Miracle-dz/UniFAR-FTUs huggingface dataset:
A natural knockout of the MYO7A gene leads to pre‐weaning mortality in pigs

Summary The pig breeding system provides a unique framework to study recessive defects and the consequence on the phenotype. We examined a commercial synthetic Duroc population for recessive defects and identified a haplotype on chromosome 9 significantly affecting pre‐weaning mortality. To identify the causal variant underlying the mortality, we examined sequence data of four carrier animals and 21 non‐carrier animals from the same population. The results yield a strong candidate causal stop‐gained variant (NM_001099928.1:c.541C>T) affecting the MYO7A gene in complete linkage disequilibrium with the lethal haplotype. The variant leads to an impaired (p.Gln181*) MYO7A protein that truncates 2032 amino acids from the protein. We examined a litter from a carrier sow inseminated by a carrier boar. From the resulting piglets, two confirmed homozygous piglets suffered from severe balance difficulties and the inability to walk properly. The variant segregates at a carrier frequency of 8.2% in the evaluated population and will be gradually purged from the population, improving animal welfare. Finally, this 'natural knockout' will increase our understanding of the functioning of the MYO7A gene and provides a potential model for Usher syndrome in humans.
Sleep disturbance and memory dysfunction in early multiple sclerosis

Sleep‐dependent memory processing occurs in animals including humans, and disturbed sleep negatively affects memory. Sleep disturbance and memory dysfunction are common in multiple sclerosis (MS), but little is known about the contributions of sleep disturbance to memory in MS. We investigated whether subjective sleep disturbance is linked to worse memory in early MS independently of potential confounders.
Dopamine Receptors in Parkinson's Disease: A Meta‐Analysis of Imaging Studies

Dopamine receptors are abundant along the central nigrostriatal tract and are expressed as 5 subtypes in two receptor families. In PD, compensatory changes in dopamine receptors emerge as a consequence of the loss of dopamine nerve terminals or dopaminergic pharmacotherapy. We performed a systematic review and meta‐analysis of the available PET and single‐photon emission computed tomography studies that have investigated dopamine receptors in PD, PSP and MSA. The inclusion criteria were studies including human PET or single‐photon emission computed tomography imaging; dopamine receptor tracers (D1‐like or D2‐like) and idiopathic PD, PSP, or MSA patients compared with healthy controls. The 67 included D2‐like studies had 1925 patients. Data were insufficient for an analysis of D1‐like studies. PD patients had higher striatal binding early in the disease, but after a disease duration of 4.36 years, PD patients had lower binding values than healthy controls. Striatal D2R binding was highest in unmedicated early PD patients and in the striatum contralateral to the predominant motor symptoms. PSP and MSA‐P patients had lower striatal D2R binding than PD patients (14.2% and 21.8%, respectively). There is initial upregulation of striatal D2Rs in PD, which downregulate on average 4 years after motor symptom onset, possibly because of agonist‐induced effects. The consistent upregulation of D2Rs in the PD striatum contralateral to the predominant motor symptoms indicates that receptor changes are driven by neurodegeneration and loss of striatal neuropil. Both PSP and MSA patients have clearly lower striatal D2R binding values than PD patients, which offers an opportunity for differential diagnostics. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Seroprevalence of Bordetella pertussis Infection in Patients With Chronic Obstructive Pulmonary Disease in England: Analysis of the AERIS Cohort

