bluuebunny/crossref_metadata_2025 huggingface dataset:
Variability in Medicaid Coverage for Gender-affirming Surgeries Across U.S. States
Authors: Wu Catherine A. , Ho Isabella , Minasian Alexandra , Keuroghlian Alex S. , O’Brien-Coon Devin , Ranganathan Kavitha
Published: July 2023

Objective:

We sought to describe the current Medicaid coverage landscape for gender-affirming surgery across the U.S. at the procedure level and identify factors associated with coverage.

Summary Background Data:

Medicaid coverage for gender-affirming surgery differs by state, despite a federal ban on gender identity-based discrimination in health insurance. States that cover gender-affirming surgery also differ in which procedures are included in Medicaid coverage, leading to confusion among patients and clinicians.

Methods:

State Medicaid policies in 2021 for gender-affirming surgery were queried for each of the 50 states, and District of Columbia (D.C.). State partisanship, state-level Medicaid protections, and coverage of gender-affirming procedures in 2021 were recorded. Linear correlation between electorate partisanship and total procedures covered was assessed. Pairwise t-tests were used to compare coverage based on state partisanship and presence of absence of state-level Medicaid protections.

Results:

Medicaid coverage for gender-affirming surgery was covered in 30 states and Washington D.C. The most commonly covered procedures were genital surgeries and mastectomy (n=31), followed by breast augmentation (n=21), facial feminization (n=12), and voice modification surgery (n=4). More procedures were covered in Democrat-controlled or leaning states, as well as in states with explicit protections for gender-affirming care in Medicaid coverage.

Conclusion:

Medicaid coverage for gender-affirming surgery is patchwork across the United States and is especially poor for facial and voice surgeries. Our study provides a convenient reference for patients and surgeons detailing which gender-affirming surgical procedures are covered by Medicaid within each state.
Dispersing attentional resources reduces negative emotions
Authors: Izaki Tsubasa , Ogawa Keiko
Published: July 2023

Research shows that human attentional focus expands under positive emotions and narrows under negative emotions. Moreover, expanding (or contracting) the attentional focus is associated with dispersing (or concentrating) attentional resources. This study investigated whether dispersing or concentrating attentional resources on a target stimulus can change negative emotions to positive ones. We used the flanker task to manipulate the attentional resource allocation range by displaying a peripheral, task-unrelated induction stimulus far from the target stimulus or a central, task-unrelated induction stimulus near the target stimulus. The attentional resources allocated to the target stimulus were measured by recording the P300 component, an event-related potential indicating attention allocation. We also presented negative images before and after the task and used the Self-Assessment Manikin and the Affect Grid to assess the negative emotions induced by the images. The P300 amplitudes for the target stimuli were smaller in the peripheral than in the central condition. Moreover, self-reported negative emotions in the peripheral condition decreased after the task but did not change in the central condition. The dispersion of attentional resources changes negative emotions into a positive orientation.
Stroke, depression, and self-harm in later life
Authors: Almeida Osvaldo P.
Published: July 2023

Purpose of the review

To examine recently published results of randomized placebo-controlled trials investigating the clinical effects of selective serotonin reuptake inhibitors on the prevalence of clinically significant symptoms of depression and suicidal ideation after an acute stroke.

Recent findings

The prevalence of poststroke depression varies markedly according to the approach used to define depression, with recently published data suggesting that about one in every three stroke survivors will experience clinically significant symptoms of depression over a period of 12 months. The proportion of stroke survivors with clinically significant symptoms of depression decreases progressively with time, but in 30% of them symptoms persist or recur over 12 months. Routine daily treatment with 20 mg of fluoxetine for 6 months does not affect the prevalence of depression in this population, nor is it effective at treating or preventing poststroke depressive symptoms. Treatment discontinuation, gastrointestinal adverse effects, seizures and bone fractures are more frequent among stroke survivors treated with antidepressants than placebo. Moreover, current data show that thoughts about death or suicide are more frequent among adults who had a stroke than the general population, although recurring suicidal thoughts are uncommon. Routine daily treatment with 20 mg of fluoxetine for 6 months does not change the proportion of people who disclose suicidal thoughts over a period of 12 months after an acute stroke.

Current evidence raises concerns about the efficacy and safety of antidepressants for the management and prevention of poststroke clinically significant symptoms of depression. It is unclear if these findings can be generalized to people with severe strokes or to stroke survivors with moderate to severe major depressive episodes.
High subtelomeric GC content in the genome of a zoonotic Cryptosporidium species
Authors: Li Jiayu , Li Na , Roellig Dawn M. , Zhao Wentao , Guo Yaqiong , Feng Yaoyu , Xiao Lihua
Published: July 2023

