bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Topiramate Prescribed for any Indication with Reduced Alcohol Consumption in Electronic Health Record Data
Authors: Kranzler Henry R. , Leong Shirley H. , Naps Michelle , Hartwell Emily E. , Fiellin David A. , Rentsch Christopher T.
Published: May 2022

Background and Aims

Topiramate is widely prescribed to treat a variety of conditions, including alcohol use disorder (AUD). We used electronic health record (EHR) data to examine topiramate’s effects on drinking in individuals differentiated by a history of AUD.

Design

Parallel-groups comparison of patients prescribed topiramate and a propensity-score matched comparison group.

Setting

A large U.S. integrated healthcare system.

Participants

Patients with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores prior to and after a minimum of 180 days of topiramate prescription for any indication and a propensity-score matched group. The sample included 5,918 patients with an electronic health record diagnosis of alcohol use disorder at any time (AUD-hx-pos) (1,738 topiramate exposed and 4,180 controls) and 23,614 patients with no EHR diagnosis of AUD (AUD-hx-neg) (6,324 topiramate exposed and 17,290 controls).

Measurements

Regression analyses compared difference-in-difference (DiD) estimates, separately by AUD history. DiD estimates represent exposure-group (i.e., topiramate vs. control) differences on the pre-post difference in AUDIT-C score. Effects of baseline AUDIT-C score and daily topiramate dosage were also tested.

Findings

Among AUD-hx-neg patients, those who received topiramate had a greater reduction in AUDIT-C score (−0.11) than matched controls (−0.04). This yielded a DiD score of -0.07 (95% CI= -0.11,-0.03; P =0.002), with the greatest effect among AUD-hx-neg patients with a baseline AUDIT-C score of 4+ (DiD = -0.35, 95% CI=-0.49, -0.21; P <0.0001) and those prescribed >150 mg/day of the medication (DiD = -0.15, 95%CI=-0.23, -0.07; P <0.001).

Discussion

The lack of an effect of topiramate on drinking levels in AUD-hx-pos patients contrasts with the robust reductions seen in topiramate clinical trials. Research is needed to ascertain whether AUDIT-C scores from EHR data accurately reflect medication effects on drinking and whether patient characteristics can be used to select patients most likely to reduce their drinking when treated with topiramate.
An Updated Meta-analysis of Studies Comparing Conventional to Underwater Endoscopic Mucosal Resection for Colorectal Polyps
Authors: Pamarthy Rahul , Ali Hassam , Bin Waqar Syed Hamza , Sarfraz Shiza
Published: May 2022

Background

Underwater endoscopic mucosal resection (UEMR) is an emerging alternative to conventional endoscopic mucosal resection (CEMR). We intended to compare both techniques for colorectal polyp resection.

Methods

A comprehensive search of several databases to identify studies published until November 2021 was performed. Inclusion criteria included studies comparing UEMR to CEMR in adult patients. The calculation was done by standard meta-analysis methodology, and heterogeneity was assessed using the I2% statistics.

Results

1029 polyps were resected with the CEMR technique and 1078 polyps with UEMR. UEMR was associated with an increase in the rate of overall en-bloc resection (Odds ratios (OR) 1.77; 95% CI, 1.42-2.22; P < .0001; I2 = 20%). Subgroup analysis showed an increase in the rates of en-bloc resection in polyps greater than 20 mm (OR 1.62; 95% CI, 1.17-2.25; P = 0.004; I2 = 33%). There was a reduction in the recurrence rate of polyps (P < 0.0001) in the UEMR cohort. Post-procedural bleeding or risk of perforation was not increased in either group. Resection times were shorter in UEMR (Mean difference, -8.09; P = 0.006).

Conclusion

UEMR is associated with lower recurrence rates and shorter procedure duration. In the future, UEMR may become the standard technique for colorectal polypectomy.
Specialty Visits and Real-world Initiation of Cardioprotective Anti-hyperglycemic Medications Among US Adults with Type 2 Diabetes
Authors: Nargesi Arash A , Clark Callahan , Liu Mengni , Reddy Abraham , Amodeo Samuel , Khera Rohan
Published: May 2022

Prescription of sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) among patients with guideline-directed indications remains limited with substantial inter-prescriber variability. In this prospective study of US adults, we used administrative claims database of individuals with type 2 diabetes and compelling indications for SGLT-2i and GLP-1RA to evaluate the impact of healthcare visits with certain specialty providers on the initiation of these medications. These specialties included family medicine, internal medicine, cardiology, endocrinology, and nephrology. Overall, 294,988 individuals eligible for SGLT-2i and 198,525 for GLP-1RA were identified. In 2019-2020, SGLT-2i and GLP-1RA were initiated in 10.4% and 16.7% of eligible individuals, respectively. After accounting for patient characteristics and comorbidities, healthcare visit with endocrinologists was associated with the highest rate of initiation of either drug across specialties (OR=2.16 [2.08-2.24] for SGLT-2i, and 2.76 [2.64-2.88] for GLP-1RA). Healthcare visits with cardiologists and with family medicine and internal medicine physicians were only modestly associated with initiation of SGLT-2i and GLP-1RA. The study highlights the need for broad education for expansion of the use of these medications rather than focus on dedicated specialty clinics.
A Predictive Model to Identify Complicated Clostridiodes difficile Infection
Authors: Berinstein Jeffrey A. , Steiner Calen A. , Rifkin Samara , Perry D. Alexander , Micic Dejan , Shirley Daniel , Higgins Peter D.R. , Young Vincent B. , Lee Allen , Rao Krishna
Published: May 2022

Background

Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated infections and may result in organ dysfunction, colectomy, and death. We recently showed that published risk scores to predict severe complications from CDI demonstrate poor performance upon external validation. We hypothesized that building and validating a model using geographically and temporally distinct cohorts would more accurately identify patients at risk for complicated CDI.