Abstract Pertussis is underdiagnosed and underreported in adults and patients with underlying conditions. Patients with chronic obstructive pulmonary disease (COPD) may be at increased risk of severe pertussis. Understanding the true prevalence of pertussis infections in such patients is important. We therefore evaluated the seroprevalence of anti-pertussis toxin (PT) antibodies in a cohort of 40–85-year-old patients diagnosed with moderate, severe or very severe COPD enrolled (between June 2011 and June 2012) in the prospective, observational “Acute Exacerbation and Respiratory InfectionS in COPD” (AERIS; NCT01360398) study, conducted in England. Serum anti-PT antibodies were measured in 104 patients using an enzyme-linked immunosorbent assay on samples collected 12 months (M12) and 24 months (M24) after enrollment. Overall, 14/104 (13.5%) patients had anti-PT concentrations ≥50 IU/mL at M12 or M24, indicative of exposure to Bordetella pertussis during the preceding 2–3 years. Of these, 6/104 (5.8%) had anti-PT ≥70 IU/mL, of whom 3/104 (2.9%) had anti-PT ≥120 IU/mL, indicative of exposure within 12 and 6 months, respectively. These results show a high circulation of B. pertussis in 40–85-year-old patients with moderate, severe or very severe COPD in England between 2012 and 2014, and call for enhanced immunization to prevent pertussis infections in such patients.
Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia

Abstract Acalabrutinib is a highly selective, potent, next-generation, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. Matching-adjusted indirect comparisons (MAICs) were performed to estimate the safety and efficacy of acalabrutinib compared to other targeted therapies for treatment-naïve patients with chronic lymphocytic leukemia (CLL). Individual patient data for acalabrutinib (ELEVATE-TN trial) were matched to aggregate baseline characteristics for comparators. After matching, acalabrutinib (with or without obinutuzumab) showed improved safety outcomes, except for increased risk of neutropenia (p < 0.001) for acalabrutinib plus obinutuzumab versus ibrutinib and increased risk of leukopenia (p < 0.05) for acalabrutinib (with or without obinutuzumab) versus venetoclax plus obinutuzumab. There was no statistically significant difference in progression-free survival between acalabrutinib (with or without obinutuzumab) and any of the comparators. This MAIC demonstrated a favorable safety profile for acalabrutinib-based therapy compared with other targeted therapies in treatment-naïve patients with CLL, without compromising efficacy.
Distal Stimulation Site at the Medial Tibia for Saphenous Nerve Somatosensory Evoked Potentials (DSn-SSEPs) in Lateral Lumbar Spine Procedures

ABSTRACT Lateral lumbar interbody fusion procedures are performed with multimodality neuromonitoring of the femoral nerve to prevent lumbosacral plexus and peripheral nerve injury from positioning, dilation, retraction, and hardware implantation. The integrity of the femoral nerve can be continuously assessed during these procedures by Somatosensory Evoked Potentials of the Saphenous nerve (Sn-SSEPs). Sn-SSEPs are technically challenging to acquire and necessitate advanced troubleshooting skills with a more rigid anesthetic regimen and physiological parameters. We performed a retrospective analysis of Sn-SSEP data for 100 consecutive lateral lumbar surgeries where the stimulation electrodes were placed distally below the knee and medial to the tibia bone (i.e., DSn-SSEPs). Monitorable baseline responses were present in 87% of patients after the exclusion of fourteen cases where the tibial nerve SSEP was absent, quadriceps transcranial electrical motor evoked potentials (TCeMEPs) were absent or not utilized. Sex, age, body mass index (BMI), diagnosis, mean arterial pressure (MAP), inhalational anesthetic levels, reliability of ulnar and posterior tibial nerve SSEPs, and the reliability of femoral nerve innervated quadriceps TCeMEPs were evaluated but were not of statistically significant consequence between cases where the DSn-SSEP was present or absent in this study. We found the utilization of DSn-SSEPs to be a valuable adjunct to femoral nerve monitoring. Stimulation electrode placement is easy to palpate with clear anatomical borders. Significant muscle artifact and patient movement from stimulation do not affect waveform morphology, allowing for continuous and reliable monitoring. We recommend including DSn-SSEPs to optimize recordings during lateral lumbar procedures.
Epidemiology and reporting characteristics of preclinical systematic reviews