Cryptosporidium canis is a zoonotic species causing cryptosporidiosis in humans in addition to its natural hosts dogs and other fur animals. To understand the genetic basis for host adaptation, we sequenced the genomes of C. canis from dogs, minks, and foxes and conducted a comparative genomics analysis. While the genomes of C. canis have similar gene contents and organisations, they (~41.0 %) and C. felis (39.6 %) have GC content much higher than other Cryptosporidium spp. (24.3–32.9 %) sequenced to date. The high GC content is mostly restricted to subtelomeric regions of the eight chromosomes. Most of these GC-balanced genes encode Cryptosporidium-specific proteins that have intrinsically disordered regions and are involved in host-parasite interactions. Natural selection appears to play a more important role in the evolution of codon usage in GC-balanced C. canis, and most of the GC-balanced genes have undergone positive selection. While the identity in whole genome sequences between the mink- and dog-derived isolates is 99.9 % (9365 SNVs), it is only 96.0 % (362 894 SNVs) between them and the fox-derived isolate. In agreement with this, the fox-derived isolate possesses more subtelomeric genes encoding invasion-related protein families. Therefore, the change in subtelomeric GC content appears to be responsible for the more GC-balanced C. canis genomes, and the fox-derived isolate could represent a new Cryptosporidium species.
Fibroblast growth factor-21 induces skeletal muscle atrophy and increases plasma amino acids in female mice: a potential role for glucocorticoids
Authors: Larson Karlton R. , Jayakrishnan Devi , Soto Sauza Karla A. , Goodson Michael L. , Chaffin Aki T. , Davidyan Arik , Pathak Suraj , Fang Yanbin , Magaña Diego Gonzalez , Miller Benjamin F. , Ryan Karen K.
Published: July 2023

Background

Fibroblast growth factor-21 (FGF21) is an intercellular signaling molecule secreted by metabolic organs, including skeletal muscle, in response to intracellular stress. FGF21 crosses the blood brain barrier and acts via the nervous system to coordinate aspects of the adaptive starvation response, including increased lipolysis, gluconeogenesis, hepatic fatty acid oxidation, and activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Given its beneficial effects for hepatic lipid metabolism, pharmaceutical FGF21 analogues are in clinical trials treatment of fatty liver disease. We predicted pharmacologic treatment with FGF21 in-creases HPA axis activity and skeletal muscle glucocorticoid signaling and induces skeletal muscle atrophy in mice.

Methods

We treated male and female mice with FGF21 or saline, delivered either pe-ripherally or directly to the brain, to determine its effect on skeletal muscle. To identify metabolic pathways affected by FGF21, we analyzed untargeted primary metabolites measured in plasma by GCTOF-MS. To determine mechanisms underlying sex-and FGF21-dependent changes in muscle mass, we measured hormonal and molecular mediators of muscle protein synthesis and degradation. We performed stable isotope labeling with deuterium oxide to directly measure muscle protein synthesis.

Results

A short course of systemic FGF21 treatment decreased muscle protein synthe-sis (P< 0.001) and reduced tibialis anterior weight (P< 0.05); this was driven primarily by its effect in female mice (P< 0.05). Similarly, intracerebroventricular FGF21 reduced TA muscle fiber cross sectional area (P< 0.01); this was more apparent among female mice compared to male littermates (P< 0.05). In agreement with the reduced muscle mass, the topmost enriched meta-bolic pathways in FGF21-treated females were related to amino acid metabolism, and the relative abundance of plasma proteinogenic amino acids were increased up to three-fold (P< 0.05). FGF21 treatment increased hypothalamicCrhmRNA (P< 0.01), plasma corticosterone (P< 0.01), and adrenal weight (P< 0.05), and increased expression of glucocorticoid receptor target genes known to reduce muscle protein synthesis and/or promote degradation includingFoxo1,Redd1, andKlf15(P < 0.05). Again, these changes were driven primarily by effects of FGF21 in females (P< 0.05).

Conclusions

FGF21 increased plasma amino acids and decreased skeletal muscle mass, together with activation of the HPA axis and glucocorticoid receptor target genes in skeletal muscle—and female mice were more sensitive to all these outcomes. Given the proposed use of FGF21 analogues for the treatment of metabolic disease, the study is both physiologically relevant and may have important clinical implications.
Research Design Protocol: Assessing the Impact of Using ChatGPT in Radiology Reporting in an Emergency Setting in Egypt
Authors: Hamouda Noha , Ibrahim Mohamed K. , Jabal Mohamed Sobhi
Published: July 2023

This research design protocol outlines a study conducted in Egypt as an example of a developing country with limited resources. The objective is to assess the impact of using ChatGPT, a language model, in radiology reporting in the context of an emergency setting where reporting is traditionally done manually. The study aims to evaluate the effectiveness of ChatGPT in helping format structured reports, drawing impressions from the reports, and improving the efficiency of communication between radiologists and treating clinicians. A standardized survey will be utilized to compare the differences between the older subjective reporting format and ChatGPT-assisted reports.
AI-based analysis of the shunt treatment in pre- and post-surgery computed tomography brain scans of iNPH patients
Authors: Shailja S. , Nguyen Christopher , Thanigaivelan Krithika , Bhagavatula Vikram , Chen Jefferson W. , Manjunath B. S.
Published: July 2023

Background

This study examines whether quantifiable changes can be detected in ventricular volume in Idiopathic Normal Pressure Hydrocephalus (iNPH) patients that undergo ventriculo-peritoneal shunt procedures. There is no known metric that characterizes the change in ventricular volume for iNPH patients after shunt placement.

Methods

Two de-identified and independent datasets are studied:

45 brain CT scans (24 diagnosed with iNPH and 21 normal elderly individuals) are used to evaluate the effectiveness of our proposed ventricular volume metric as a diagnostic tool for iNPH. The performance of our deep learning model-based metric is compared to the traditional Evan’s Index using ROC analysis.