Methods

We conducted a multi-center retrospective cohort study of adult subjects diagnosed with CDI in the US. After randomly partitioning the data into training/validation set, we developed and compared three machine learning algorithms (Lasso regression, random forest, stacked ensemble models) with 10-fold cross-validation that used structured EHR data collected within 48 hours of CDI diagnosis to predict disease-related complications from CDI (intensive care unit admission, colectomy, or death attributable to CDI within 30 days of diagnosis). Model performance was assessed using area under the receiver operating curve (AUC).

Results

A total of 3,762 patients with CDI were included of which 218 (5.8%) had complications. Lasso regression, random forest, and stacked ensemble models all performed well with AUC ranging between 0.89-0.9. Variables of importance were similar across models, including albumin, bicarbonate, change in creatinine, systolic blood pressure, non-CDI-related ICU admission, and concomitant non-CDI antibiotics. Sensitivity analyses indicated that model performance was robust even when varying derivation cohort inclusion and CDI testing approach.

Conclusion

Using a large heterogeneous population of patients, we have developed and validated a prediction model based on structured EHR data that accurately estimates risk for complications from CDI.

Key Points

Machine learning models using structured electronic health records can be leveraged to accurately predict risk of severe complications related to Clostridiodes difficile infection, including intensive care unit admission, colectomy, and/or death.
Survival and predictors of mortality after completion of TB treatment among people living with HIV
Authors: Lumu Ivan , Musaazi Joseph , Semeere Aggrey , Handel Ian , Castelnuovo Barbara
Published: May 2022

Background

After completion of TB treatment patients may remain at-risk of complications and mortality. We determined the survival and predictors of all-cause mortality after completing TB treatment among ART experienced patients.

Methods

This was a retrospective cohort analysis of all ART experienced patients who completed TB treatment at a specialist HIV clinic in Uganda, between 2009 and 2014. The patients were followed for five years after TB treatment. We determined mortality rate, probability of death, and predictors of all-cause mortality after TB treatment using Poisson methods, Kaplan-Meier methods, and Cox proportional hazard models, respectively.

Results

A total 1,287 patients completed TB treatment between 2009 and 2014, of which 1,111 were included in the analysis. At TB treatment completion, the median age was 36 years (IQR: 31-42), 563 (50.7%) were males, and median CD4 count was 235 cells/mL (IQR: 139-366). The person time at risk was 4410.60 person-years. The all-cause mortality rate was 15.42 per 1000 person-years (95% CI: 12.14-19.59). The probability of death at five years was 6.9% (95%CI: 5.5%-8.8%). In the multivariable analysis, CD4 count<200 cells/mL was a predictor of all-cause mortality (aHR=1.81, 95%CI:1.06 - 3.11, p=0.03) alongside TB history (aHR=2.12, 95%CI: 1.16 - 3.85, p=0.01).

Conclusion

Survival post TB treatment in ART experienced PLHIV is reasonably good and most deaths occur within two years of TB treatment completion. Patients with low CD4 and those with history of treatment have an increased risk of mortality which underscores the need for TB prophylaxis, detailed assessment, and close monitoring after TB treatment.

What is already known on this topic

Tuberculosis is the leading cause of death in PLHIV and patients who complete treatment remain at risk of mortality. However, it is not clear what the mortality rate is, when it occurs, and what factors are associated with mortality in exclusively ART experienced patients.

What this study adds

Most deaths occur within two years after treatment completion decreasing drastically by year five. Patients with low CD4 count after TB treatment have an 81% increased risk of death and those with a history of TB have a 200% increased risk of mortality.

How this study might affect research, practice or policy

The study provides a detailed understanding of post-TB survival in ART experienced PLHIV and underscores the need for programs and clinics to re-define TB treatment success and consider the use of enhanced prophylaxis after TB treatment.
B cells, BAFF and interferons in MIS-C
Authors: Klocperk Adam , Bloomfield Marketa , Parackova Zuzana , Aillot Ludovic , Fremuth Jiri , Sasek Lumir , David Jan , Fencl Filip , Skotnicova Aneta , Rejlova Katerina , Magner Martin , Hrusak Ondrej , Sediva Anna
Published: May 2022

Multisystem Inflammatory Syndrome in Children associated with COVID-19 (MIS-C) is a late complication of pediatric COVID-19, which follows weeks after original SARS-CoV-2 infection, regardless of its severity. It is characterized by hyperinflammation, neutrophilia, lymphopenia and activation of T cells with elevated IFN-γ. Observing production of autoantibodies and parallels with systemic autoimmune disorders, such as systemic lupus erythematodes (SLE), we explored B cell phenotype and serum levels of type I, II and III interferons, as well as the cytokines BAFF and APRIL in a cohort of MIS-C patients and healthy children after COVID-19.