In an effort to better utilize published evidence obtained from animal experiments, systematic reviews of preclinical studies are increasingly more common—along with the methods and tools to appraise them (e.g., SYstematic Review Center for Laboratory animal Experimentation [SYRCLE’s] risk of bias tool). We performed a cross-sectional study of a sample of recent preclinical systematic reviews (2015–2018) and examined a range of epidemiological characteristics and used a 46-item checklist to assess reporting details. We identified 442 reviews published across 43 countries in 23 different disease domains that used 26 animal species. Reporting of key details to ensure transparency and reproducibility was inconsistent across reviews and within article sections. Items were most completely reported in the title, introduction, and results sections of the reviews, while least reported in the methods and discussion sections. Less than half of reviews reported that a risk of bias assessment for internal and external validity was undertaken, and none reported methods for evaluating construct validity. Our results demonstrate that a considerable number of preclinical systematic reviews investigating diverse topics have been conducted; however, their quality of reporting is inconsistent. Our study provides the justification and evidence to inform the development of guidelines for conducting and reporting preclinical systematic reviews.
Systematic review on the instruments used for measuring the association of the level of multimorbidity and clinically important outcomes

Objectives There are multiple instruments for measuring multimorbidity. The main objective of this systematic review was to provide a list of instruments that are suitable for use in studies aiming to measure the association of a specific outcome with different levels of multimorbidity as the main independent variable in community-dwelling individuals. The secondary objective was to provide details of the requirements, strengths and limitations of these instruments, and the chosen outcomes. Methods We conducted the review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO registration number: CRD42018105297). We searched MEDLINE, Embase and CINAHL electronic databases published in English and manually searched the Journal of Comorbidity between 1 January 2010 and 23 October 2020 inclusive. Studies also had to select adult patients from primary care or general population and had at least one specified outcome variable. Two authors screened the titles, abstracts and full texts independently. Disagreements were resolved with a third author. The modified Newcastle-Ottawa Scale was used for quality assessment. Results Ninety-six studies were identified, with 69 of them rated to have a low risk of bias. In total, 33 unique instruments were described. Disease Count and weighted indices like Charlson Comorbidity Index were commonly used. Other approaches included pharmaceutical-based instruments. Disease Count was the common instrument used for measuring all three essential core outcomes of multimorbidity research: mortality, mental health and quality of life. There was a rise in the development of novel weighted indices by using prognostic models. The data obtained for measuring multimorbidity were from sources including medical records, patient self-reports and large administrative databases. Conclusions We listed the details of 33 instruments for measuring the level of multimorbidity as a resource for investigators interested in the measurement of multimorbidity for its association with or prediction of a specific outcome.
Photoperiod affects the laying performance of the mountain duck by regulating endocrine hormones and gene expression

Abstract Light mainly affects animal reproductive performance through the hypothalamus‐ pituitary‐gonadal axis, but the specific regulating mechanism is not yet clear in duck. To reveal the effects of light on the laying performance of ducks and its possible regulatory mechanisms, Shanma ducks at 52 weeks age were divided into three group treated with different photoperiods of 16 hr (control group), 24 hr (long‐photoperiod group, LP), and 8 hr (short‐photoperiod group, SP). Laying performance, endocrine‐related hormones and gene expression of three groups were compared. The results showed that laying performance was greatest in the LP group; including laying rate, average egg weight and feed‐egg ratio. Compared to the SP group, GnIH plasma concentration was decreased in the LP group, whilst FSH was increased in the LP group. GnIHR gene expression in the pituitary and large yellow follicles were downregulated in the LP group. The expression of Mel‐a in large white follicles, and Mel‐b and Mel‐c in the hypothalamus were also downregulated in the LP group. Altogether these results suggest that extended photoperiods may promote the laying performance of ducks by inhibiting the secretion of GnIH and the expression of GnIHR and melatonin receptor genes.
Comparative analysis of the pivotal studies of extended half‐life recombinant FVIII products for treatment of haemophilia A