16 subjects with a total of 50 longitudinal CT scans taken before and after shunt surgery across different imaging centers are studied to quantify the impact of shunt treatment. Clinical symptoms of gait, balance, cognition, and bladder continence are studied with respect to the proposed metric.

Results

Our proposed metric achieves high accuracy (0.95), precision (0.96), and recall (0.96) in distinguishing between normal and iNPH subjects, surpassing the performance of the Evan’s Index. This metric allows us to track changes in ventricular volume before and after shunt surgery for 16 subjects. Notably, the 15 subjects with iNPH demonstrate a decrease in ventricular volume post-surgery and a concurrent clinical improvement in their iNPH symptomatology.

Conclusion

Our novel metric accurately quantifies changes in ventricular volume before and after shunt surgery for iNPH patients, serving as an effective radiographic marker for a functioning shunt in a patient with iNPH.

What is already known on this topic – The diagnosis of iNPH involves both clinical and radiographic stigmata. Radiologists rely largely on visual examination of CT scans and provide qualitative evaluations about ventricular volume.

What this study adds – Our study provides quantitative information about the patency and function of the shunt.

How this study might affect research, practice, or policy – The validated deep learning-based metric enhances iNPH diagnosis accuracy by tracking radiographic biomarkers. This facilitates decision-making regarding the efficacy of shunt surgery and the effect on brain compliance. We provide a web interface to apply the metric, its reliable performance across multiple institutional scanner types could be adapted to the real-time clinical evaluation of iNPH and improve treatment workflows.
Personalized connectivity-based network targeting model of TMS for treatment of psychiatric disorders: computational feasibility and reproducibility
Authors: Cao Zhengcao , Xiao Xiang , Xie Cong , Wei Lijiang , Yang Yihong , Zhu Chaozhe
Published: July 2023

Consider the limited clinical efficacy of transcranial magnetic stimulation (TMS) due to heterogeneity in treatment outcomes, the utilization of individual functional connectivity (FC) can enhance the prediction accuracy in the network targeting model. However, the low signal-to-noise ratio (SNR) of FC poses a challenge when utilizing individual resting-state FC (rsFC). To overcome this challenge, proposed solutions include increasing the scan duration and employing clustering approaches to enhance the stability of FC. In this study, we aimed to evaluate the stability of a personalized functional-based network targeting model in individuals with major depressive disorder (MDD) and schizophrenia with auditory verbal hallucinations (AVH). Using resting-state functional magnetic resonance imaging (rsfMRI) data from the Human Connectome Project (HCP), we assessed the model’s stability and employed longer scan durations (7 minutes, 14 minutes, 21 minutes, 28 minutes) and clustering methodologies to improve the precision of identifying optimal individual sites. Our findings demonstrate that a scan duration of 28 minutes and the utilization of the clustering approach lead to stable identification of individual sites, as evidenced by the intraindividual distance falling below the ∼1cm spatial resolution of TMS. These findings contribute to the understanding of individualized TMS targeting and have implications for improving treatment outcomes in psychiatric disorders.
Method to quickly map multifocal Pupillary Response Fields (mPRF) using Frequency Tagging
Authors: Lorenceau Jean
Published: July 2023

We present a method for mapping multifocal Pupillary Response Fields in a short amount of time, using a visual stimulus covering 40° of visual angle, divided in 9 contiguous sectors, simultaneously modulated in luminance at specific, incommensurate, temporal frequencies. We tested this multiple Pupillary Frequency Tagging (mPFT) approach with young healthy participants (N=36), and show that the spectral power of the sustained pupillary response elicited by 45 seconds of fixation of this multipartite stimulus reflects the relative contribution of each sector/frequency to the overall pupillary response. We further analyze the phase lag for each temporal frequency as well as several global features related to pupil state. Test retest performed on a subset of participants indicates good repeatability. We also investigate the existence of structural (RNFL)/functional (mPFT) relationships. We then summarize results of clinical studies conducted with mPFT on patients with neuropathies and retinopathies and show that the features derived from pupillary signal analyzes, the distribution of spectral power in particular, allows sorting patients from healthy participants with excellent sensitivity and specificity. This method thus appears a convenient, objective and fast tool for assessing the integrity of retino-pupillary circuits, as well as idiosyncrasies, that permits to objectively detect or follow-up retinopathies or neuropathies in a short amount of time.
Decoding object categories from EEG during free viewing reveals early information evolution compared to passive viewing
Authors: Carmel R. Auerbach-Asch , Gal Vishne , Oded Wertheimer , Leon Y. Deouell
Published: July 2023

Object processing is fundamental to visual perception, and understanding its neural substrates informs many cognitive and computational visual processing models. Thus far, most human studies have used passive viewing paradigms, during which self-driven behavior, such as eye movements, is constrained, and brain activity is evoked by abrupt stimuli onsets. This artificial dissociation of perception and action ignores the natural dynamics of visual processing. Thus, conclusions based on such passive viewing paradigms may not apply to active vision. Here, we study the human neural correlates of category representations during active visual processing by time-locking EEG to self-driven fixations during visual search for natural objects. We combine the deconvolution of overlapping responses to consecutive fixations with multivariate pattern analysis (MVPA) to decode object categories from responses to single fixation. We bridge the active and passive viewing literature by comparing the temporal dynamics of multivariate object representations during free visual search (active viewing) and rapid serial visual presentation (passive viewing), leveraging the high temporal resolution of EEG. We found that categorical information, at different levels of abstraction, can be decoded from single fixations during natural visual processing, and cross-condition decoding revealed that object representations are similar between active and passive viewing conditions. However, representational dynamics emerge significantly earlier in active compared to passive conditions, likely due to the availability of predictive information in free viewing. We highlight methodological considerations for combining MVPA with deconvolution methods.