We documented a significant elevation of IFN-γ, but not IFN-α and IFN-λ in MIS-C patients. BAFF was elevated in MIS-C patient sera and accompanied by decreased BAFFR expression on all B cell subtypes. The proportion of plasmablasts was significantly lower in patients compared to healthy post-COVID children. We noted the presence of ENA Ro60 autoantibodies in 4/35 tested MIS-C patients.

Our work shows the involvement of humoral immunity in MIS-C and hints at parallels with the pathophysiology of SLE, with autoreactive B cells driven towards autoantibody production by elevated BAFF.

Graphical abstract

Summary sentence

Elevated serum BAFF in children with MIS-C supports the state of polyclonal B cell activation and autoimmune phenomena characterizing this disease.
In Utero Exposure to the Great Depression is Reflected in Late-Life Epigenetic Aging Signatures
Authors: Schmitz Lauren L. , Duque Valentina
Published: May 2022

Research on maternal-fetal epigenetic programming argues that adverse exposures to the intrauterine environment can have long-term effects on adult morbidity and mortality. However, causal research on epigenetic programming in humans at a population level is rare and is often unable to separate intrauterine effects from conditions in the postnatal period that may continue to impact child development. In this study, we used a quasi-natural experiment that leverages state-year variation in economic shocks during the Great Depression to examine the causal effect of environmental exposures in early life on late-life accelerated epigenetic aging for 832 participants in the U.S. Health and Retirement Study (HRS). HRS is the first population-representative study to collect epigenome-wide DNA methylation data that has the sample size and geographic variation necessary to exploit quasi-random variation in environments, which expands possibilities for causal research in epigenetics. Our findings suggest that exposure to changing economic conditions in the 1930s had lasting impacts on next-generation epigenetic aging signatures that were developed to predict mortality risk (GrimAge) and physiological decline (DunedinPoAm). We show that these effects are localized to the in utero period specifically as opposed to the pre-conception, postnatal, childhood, or early adolescent periods. After evaluating changes in mortality rates for Depression-era birth cohorts, we conclude that these effects likely represent lower bound estimates of the true impacts of the economic shock on long-term epigenetic aging.
Automatically Identifying Twitter Users for Interventions to Support Dementia Family Caregivers: Annotated Data Set and Benchmark Classification Models
Authors: Klein Ari Z. , Magge Arjun , O’Connor Karen , Gonzalez-Hernandez Graciela
Published: May 2022

Background

More than 6 million people in the United States have Alzheimer’s disease and related dementias, receiving help from more than 11 million family or other informal caregivers. A range of traditional interventions have been developed to support family caregivers; however, most of them have not been implemented in practice and remain largely inaccessible. While recent studies have shown that family caregivers of people with dementia use Twitter to discuss their experiences, methods have not been developed to enable the use of Twitter for interventions.

Objective

The objective of this study was to develop an annotated data set and benchmark classification models for automatically identifying a cohort of Twitter users who have a family member with dementia.

Methods

Between May 4, 2021 and May 20, 2021, we collected 10,733 tweets, posted by 8846 users, that mention a dementia-related keyword, a linguistic marker that potentially indicates a diagnosis, and a select familial relationship. Three annotators annotated one random tweet per user to distinguish those that indicate having a family member with dementia from those that do not. We used the annotated tweets to train and evaluate deep neural network classifiers based on pretrained transformer models. To assess the scalability of our approach, we, then, deployed automatic classification on tweets that were continuously collected between May 4, 2021 and March 9, 2022.

Results

Inter-annotator agreement was 0.82 (Fleiss’ kappa). A classifier based on a BERT model pretrained on tweets achieved the highest F1-score of 0.962 (precision = 0.946, recall = 0.979) for the class of tweets indicating that the user has a family member with dementia. The classifier detected 128,838 tweets that indicate having a family member with dementia, posted by 74,290 users between May 4, 2021 and March 9, 2022—that is, approximately 7500 users per month.

Conclusions

Our annotated data set can be used to automatically identify Twitter users who have a family member with dementia, enabling the use of Twitter on a large scale to not only explore family caregivers’ experiences, but also directly target interventions at these users.
Artificial intelligence and opioid use: a narrative review
Authors: Gadhia Seema , Richards Georgia C. , Marriott Tracey , Rose James
Published: May 2022

Background

Opioids are strong pain medications that can be essential for acute pain. However, opioids are also commonly used for chronic conditions and illicitly where there are well recognised concerns about the balance of their benefits and harms. Technologies using artificial intelligence (AI) are being developed to examine and optimise the use of opioids. Yet, this research has not been synthesised to determine the types of AI models being developed and the application of these models.

Methods

We aimed to synthesise studies exploring the use of AI in people taking opioids. We searched three databases: the Cochrane Database of Systematic Reviews, EMBASE, and Medline on 4 January 2021. Studies were included if they were published after 2010, conducted in a real-life community setting involving humans, and used AI to understand opioid use. Data on the types and applications of AI models were extracted and descriptively analysed.

Results

Eighty-one articles were included in our review, representing over 5.3 million participants and 14.6 million social media posts. Most (93%) studies were conducted in the USA. The types of AI technologies included natural language processing (46%) and a range of machine learning algorithms, the most common being random forest algorithms (36%). AI was predominately applied for the surveillance and monitoring of opioids (46%), followed by risk prediction (42%), pain management (10%), and patient support (2%). Few of the AI models were ready for adoption, with most (62%) being in preliminary stages.

