaor betweenDrosophila melanogaster DarkandPalelines, for which only the posterior abdomen is differentially pigmented, we detected a temperature difference of about 0.14°C ±0.10°C. This demonstrates that cuticle pigmentation has ecological implications in drosophilids regarding adaptation to environmental temperature.
Redox-active molecules in bacterial cultivation media produce photocurrent
Authors: Shlosberg Yaniv , Smith Matthew C. , Nasseri Nathan. S. , Morin Emile J. , Limwongyut Jakkarin , Moreland Alex S. , Bazan Guillermo C. , Carlini Andrea S.
Published: December 2022

In recent years, global climate change has urged the importance of developing new clean energy technologies that may replace the combustion of fossil fuels and help to reduce carbon emissions. A promising, yet intrinsically complex solution, is the utilization of bacteria as electron donors in microbial fuel cells (MFCs). In this work, we show that just the cultivation media for bacterial growth, which is based on yeast extract, is sufficient for generating electrical current in a bio-electrochemical cell (BEC). We apply cyclic voltammetry and 2-dimensional fluorescence spectroscopy to identify redox active molecules such as NADH, NAD+, and flavines that may play key roles in electron donation. Finally, we show that upon illumination, current production is enhanced 2-fold. This photocurrent is generated by a variety of metabolites capable of photochemical reduction, enabling them to donate electrons at the anode of the BEC. Future investigations into the role of culture media versus that of living cells in MFCs may aid in reducing overall production and maintenance costs, and enhance power output performance.