Significance Statement

Understanding the neural correlates of visual perception is crucial for advancing cognitive and computational models of human vision. This study bridges the gap between passive- and active-vision literature while shedding light on the intricate relationship between perception and action in visual processing. Although eye movements are a fundamental behavior through which visual information is naturally sampled, most neuroimaging studies probe the brain by presenting stimuli abruptly at the center of the screen while participants refrain from moving their eyes. We investigated EEG correlates of visual processing during active visual search and demonstrated that object categories of naturally fixated objects can be decoded from the EEG. We provide novel findings regarding the dynamics of active, compared to passive, visual processing, while contributing to the advancement of EEG analysis methodology.
Reducing tinnitus via inhibitory influence of the sensorimotor system on auditory cortical activity
Authors: Schmitt Anne , Kim Cora , Rampp Stefan , Bergherr Elisabeth , Buchfelder Michael , Schnell Oliver , Müller-Voggel Nadia
Published: July 2023

Tinnitus is the subjective perception of a sound in absence of corresponding external acoustic stimuli. Research highlights the influence of the sensorimotor system on tinnitus perception. Associated neuronal processes, however, are insufficiently understood and it remains unclear how and at which hierarchical level the sensorimotor system interacts with the tinnitus-processing auditory system. We therefore asked 23 patients suffering from chronic tinnitus (11 males) to perform specific exercises, aimed at relaxing or tensing the jaw area, which temporarily modulated tinnitus perception. Associated neuronal processes were assessed using Magnetencephalography. Results show that chronic tinnitus patients experienced their tinnitus as weaker and less annoying after completion of relaxing compared to tensing exercises. Furthermore, (1) sensorimotor alpha power and alpha-band connectivity directed from the somatosensory to the auditory cortex increased, and (2) gamma power in the auditory cortex, reduced, which (3) related to reduced tinnitus annoyance perception on a trial-by-trial basis in the relaxed state. No effects were revealed for 23 control participants without tinnitus (6 males) performing the same experiment. We conclude that the increase in directed alpha-band connectivity from somatosensory to auditory cortex is most likely reflecting the transmission of inhibition from somatosensory to auditory cortex during relaxation, where concurrently tinnitus-related gamma power reduces. We suggest that revealed neuronal processes are transferable to other tinnitus modulating systems beyond the sensorimotor one that are e.g. involved in attentional or emotional tinnitus modulation and provide deeper mechanistic insights into how and through which channels phantom sound perception might be modulated on a neuronal level.

Significance Statement

Tinnitus describes the perception of auditory phantom sounds. Research suggests that the sensorimotor system impacts on tinnitus perception, associated neuronal mechanisms, however, have remained unclear. Here, chronic tinnitus patients performed exercises with the jaw temporarily reducing (versus increasing) tinnitus perception. Tinnitus reduction was accompanied by an increase of alpha-band connectivity directed from the somatosensory to the auditory cortex and gamma power reduction in the auditory cortex. We suggest that the increase in alpha-band connectivity, when tinnitus is reduced, reflects the transmission of inhibition from somatosensory to auditory cortex, where, in parallel, probably tinnitus related, gamma power reduces. The findings have important implications both for the understanding of phantom sound perception and, more generally, of top-down modulation in healthy and impaired cognition.
Age-dependent decrease in inhibitory drive on the excitatory superficial spinal dorsal horn neurons
Authors: Rayi Prudhvi Raj , Lev Shaya , Binshtok Alexander M
Published: July 2023

The excitatory and inhibitory interneurons of superficial laminae I-II of the spinal dorsal horn (SDH) receive and process pain-related information from the primary afferents and transmit it to the brain via the projection neurons. Thus, the interaction between excitatory and inhibitory SDH interneurons is crucial in determining the output from the spinal cord network. Disruption of this interaction in pathological conditions leads to increased SDH output to the higher brain centers, which could underlie pathological pain. Here, we examined whether the changes in the intrinsic SDH connectivity also occur with age, possibly underlying age-related increase in pain sensitivity. UsingVgat;tdTomatotransgenic mouse line, we compared the spontaneous inhibitory postsynaptic currents (sIPSCs) in inhibitory tdTomato+and excitatory tdTomato−interneurons between adult (3-5 m.o.) and aged (12-13 m.o.) mice. We demonstrate that in adult mice, the amplitude and frequency of the sIPSCs in the excitatory interneurons were significantly higher than in inhibitory interneurons. These differences were annulled in aged mice. Further, we show that in aged mice, excitatory neurons receive less inhibition than in adult mice. This could lead to overall disinhibition of the SDH network, which might underlie increased pain perception among the aged population.
Fundamental Sex Differences in Cocaine-Induced Plasticity of D1- and D2-MSNs in the Mouse Nucleus Accumbens Shell
Authors: Chapp Andrew D. , Nwakama Chinonso A. , Jagtap Pramit P. , Phan Chau-Mi H. , Thomas Mark J. , Mermelstein Paul G.
Published: July 2023