Conclusions

Many AI models are being developed and applied to understand opioid use. However, there is a need for these AI technologies to be externally validated and robustly evaluated to determine whether they can improve the use and safety of opioids.

SUMMARY BOX

Key Points

Across the landscape of opioid research, natural language processing models (46%) and ensemble algorithms, particularly random forest algorithms (36%), were the most common types of AI technologies studied.

There were four domains to which AI was applied to assess the use of opioids, including surveillance and monitoring (46%), risk prediction (42%), pain management (10%), and patient support (2%).

The AI technologies were at various stages of development, validation, and deployment, with most (62%) models in preliminary stages, 11% required external validation, and few models were openly available to access (6%).
LONG-LASTING INSECTICIDE NETS OWNERSHIP AND MALARIA MORBIDITY IN KRACHI EAST MUNICIPALITY, GHANA
Authors: Wuresah Israel , Elmi Siman , Adjuiky Martin
Published: May 2022

Background

Malaria-related morbidity and mortality are issues of great concern to public health globally though, a higher proportion of cases reside within Sub-Saharan Africa. The situation in Ghana though not new, is very disturbing, as millions of people especially children and pregnant women suffer severely from malaria. Seasonal chemoprevention and indoor residual spraying are among many measures deployed in the northern parts of Ghana with nationwide outreach and point distribution of LLINs across the country but reports from OPDs indicate millions of malaria cases annually.

Objective

To identify the levels of ownership and usage of the treated bed nets, and describe the relationship between ownership of LLINs and malaria morbidity.

Methods

The 30-cluster sampling method was deployed. Using both a modified WHO EPI survey method for more rural areas and a random walk sampling for more urban areas, each community had a listed starting point where the use of a spun pen determined the direction to conduct the surveys within the specified cluster. Selected households’ heads/representatives (any adult aged 18 years and above, in a household where the head is absent) participated voluntarily. STATA version 16.0 was used to run the statistical analysis and the results were presented in tables and figures.

Results

Findings revealed high levels of ownership of LLINs (73.4%) but moderately low usage levels (49.5%). Some other uses of LLINs (22.9%) aside from sleeping under them were identified. Malaria morbidity (59.6%) was also determined. Multivariate analysis results revealed statistically significant association between some socio-demographic characteristics and LLINs ownership including female sex (AOR = 2.1 (95% CI: 1.15, 3.87) p=0.016), being married (AOR = 3.4 (95% CI: 1.76, 6.74) p<0.001), cohabiting (AOR = 6.1 (95% CI: 2.15, 17.02) p=0.001) and being separated or divorced (AOR = 9.4 (95% CI: 1.09, 81.27) p=0.041). A positive correlation was identified between ownership of LLINs and their usage.

Conclusion

Despite high levels of ownership of LLINs, usage is minimal with a consequential effect on malaria morbidity. The study recommended service points and periodic household and/or community sensitization on LLINs usage as measures to increase usage levels.
Brain morphometric changes in congenitally blind subjects: a 7 Tesla MRI study
Authors: Kupers Ron , Zhan Minye , Paré Samuel , Dricot Laurence , Vaessen Maarten , de Gelder Beatrice
Published: May 2022

We used ultra-high field (7 Tesla) magnetic resonance imaging (MRI) at submillimeter resolution to assess structural brain changes in congenitally blind (CB) compared to matched normal sighted control (SC) subject groups. Region-of-interest analysis revealed grey matter (GM) volumetric reductions in the CB group in left cuneus and occipital pole, right posterior collateral sulcus and right occipito-temporal medial lingual sulcus. Non-visual areas with GM reductions in CB included the left central, postcentral and superior frontal gyri, and the right subcallosal gyrus. In contrast, there were no significant group differences in cortical thickness when using stringent statistical criteria. Regional differences in white matter (WM) showed an overall pattern similar as that of GM changes, characterized by volume reductions in occipital, parietal and temporal areas, but with additional reductions in precuneus and medial orbitofrontal cortex. Differences in cortical curvature were mostly situated in the occipital cortex and bore a close relationship with areas showing GM alterations; they may be indicative of increased cortico-cortical connectivity of the visually-deprived occipital cortex. The CB group had GM reductions in the basal ganglia, i.e., caudate nucleus, putamen, nucleus accumbens, globus pallidus, and thalamus. Within the cerebellum, GM and WM volumes were also reduced in the CB. Segmentation of the thalamus, hippocampus and amygdala into anatomic divisions revealed GM reductions in a number of thalamic nuclei, a few hippocampal regions, but not within amygdala. There were no findings of increased volume or cortical thickness in the CB group. Together, these data reveal a multitude of GM and WM reductions in CB, comprising not only the occipital cortex, but also temporal, parietal, and prefrontal cortices, as well as the basal ganglia and cerebellum. These findings in the CB may seem at odds with the large literature showing that the visually-deprived occipital cortex becomes a multimodal cortex responding to diverse non-visual sensory and cognitive inputs. The seeming mismatch between morphological atrophy and enhanced multimodality of occipital areas combined with superior performance by the CB in various non-visual tasks poses a challenge for our understanding of brain plasticity.
Fusome topology and inheritance during insect gametogenesis
Authors: Diegmiller Rocky , Alsous Jasmin Imran , Li Duojia , Yamashita Yukiko M. , Shvartsman Stanislav Y.
Published: May 2022