Cocaine-induced plasticity in the nucleus accumbens shell of males occurs primarily in D1 dopamine receptor expressing neurons (D1-MSNs), with little if any impact on D2 dopamine receptor neurons (D2-MSNs). Usingex vivowhole cell recordings in male and female mice, we observe alterations in D1-MSN excitability across the estrous cycle similar in magnitude to the actions of cocaine in males. Furthermore, cocaine shifts estrous cycle-dependent plasticity from intrinsic excitability changes in D1-MSNs to D2-MSNs. Overall, while there are similar cocaine-induced disparities regarding the relative excitability of D1-MSN versus D2-MSN between the sexes, in males this is mediated through reduced D1-MSN excitability, whereas in females it is due to heightened D2-MSN excitability.
Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank
Authors: Lassen Frederik H. , Venkatesh Samvida S. , Baya Nikolas , Zhou Wei , Bloemendal Alex , Neale Benjamin M. , Kessler Benedikt M. , Whiffin Nicola , Lindgren Cecilia M. , Palmer Duncan S.
Published: July 2023

Exome-sequencing association studies have successfully linked rare protein-coding variation to risk of thousands of diseases. However, the relationship between rare deleterious compound heterozygous (CH) variation and their phenotypic impact has not been fully investigated. Here, we leverage advances in statistical phasing to accurately phase rare variants (MAF ∼ 0.001%) in exome sequencing data from 175,587 UK Biobank (UKBB) participants, which we then systematically annotate to identify putatively deleterious CH coding variation. We show that 6.5% of individuals carry such damaging variants in the CH state, with 90% of variants occurring at MAF < 0.34%. Using a logistic mixed model framework, systematically accounting for relatedness, polygenic risk, nearby common variants, and rare variant burden, we investigate recessive effects in common complex diseases. We find six exome-wide significant (𝑃 < 1.68 × 10−7) and 17 nominally significant (𝑃 < 5.25 × 10−5) gene-trait associations. Among these, only four would have been identified without accounting for CH variation in the gene. We further incorporate age-at-diagnosis information from primary care electronic health records, to show that genetic phase influences lifetime risk of disease across 20 gene-trait combinations (FDR < 5%). Using a permutation approach, we find evidence for genetic phase contributing to disease susceptibility for a collection of gene-trait pairs, includingFLG-asthma (𝑃 = 0.00205) andUSH2A-visual impairment (𝑃 = 0.0084). Taken together, we demonstrate the utility of phasing large-scale genetic sequencing cohorts for robust identification of the phenome-wide consequences of compound heterozygosity.
Unraveling the Decline: Search for Factors Behind the Trend in Parkinson’s Disease Incidence Rates – A Cohort Study of German Health Claims Data
Authors: Anne Fink , Pavlou Maria Angeliki S. , Kirsten Roomp , Gabriele Doblhammer , Schneider Jochen G.
Published: July 2023

Importance

Sporadic Parkinson’s disease (PD) is the second most common neurodegenerative disease in older age. Recent studies have led to a debate regarding trends in incidence and prevalence.

Objective

We aimed to investigate age-specific incidence rates of PD and possible explanations for the observed trend in Germany.

Design

We studied two randomly selected longitudinal cohorts, each consisting of 250,000 individuals aged 50 and above.

Setting

We started observing them at the beginning of 2004 and 2014, and followed them through the end of 2009 and 2019, respectively. We compared age-specific incidence rates for both cohorts and performed Cox regression models to calculate the hazard ratios (HR) of PD in the second period compared with the first period ten years earlier, adjusted for age, sex, and several prodromal factors, comorbidities, and risk factors of PD.

Main outcome and Measures

Main outcome was the age-specific incidence trends of Parkinson’s disease (PD) in two cohorts using routine health claims data

Results

For each age-group in men and women, we found lower age-specific PD incidence rates in the second period, except for the lowest age-group (50-54) in men. Cox regression analysis demonstrated an overall 20% risk reduction of PD incidence (HR=0.80, 95% confidence interval [0.75-0.86]). Mean age at diagnosis increased in men (+1.98 years) and women (+0,87 years). Stepwise adjustment for prodromal symptoms, comorbidities, and risk factors revealed a 22%-49% risk reduction of PD incidence. Sensitivity analysis considering the competing event of death showed a 48% risk reduction (HR=0.52 [0.48-0.56]), demonstrating the independence of the time trends from changes in death rates.

Conclusion

Our data show that the risk of PD has decreased over time, and that this decrease is independent of factors such as changes in death rates, age structure, sex, motor and sensory impairments, sleep and psychiatric conditions, comorbidities, and specific risk factors.

Key points

Question

While several studies have reported on the incidence and prevalence of PD, recent data from Germany have sparked a debate regarding the validity and interpretation of these trends. This study aims to investigate the age-specific incidence rates of Parkinson’s Disease (PD) and explore possible explanations for the observed reduced trend in Germany.