From insects to mammals, oocytes ad sperm develop within germline cysts comprising cells connected by intercellular bridges (ICBs). In numerous insects, formation of the cyst is accompanied by growth of the fusome – a membranous that permeates the cyst. Fusome composition and function are best understood in Drosophila melanogaster: during oogenesis, the fusome dictates cyst topology and size and facilitates oocyte selection, while during spermatogenesis, the fusome synchronizes the cyst’s response to DNA damage. Despite its myriad and sex-specific roles during insect gametogenesis, fusome growth and inheritance in females and its structure and connectivity in males have remained challenging to investigate. Here, we take advantage of advances in high resolution confocal microscopy and computational image processing tools to reconstruct the topology, growth, and distribution of the fusome in both sexes. Our findings inform a theoretical model for fusome assembly and inheritance during oogenesis, shedding light on symmetry-breaking processes that lead to oocyte selection. In males, we find that cell divisions can deviate from the maximally branched pattern observed in females, leading to greater topological variability. Our work consolidates existing disjoint experimental observations and contributes a readily generalizable computational approach for quantitative studies of gametogenesis within and across species.

Author summary

The ubiquity of germline cysts across animals and accelerating advances in microscopy call for quantitative and highly resolved studies of their developmental dynamics. Here we use Drosophila melanogaster gametogenesis as a model system, alongside a supervised learning algorithm to study a shared organelle that arises during sperm and oocyte development – the fusome. The fusome is a highly specialized membranous organelle that permeates the cyst in both sexes. Our three-dimensional (3D) reconstructions of the fusome and quantitative measurements at successive stages of cyst development during oogenesis shed light on the evolution of cell fate asymmetry within the germline cyst in females, where the cyst gives rise to a single oocyte. In males, where each cell of the cyst goes on to form sperm, the fusome fragments and exhbits topologies that deviate from the stereotypic maximally branched topology found in females. Our findings can be interpreted in the context of the divergent outcomes of gametogenesis in both sexes and highlight the centrality of quantitative measurements in evaluating hypotheses in biological sciences.
A “cooperative collaboration” between HAND2 and MYCN shapes neuroblastoma cell identity
Authors: Xu Man , Sun Ming , Zhang Xiyuan , Nguyen Rosa , Lei Haiyan , Shern Jack F. , Thiele Carol J. , Liu Zhihui
Published: May 2022

Noradrenergic neuroblastoma (NB) is characterized by a core transcriptional regulatory circuitry (CRC) comprised of transcription factors (TFs) such as PHOX2B, HAND2 and GATA3, which form a network with MYCN. Physiological levels of MYCN mainly binds to promoters but aberrantly upregulated MYCN in NB also binds to enhancers. How MYCN invades enhancers, and what role the CRC TFs play in this process is unknown. Here we find that HAND2 assists MYCN to invade enhancers through an “indirect cooperative” TF-DNA binding mechanism. HAND2 cooperates with MYCN to compete with nucleosomes and regulate global gene transcription. The treatment of NB with an Aurora A kinase inhibitor plus HDAC inhibitor potently downregulates both MYCN and the CRC TFs and suppresses MYCN-amplified NB tumor growth. Our study identifies a “cooperative collaboration” among MYCN and CRC TFs and the simultaneous targeting these TFs is an effective way to treat this aggressive pediatric tumor.
Single-cell Ca2+parameter inference reveals how transcriptional states inform dynamic cell responses
Authors: Wu Xiaojun , Wollman Roy , MacLean Adam L.
Published: May 2022

Single-cell genomic technologies offer vast new resources with which to study cells, but their potential to inform parameter inference of cell dynamics has yet to be fully realized. Here we develop methods for Bayesian parameter inference with data that jointly measure gene expression and Ca2+dynamics in single cells. We propose to share information between cells via transfer learning: for a sequence of cells, the posterior distribution of one cell is used to inform the prior distribution of the next. In application to intracellular Ca2+signaling dynamics, we fit the parameters of a dynamical model for thousands of cells with variable single-cell responses. We show that transfer learning accelerates inference with sequences of cells regardless of how the cells are ordered. However, only by ordering cells based on their transcriptional similarity can we distinguish Ca2+dynamic profiles and associated marker genes from the posterior distributions. Inference results reveal complex and competing sources of cell heterogeneity: parameter covariation can diverge between the intracellular and intercellular contexts. Overall, we discuss the extent to which single-cell parameter inference informed by transcriptional similarity can quantify relationships between gene expression states and signaling dynamics in single cells.
Real-World Effectiveness of Casirivimab and Imdevimab Among Patients Diagnosed With COVID-19 in the Ambulatory Setting: A Retrospective Cohort Study Using a Large Claims Database
Authors: Hussein Mohamed , Wei Wenhui , Mastey Vera , Sanchez Robert J. , Wang Degang , Murdock Dana J. , Hirshberg Boaz , Weinreich David M. , Jalbert Jessica J.
Published: May 2022

Importance

Data on real-world effectiveness of casirivimab and imdevimab (CAS+IMD) for treatment of coronavirus 2019 (COVID-19) are limited, especially with regard to variants of concern such as Delta.

Objective

To assess effectiveness of CAS+IMD versus no COVID-19 antibody treatment among patients diagnosed with COVID-19 in the ambulatory setting overall and among subgroups, including patients diagnosed during the Delta-dominant period prior to Omicron emergence.

Design

Retrospective cohort study.

Setting

Komodo Health closed claims database.