Findings

We assessed data from a longitudinal cohort from 2004 to 2009 and 2014 to 2019, respectively. By comparing age-specific incidence rates between the two cohorts we reveal a consistent reduction in the age-specific incidence rates of PD in the second period compared to the first period, except for the lowest age-group (50-54)

Meaning

While several studies have reported on the incidence and prevalence of PD, we identified intriguing trends that warrant further investigation.
Comparison of ChatGPT vs. Bard to Anesthesia-related Queries
Authors: Patnaik Sourav S. , Hoffmann Ulrike
Published: July 2023

We investigated the ability of large language models (LLMs) to answer anesthesia related queries prior to surgery from a patient’s point of view. In the study, we introduced textual data evaluation metrics, investigated “hallucinations” phenomenon, and evaluated feasibility of using LLMs at the patient-clinician interface. ChatGPT was found to be lengthier, intellectual, and effective in its response as compared to Bard. Upon clinical evaluation, no “hallucination” errors were reported from ChatGPT, whereas we observed a 30.3% error in response from Bard. ChatGPT responses were difficult to read (college level difficulty) while Bard responses were more conversational and about 8thgrade level from readability calculations. Linguistic quality of ChatGPT was found to be 19.7% greater for Bard (66.16 ± 13.42 vs. 55.27 ± 11.76;p=0.0037) and was independent of response length. Computational sentiment analysis revelated that polarity scores of on a Bard was significantly greater than ChatGPT (mean 0.16 vs. 0.11 on scale of −1 (negative) to 1 (positive);p=0.0323) and can be classified as “positive”; whereas subjectivity scores were similar across LLM’s (mean 0.54 vs 0.50 on a scale of 0 (objective) to 1 (subjective),p=0.3030). Even though the majority of the LLM responses were appropriate, at this stage these chatbots should be considered as a versatile clinical resource to assist communication between clinicians and patients, and not a replacement of essential pre-anesthesia consultation. Further efforts are needed to incorporate health literacy that will improve patient-clinical communications and ultimately, post-operative patient outcomes.
Allopurinol and Blood Pressure Variability Following Ischemic Stroke and Transient Ischemic Attack: A Secondary Analysis of XILO-FIST
Authors: MacDonald Alexander Stuart , Robertson Michele , Dickie David Alexander , Bath Phillip , Forbes Kirsten , Quinn Terence , Broomfield Niall M , Dani Krishna , Doney Alex , Muir Keith W , Struthers Allan , Walters Matthew , Barber Mark , Bhalla Ajay , Cameron Alan , Dyker Alexander , Guyler Paul , Hassan Ahamad , Kearney Mark , Keegan Breffni , Sekaran Lakshmanan , Macleod Mary Joan , Randall Marc , Shaw Louise , Subramanian Ganesh , Werring David , McConnachie Alex , Dawson Jesse
Published: July 2023

Background

Blood Pressure Variability (BPV) is associated with cardiovascular risk and serum uric acid level. We investigated whether BPV is lowered by allopurinol and whether it is related to markers of cerebral small vessel disease.

Methods

We used data from a randomised, double-blind, placebo-controlled trial of two years allopurinol treatment after recent ischemic stroke or transient ischaemic attack. Visit-to-visit BPV was assessed using brachial blood pressure (BP) recordings. Short-term BPV was assessed using ambulatory BP monitoring (ABPM) performed at 4 weeks and 2 years. Brain MRI was performed at baseline and 2 years. BPV measures were compared between the allopurinol and placebo groups and with white matter hyperintensity progression.

Results

409 participants were included (205 allopurinol; 204 placebo) were included in analyses of visit-to-visit BPV and there were no significant differences between groups. 196 participants were included in analyses of short-term BPV at week 4. Two measures were reduced by allopurinol: the standard deviation (SD) of systolic BP (by 1.30mmHg (95% confidence interval (CI) 0.18–2.42, p=0.023)); and the average real variability (ARV) of systolic BP (by 1.31mmHg (95% CI 0.31–2.32, p=0.011)). There were no differences in other measures at week 4 or in any measure at 2 years.

Conclusions

Allopurinol treatment did not affect visit-to-visit BPV in people with recent ischemic stroke or TIA. Two BPV measures were reduced at week 4 by allopurinol but not at 2 years. Allopurinol is unlikely to lead to an important reduction in BPV in people with ischemic stroke or TIA.
Tuneable hydrogel stiffness in a 3Din vitromodel induces epithelial to mesenchymal transition in MCF7 but not MDA-MB-231 breast cancer cells
Authors: Wise JA , Currie MJ , Woodfield TBF , Lim KS , Phillips E
Published: July 2023

The study ofin vitromodels of breast cancer is crucial for understanding and treating the malignancy in patients, with 3Din vitromodels providing researchers with more biomimetic systems to overcome limitations of current to 2D cultures andin vivoanimal models.Ex vivopatient tissues have shown that malignant breast tissues are stiffer than healthy or benign tissues, and that the stiffness corresponds with increasing tumour grade. Stiffening of the breast tumour environment alters tumour cell phenotype and facilitates tumour progression, invasion and metastasis. Better understanding of the relationship between extracellular matrix stiffness and breast cancer cell phenotype, and how that is important in the initiation of metastasis, should lead to designing 3D models that mimic the breast tumour microenvironment at different stages of breast cancer progression.

This study investigated phenotypic response of two breast cancer cell lines that are representative of clinical breast cancer subtypes (MCF7, Luminal A; MDA-MB-231, Triple Negative Breast Cancer) in gelatin-methacryloyl (GelMA) hydrogels of varying stiffness. A visible light photoinitiation system was adopted to provide a tuneable photocrosslinking platform to systematically control hydrogel stiffness and tumour microenvironment. This allowed rapid fabrication of biocompatible hydrogels supporting high cell viability over long-term culture.