Participants

Patients diagnosed with COVID-19 in ambulatory settings from December 2020 through September 2021 treated with CAS+IMD or untreated but treatment-eligible under the Emergency Use Authorization (EUA). Each treated patient was exact- and propensity score-matched without replacement to up to 5 untreated EUA-eligible patients.

Exposure

CAS+IMD treatment.

Main Outcomes and Measures

Composite endpoint of 30-day all-cause mortality or COVID-19-related hospitalization. Kaplan-Meier estimators were used to calculate risk of outcome overall and across subgroups defined by age groups, COVID-19 vaccination status, immunocompromised, and timing of COVID-19 diagnosis (December 2020 to June 2021, and July 2021 to September 2021). Cox proportional-hazards models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI).

Results

Among 75 159 patients treated with CAS+IMD and 1 670 338 EUA-eligible untreated patients, 73 759 treated patients were matched to 310 688 untreated patients; matched patients had an average age ∼50 years, approximately 60% were women and were generally well-balanced across risk factors. The 30-day risk of the composite outcome was 2.1% and 5.2% in the CAS+IMD -treated and untreated patients, respectively; CAS+IMD treatment was associated with a 60% lower risk of the outcome (aHR 0.40; 95% CI, 0.38-0.42). The effect of CAS+IMD treatment was consistent across subgroups, including those who received a COVID-19 vaccine (aHR 0.48, 95% CI, 0.41-0.56), and those diagnosed during the Delta-dominant period (aHR 0.40, 95% CI, 0.38-0.42).

Conclusions and Relevance

The real-world effectiveness of CAS+IMD is consistent with the efficacy for reducing all-cause mortality or COVID-19-related hospitalization reported in clinical trials. Effectiveness is maintained across patient subgroups, including those who may be prone to breakthrough infections, and was effective against susceptible variants including Delta.□
Metagenomics Combined with Activity-Based Proteomics Point to Gut Bacterial Enzymes that Reactivate Mycophenolate
Authors: Simpson Joshua B. , Sekela Josh J. , Graboski Amanda L. , Borlandelli Valentina B. , Barker Natalie K. , Sorgen Alicia A. , Bivins Marissa M. , Mordant Angie L. , Johnson Rebecca L. , Bhatt Aadra P. , Fodor Anthony A. , Herring Laura E. , Overkleeft Hermen , Lee John R. , Redinbo Matthew. R.
Published: May 2022

Mycophenolate Mofetil (MMF) is an important immunosuppressant prodrug prescribed to prevent organ transplant rejection and to treat autoimmune diseases. MMF usage, however, is limited by severe gastrointestinal toxicity that is observed in approximately 45% of MMF recipients. The active form of the drug, mycophenolic acid (MPA), undergoes extensive enterohepatic recirculation by bacterial β-glucuronidase (GUS) enzymes, which reactivate MPA from mycophenolate glucuronide (MPAG) within the gastrointestinal tract. GUS enzymes demonstrate distinct substrate preferences based on their structural features, and gut microbial GUS enzymes that reactivate MPA have not been identified. Here, we compare the fecal microbiomes of transplant recipients receiving MMF to healthy individuals using shotgun metagenomic sequencing. We find that neither microbial composition nor the presence of specific structural classes of GUS genes are sufficient to explain the differences in MPA reactivation measured between fecal samples from the two cohorts. We next employed a GUS-specific activity-based chemical probe and targeted metaproteomics to identify and quantify the GUS proteins present in the human fecal samples. The identification of specific GUS enzymes was improved by using the metagenomics data collected from the fecal samples. We found that the presence of GUS enzymes that bind the flavin mononucleotide (FMN) is significantly correlated with efficient MPA reactivation. Furthermore, structural analysis identified motifs unique to these FMN-binding GUS enzymes that provide molecular support for their ability to process this drug glucuronide. These results indicate that FMN-binding GUS enzymes may be responsible for reactivation of MPA and could be a driving force behind MPA-induced GI toxicity.
GWAS of preeclampsia and hypertensive disorders of pregnancy uncovers genes related to cardiometabolic, endothelial and placental function
Authors: Tyrmi Jaakko S. , Kaartokallio Tea , Lokki Inkeri , Jääskeläinen Tiina , Kortelainen Eija , Ruotsalainen Sanni , Karjalainen Juha , Ripatti Samuli ,   FINNPEC Study Group,   FinnGen,   Estonian Biobank Research Team, Laisk Triin , Kettunen Johannes , Pouta Anneli , Kivinen Katja , Kajantie Eero , Heinonen Seppo , Kere Juha , Laivuori Hannele
Published: May 2022

Preeclampsia is a vascular pregnancy disorder that affects 3-5% of all pregnancies. Genetic contribution to preeclampsia susceptibility is well established, but the actual risk loci have remained largely unknown. To make further discoveries of the underlying genetic architecture, we performed a new genome-wide association study (GWAS) for maternal preeclampsia and for two other combination phenotypes encompassing maternal preeclampsia and other types of gestational hypertension disorders. We combined the data resources of the Finnish pre-eclampsia cohort ‘FINNPEC’, the Finnish FinnGen project and the Estonian Biobank to obtain cases for the three abovementioned phenotypes. In addition, we performed meta-analyses of the preeclampsia phenotype combining results with the previous largest GWAS results. The controls for each phenotype comprised all parous women in the cohorts not diagnosed with these conditions. In total, we found 18 genome-wide significant associations, of which 12 have not been associated with preeclampsia in any previous maternal GWAS for maternal preeclampsia. Seven of the novel loci were near genes previously associated with blood pressure traits – supporting the concept of pregnancy as a window to future cardiovascular health. The genetic susceptibility to cardiovascular disease may manifest for the first time during pregnancy. Alterations in the integrity of the endothelium or specifically in the glomerular filtration barrier may modify disease susceptibility. Interesting novel associations are in proximity of genes involved in the development of placenta, remodeling of uterine spiral arteries and maintenance of proteostasis in pregnancy serum. Overall, the novel associated genes shed more light on the pathophysiology of preeclampsia.
Decoding Depression Severity from Intracranial Neural Activity
Authors: Xiao Jiayang , Provenza Nicole R. , Asfouri Joseph , Myers John , Mathura Raissa K. , Metzger Brian , Adkinson Joshua A. , Allawala Anusha B. , Pirtle Victoria , Oswalt Denise , Shofty Ben , Robinson Meghan E. , Mathew Sanjay J. , Goodman Wayne K. , Pouratian Nader , Schrater Paul R. , Patel Ankit B. , Tolias Andreas S. , Bijanki Kelly R. , Pitkow Xaq , Sheth Sameer A.
Published: May 2022

Disorders of mood and cognition are prevalent, disabling, and notoriously difficult to treat. Fueling this challenge in treatment is a significant gap in our understanding of their neurophysiological basis. Here, we used intracranial neural recordings in three patients with severe depression to investigate the neural substrates of this disorder. Across prefrontal regions, we found that reduced depression severity is associated with decreased low-frequency neural activity and increased high-frequency activity. When constraining our model to decode using a single region, spectral changes in the anterior cingulate cortex best predicted depression severity in all three subjects. Relaxing this constraint revealed unique, individual-specific sets of spatio-spectral features predictive of symptom severity, reflecting the heterogeneous nature of depression. The ability to decode depression severity from neural activity increases our fundamental understanding of how depression manifests in the human brain and provides a target neural signature for personalized neuromodulation therapies.
Perturbation of the Gut Microbiome and Association with Outcomes Following Autologous Stem Cell Transplantation in Patients with Multiple Myeloma
Authors: D’Angelo Christopher , Sudakaran Sailendharan , Asimakopoulos Fotis , Hematti Peiman , El-Gamal Dalia , Safdar Nasia , Callander Natalie
Published: May 2022

The gut microbiome is an important feature of host immunity with associations to hematologic malignancies and cellular therapy. We evaluated the gut microbiome and dietary intake in patients with multiple myeloma undergoing autologous stem cell transplantation. Thirty patients were enrolled and samples were collected at 4 timepoints: pre-transplant, engraftment, day +100 (D+100), and 9-12 months post-transplant. Microbiome analysis demonstrated a loss of alpha diversity at the engraftment timepoint driven by decreases in Blautia, Ruminococcus, and Faecalibacterium genera and related to intravenous antibiotic exposure. Higher fiber intake was associated with increased relative abundance of Blautia at the pre-transplant timepoint. Lower alpha diversity at engraftment was associated with a partial response to therapy compared to complete response (CR) or very good partial response (VGPR) (CR/VGPR vs. PR, p <0.05). We conclude that loss of bacterial diversity at engraftment may be associated with impaired response to stem cell transplantation in multiple myeloma.
Barriers to help-seeking for Malaysian women with symptoms of breast cancer: a mixed-methods, two-step cluster analysis
Authors: Rajaram Nadia , Jaganathan Maheswari , Muniandy Kavitha , Rajoo Yamuna , Zainal Hani , Rahim Norlia , Tajudeen Nurul Ain , Zainal Nur Hidayati , Khairy Azuddin Mohd , Abdul Wahab Mohamed Yusof , Teo Soo Hwang
Published: May 2022

Objectives

Improving help-seeking behaviour is a key component of down-staging breast cancer and improving survival, but the specific challenges faced by low-income women in an Asian setting remain poorly characterized. Here, we determined the extent of help-seeking delay among Malaysian breast cancer patients and explored sub-groups of women who may face specific barriers.

Methods

Time to help-seeking was assessed in 303 women diagnosed with advanced breast cancer between January 2015 and March 2020 at a suburban tertiary hospital in Malaysia. Two-step cluster analysis was conducted to identify subgroups of women who share similar characteristics and barriers. Barriers to help-seeking were identified from nurse interviews and were analyzed using behavioural frameworks.

Results

The average time to help-seeking was 65 days (IQR = 250 days), and up to 44.5% of women delayed by at least 3 months. Three equal-sized clusters emerged with good separation by time to help-seeking (p<0.001). The most reported barrier across clusters was poor knowledge (36.3%), regardless of help-seeking behaviour (p=0.931). Unexpectedly, women with no delay (9 days average) and great delay (259 days average) were more similar to each other than to women with mild delays (58 days average). In contrast, women who experienced great delay reported poor motivation (p=0.066) and social opportunities (p=0.374) to seek help.