The impact of a clinically relevant range of microenvironmental stiffness on breast cancer cell behaviour and phenotype was examined over a 21-day culture period using GelMA hydrogels. Results showed that MCF7 cells cultured for 21 days in high stiffness hydrogels (10 wt%; 28 kPa) responded by downregulating the epithelial marker E-cadherin and upregulating mesenchymal markers N-cadherin and Vimentin, whereas MDA-MB-231 cells showed no changes in EMT-markers when cultured in hydrogels of corresponding stiffness (10 wt%; 33 kPa). Culturing both cell lines in soft hydrogels (5 wt%; 11 kPa) maintained their phenotype over 21 days, highlighting the importance of controlling hydrogel mechanical properties when studying breast cancer cell phenotype.
Grb7 knockout mice develop normally but litters born to knockout females fail to thrive
Authors: Lofgren Kristopher A. , Kenny Paraic A.
Published: July 2023

Growth factor receptor-bound 7 (Grb7) is an adaptor protein involved in signal transduction downstream of multiple receptor tyrosine kinases, including ERBB, FGFR and PDGFR pathways. Experimental studies have implicated Grb7 in regulating cell proliferation, survival, migration and invasion through its large repertoire of protein-protein interactions. Here, we describe the generation and characterization of aGrb7knockout mouse. These mice are viable and fertile. AlacZknock-in reporter was used to visualizeGrb7promoter activity patterns in adult tissues, indicating widespread Grb7 expression in glandular epithelium, the central nervous system and other tissues. The sole defect observed in these animals was a failure ofGrb7knockout females to successfully raise pups to weaning age, a phenotype that was independent of both paternal and pup genotypes. These data suggest a regulatory role for Grb7 in mammary lactational physiology.
Easing OMERO adoption with ezomero
Authors: Ratamero Erick Martins , Govek Kiya , Langerak Julio Mateos , Sanchez Fernando Cervantes , Mellert David J.
Published: July 2023

Many research laboratories need to manage, process, and analyze the increasingly large volumes and complexity of data being produced by state-of-the-art bioimaging platforms. OMERO is a popular open-source client-server application that provides a unified interface for managing and working with bioimages and their associated measurements and metadata. Integrating OMERO into analysis pipelines, such as those developed around the scientific Python ecosystem, will thus be a common pattern across the field of bioimaging. While OMERO has a powerful Python API, it provides minimal abstraction from the underlying OMERO object model and associated methods, which represent more complexity than most users are interested in for the context of an analysis script. We introduce ezomero, which was designed to provide a convenience layer on top of existing OMERO APIs and return data types that are either Python primitive or commonly used in scientific Python. Ezomero has minimal dependencies in addition to the OMERO Python library itself and is installable directly from PyPI. Here, we provide an overview of ezomero as well as several vignettes to illustrate how it can be used to accelerate discovery.
saseR: Juggling offsets unlocks RNA-seq tools for fast and Scalable differential usage, Aberrant Splicing and Expression Retrieval
Authors: Segers Alexandre , Gilis Jeroen , Van Heetvelde Mattias , Risso Davide , De Baere Elfride , Clement Lieven
Published: July 2023

RNA-seq data analysis relies on many different tools, each tailored to specific applications and coming with unique assumptions and restrictions. Indeed, tools for differential transcript usage, or diagnosing patients with rare diseases through splicing and expression outliers, either lack in performance, discard information, or do not scale to massive data compendia. Here, we show that replacing the normalisation offsets unlocks bulk RNA-seq workflows for scalable differential usage, aberrant splicing and expression analyses. Our method, saseR, is much faster than state-of-the-art methods, dramatically outperforms these to detect aberrant splicing, and provides a single workflow for various short- and long-read RNA-seq applications.
Molecular quantitative trait loci in reproductive tissues impact male fertility in cattle
Authors: Mapel Xena Marie , Kadri Naveen Kumar , Leonard Alexander S. , He Qiongyu , Lloret-Villas Audald , Bhati Meenu , Hiltpold Maya , Pausch Hubert
Published: July 2023

Breeding bulls are well suited to investigate inherited variation in male fertility because they are genotyped and their reproductive success is monitored through semen analyses and thousands of artificial inseminations. However, functional data from relevant tissues are lacking, which prevents fine-mapping fertility-associated genomic regions. Here, we characterize gene expression and splicing variation in testis, epididymis, and vas deferens transcriptomes of 118 mature bulls and conduct association tests between 417k molecular phenotypes and 21M genome-wide variants to identify 41k regulatory loci. We show broad consensus in tissue-specific and tissue-enriched gene expression between the three bovine tissues and their human and murine counterparts. Expression- and splicing-mediating variants are more than three times as frequent in testis than epididymis and vas deferens, highlighting the transcriptional complexity of testis. Finally, we identify genes (WDR19,SPATA16,KCTD19,ZDHHC1) and molecular phenotypes that are associated with quantitative variation in male fertility through transcriptome-wide association and colocalization analyses.
Endothelial Knockdown of the Tumor Suppressor, WWOX, Increases Inflammation in Ventilator-Induced Lung Injury
Authors: Zeng Zhenguo , Abdelwahid Eltyeb , Chen Weiguo , Ascoli Christian , Pham Trinh , Jacobson Jeffrey R. , Dudek Steven M. , Natarajan Viswanathan , Aldaz C. Marcelo , Machado Roberto F. , Singla Sunit
Published: July 2023

Background

Chronic cigarette smoke exposure downregulates lung expression of WWOX, an ARDS relevant tumor suppressor. Prior work has revealed a barrier protective function of WWOX during infectious models of ARDS. Proteomic analysis ofWWOX-silenced lung endothelial cells suggest involvement of WWOX in protection against mechanical stretch-induced inflammation.

Methods

Protein lysates fromWWOX-silenced endothelial cells (ECs) were analyzed using tandem mass tag mass spectrometry (TMT-MS) to determine the differential expression status of the proteome compared to wild type ECs.WWOX-silenced ECs as well as those isolated from endothelialWwoxknockout (ECWwoxKO) mice were subjected to cyclic stretch (18% elongation, 0.5 Hz, 4 hours). Cellular lysates and media supernatant were harvested for assays of cellular signaling, protein expression, and cytokine release. Dual silencing ofWWOXand zyxin was achieved to determine the role of zyxin upregulation in IL-8 production following mechanical stretch and duringWWOXknockdown. Control and ECWwoxKO mice were subjected to high tidal volume ventilation (VILI, 40ml/kg, 65 breath/min, 4hours). Bronchoalveolar lavage fluid and mouse lung tissue were harvested for cellular signaling, cytokine secretion, and histologic assays.

Results

TMT-MS revealed upregulation of zyxin expression during WWOX knockdown which predicted a heightened inflammatory response to mechanical stretch.WWOX-silenced ECs and ECs isolated from ECWwoxmice displayed significantly increased cyclic stretch-mediated secretion of various cytokines (IL-6, KC/IL-8, IL-1β, and MCP-1) relative to controls. This was associated with increased ERK and JNK phosphorylation but decreased p38 MAPK phosphorylation. ECWwoxKO mice subjected to VILI sustained a greater degree of injury than corresponding controls. Silencing of zyxin duringWWOXknockdown abrogated stretch-induced increases in IL-8 secretion.

Conclusion

Loss of WWOX function in ECs is associated with a heightened inflammatory response during mechanical stretch that is associated with increased MAPK phosphorylation and appears to be dependent on upregulation of zyxin.
Prenatal alcohol exposure and white matter microstructural changes across the first 6-7 years of life: A longitudinal diffusion tensor imaging study of a South African birth cohort
Authors: Donald KA , Hendrikse CJ , Roos A , Wedderburn CJ , Subramoney S , Ringshaw JE , Bradford L , Hoffman N , Burd T , Narr KL , Woods RP , Zar HJ , Joshi SH , Stein DJ
Published: July 2023

Prenatal alcohol exposure (PAE) can affect brain development in early life, but few studies have investigated the effects of PAE ontrajectoriesof white matter tract maturation in young children. Here we used diffusion weighted imaging (DWI) repeated over three time points in a South African birth cohort, to measure the effects of PAE on patterns of white matter microstructural development during the pre-school years. A total of 342 scans acquired from 237 children as neonates (N=82 scans: 30 PAE; 52 controls) and at ages 2-3 (N=121 scans: 27 PAE; 94 controls) and 6-7 years (N=139 scans: 45 PAE; 94 controls) were included. Maternal alcohol use during pregnancy and other antenatal covariates were collected from 28-32 weeks’ gestation. Linear mixed effects models were implemented to investigate the effects of PAE on fractional anisotropy (FA) and mean diffusivity (MD) in specific white matter tracts over time, while adjusting for child sex and maternal education. We found significant PAE-by-time effects on trajectories of FA development in the left superior cerebellar peduncle (SCP-L: p=0.001; survived FDR correction) and right superior longitudinal fasciculus (SLF-R: p=0.046), suggesting altered white matter development among children with PAE. Compared with controls, children with PAE demonstrated a more rapid change in FA in these tracts from the neonatal period to 2-3 years of age, followed by a more tapered trajectory for the period from 2-3 to 6-7 years of age, with these trajectories differing from unexposed control children. Given their supporting roles in various aspects of neurocognitive functioning (i.e., motor regulation, learning, memory, language), altered patterns of maturation in the SCP and SLF may contribute to a spectrum of physical, social, emotional, and cognitive difficulties often experienced by children with PAE. This study highlights the value of repeated early imaging in longitudinal studies of PAE, and focus for early childhood as a critical window of potential susceptibility as well as an opportunity for early intervention.
Human brain single nucleus cell type enrichments in neurodegenerative diseases
Authors: Alvarado Chelsea X. , Weller Cory A. , Johnson Nicholas , Leonard Hampton L. , Singleton Andrew B. , Reed Xylena , Blauewendraat Cornelis , Nalls Mike
Published: July 2023

Single cell RNA sequencing has opened a window into clarifying the complex underpinnings of disease, particularly in quantifying the relevance of tissue- and cell-type-specific gene expression. To identify the cell types and genes important to therapeutic target development across the neurodegenerative disease spectrum, we leveraged genome-wide association studies, recent single cell sequencing data, and bulk expression studies in a diverse series of brain region tissues. We were able to identify significant immune-related cell types in the brain across three major neurodegenerative diseases: Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, and Parkinson’s Diseases. Subsequently, we identified the major role of 30 fine-mapped loci implicating seven genes in multiple neurodegenerative diseases and their pathogenesis.