Conclusions

Down-staging of breast cancer in Malaysia will require a multi-pronged approach aimed at alleviating culturally specific social and emotional barriers, eliminating misinformation, and instilling motivation to seek help for breast health for the women most vulnerable to help-seeking delays.
Evaluation of the ID NOW Among Symptomatic Individuals During the Omicron Wave
Authors: Stokes William , Venner Allison A. , Buss Emily , Tipples Graham , Berenger Byron M.
Published: May 2022

BACKGROUND

Point of Care SARS-CoV-2 devices, such as the Abbott ID NOW have great potential, to help combat the COVID-19 pandemic. Starting in December, 2020, the ID NOW was implemented throughout the province of Alberta, Canada (population 4.4 million) in various settings. We aimed to assess the ID NOW performance during the BA.1 Omicron wave and compare it to previous waves.

METHODS

The ID NOW was assessed in two distinct locations among symptomatic individuals: acute care (emergency room, urgent care, and hospitalized patients) and community assessment centres (AC) during the period January 5 – 18, 2022. Starting January 5, Omicron represented >95% of variants detected in our population. For every individual tested, two swabs were collected: one for ID NOW testing and the other for either reverse-transcriptase polymerase chain reaction (RT-PCR) confirmation of negative ID NOW results or for variant testing of positive ID NOW results.

RESULTS

A total of 3,041 paired samples were analyzed (1,139 RT-PCR positive). 1,873 samples were from 42 COVID-19 AC and 1,168 from 69 rural hospitals. ID NOW sensitivity for symptomatic individuals presenting to community AC and patients in hospital was 96.0% [95% confidence interval (CI) 94.5-97.3%, n=830 RT-PCR positive], and 91.6% (95% CI 87.9-94.4%, n=309 RT-PCR positive), respectively. SARS-CoV 2 positivity rate was very high for both populations (44.3% at AC, 26.5% in hospital).

CONCLUSIONS

Sensitivity of ID NOW SARS-CoV-2, compared to RT-PCR, is very high during the BA.1 Omicron wave, and is significantly higher when compared to previous SARS-CoV-2 variant waves.
Medication Safety Incidents Associated with the Remote Delivery of Primary Care: A Rapid Review
Authors: Gleeson Laura L , Clyne Barbara , Barlow James W. , Ryan Benedict , Murphy Paul , Wallace Emma , De Brún Aoife , Mellon Lisa , Hanratty Marcus , Ennis Mark , Holton Alice , Pate Muriel , Kirke Ciara , Flood Michelle , Moriarty Frank
Published: May 2022

Background

The COVID-19 pandemic triggered rapid, fundamental changes in how healthcare is delivered in communities, notably increased remote delivery of primary care. While the impact of these changes on medication safety are not yet fully understood, research conducted before the pandemic may provide evidence for possible consequences. This rapid review examines the published literature on medication safety incidents associated with the remote delivery of primary care.

Objective(s)

To examine the published literature on medication safety incidents associated with the remote delivery of primary care, with a focus on telemedicine and electronic prescribing.

Methods

A rapid review was conducted according to the Cochrane Rapid Reviews Methods Group guidance. An electronic search was carried out on Embase and Medline (via PubMed) using key search terms “medication error”, “electronic prescribing”, “telemedicine” and “primary care”. Identified studies were synthesised narratively; reported medication safety incidents were categorised according to the WHO Conceptual Framework for the International Classification for Patient Safety.

Results

Fifteen studies were deemed eligible for inclusion in this review. All fifteen studies reported medication incidents associated with electronic prescribing; no studies were identified that reported medication safety incidents associated with telemedicine. The most commonly reported medication safety incidents were ‘wrong label/instruction’ and ‘wrong dose/strength/frequency’. The frequency of medication safety incidents ranged from 0.89 to 81.98 incidents per 100 electronic prescriptions analysed.

Conclusions

To our knowledge, this is the first review to examine the literature on medication safety incidents associated with the remote delivery of primary care. Common incident types associated with electronic prescriptions were identified. There was wide variation in reported frequencies of medication safety incidents associated with electronic prescriptions. A gap in the literature was identified regarding medication safety incidents associated with telemedicine. Further research is required to determine the impact of the COVID-19 pandemic on medication safety in primary care.
Goat kid recognition of their mothers’ calls is not impacted by changes in source-filter parameters
Authors: Perroux Tania , McElligott Alan G. , Briefer Elodie F.
Published: May 2022

Features varying more between than within individuals are usually considered as potential cues for individual recognition. According to the source-filter theory of vocal production, the fundamental frequency of mammal’s vocalisations depends on the characteristics of the vocal folds, while formants are determined by the characteristics of the vocal tract. Goat mothers and their kids (Capra hircus) display mutual recognition, and both source-related parameters (F0) and filter-related ones (formants) have been shown to be individualised in their vocalisations. Here, we aimed to identify if these parameters (source-related parameters (F0) and/or filter vocal parameters) are used by goat kids to recognise their mother’s vocalisations. To this aim, we used an algorithm to modify either F0 or formants of the calls of goat mothers to different degrees (within or exceeding the range of natural intra-individual variability), and we played back these modified calls to their kids. We did not observe any difference in the kid reactions to the modified maternal vocalisations and to the natural calls. We suggest that either: (i) fundamental frequency and formants are not involved in maternal recognition in goats; (ii) goat kids have a tolerance for variation when recognising their mother’s calls that exceeds the shifts we performed; (iii) goat maternal recognition is based on other vocal features than those tested here, or (iv) goat kid maternal recognition is based on a combination of different features and might be more flexible than previously thought, such that when one main feature is modified, kids focus on other features.