The need to reduce the burden of injections, and improve adherence and clinical outcomes in haemophilia A led to the development of recombinant FVIII products endowed with an extended plasma half‐life (EHL‐rFVIII) in comparison with standard half‐life products (SHL‐rFVIII). Lack of head‐to‐head studies makes difficult to grasp the relative value of each treatment option. We conducted a combined evaluation of the individual pivotal trials in order to assess between‐product differences regarding the reported efficacy results and FVIII consumption. We evaluated 4 EHL‐rFVIII products available to treat patients with haemophilia A without inhibitors and also a SHL‐rFVIII as a comparator. In the frame of these clinical studies, all the EHL‐rFVIII products showed a decrease in the injection burden coupled with good clinical efficacy, even though there were between‐product differences in terms of reduction in injection frequencies. Further, between‐product differences in terms of weekly/yearly consumption of rFVIII expressed in IU/Kg were identified, suggesting a different economic impact for the different EHL‐rFVIII products in the context of comparable clinical efficacy. The present findings based upon the review of pivotal studies done in the frame of a highly selected clinical scenario should be integrated with real‐life data.
A Systematic Review of Multi-Component Comprehensive School Physical Activity Program (CSPAP) Interventions

Objective: To identify, review, and describe multicomponent physical activity (PA) interventions in terms of: (a) number and combination of Comprehensive School Physical Activity Program (CSPAP) components, (b) study characteristics, and (c) primary outcomes. Data Source: Five electronic databases (i.e., PubMed, PsychInfo, Physical Education Index, Sport Discus, and ERIC). Study Inclusion and Exclusion Criteria: Included articles were peer-reviewed, written in English language, published since 1987, and included multicomponent school-based interventions. Data Extraction: Data items extracted were: school level, setting, CSPAP component description, health outcomes, academic outcomes, main conclusion, and reference. Data Synthesis: Included articles were synthesized by: (1) CSPAP components utilized, and (2) research outcome measured (i.e., health or academic). Results: Across 32 studies, 11 included physical education plus 1 additional CSPAP component (PE + 1); 10 included PE + 2 additional CSPAP components; 8 included PE + 3 additional CSPAP components; and 1 included all 5 CSPAP components. Two other studies included 2 or 3 CSPAP components without PE. Most interventions targeted health outcomes (94%) rather than academic outcomes (6%). Conclusions: Multicomponent approaches aligned with CSPAPs are effective in promoting PA and other positive outcomes for youth in schools. Future research should seek to understand effects of CSPAP components on a variety of outcomes and settings.
The value of health—Empirical issues when estimating the monetary value of a quality‐adjusted life year based on well‐being data

Abstract Decisions on interventions or policy alternatives affecting health can be informed by economic evaluations, like cost‐benefit or cost‐utility analyses. In this context, there is a need for valid estimates of the monetary equivalent value of health (gains), which are often expressed in € per quality‐adjusted life years (QALYs). Obtaining such estimates remains methodologically challenging, with a recent addition to the health economists' toolbox, which is based on well‐being data: The well‐being valuation approach. Using general population panel data from Germany, we put this approach to the test by investigating several empirical and conceptual challenges, such as the appropriate functional specification of income utility, the choice of health utility tariffs, or the health state dependence of consumption utility. Depending on specification, the bulk of estimated € per QALY values ranged from €20,000–60,000, with certain specifications leading to more considerable deviations, underlining persistent practical challenges when applying the well‐being valuation methodology to health and QALYs. Based on our findings, we formulate recommendations for future research and applications.
What’s in a wine? – A spot check of the integrity of European wine sold in China based on anthocyanin composition, stable isotope and glycerol impurity analysis

ABSTRACT The international wine market has been repeatedly hit by cases of fraud in recent decades. While several studies attested a special vulnerability of the fast growing wine business in China, reports on chemical analyses of commercial wine samples are rare. We examined 50 predominantly red wines with European labelling, which were purchased on the Chinese market, for fraud-relevant parameters. More than 20% of the tested samples revealed anomalies in relation to the stable isotope ratios of D/H, 18O/16O and 13C/12C, contents of technical glycerol by-products or anthocyanin composition. These results strongly suggested watering of the wines, chaptalisation, glycerol addition or the use of non-Vitis anthocyanin sources, respectively. Some of these samples also showed suspicious spelling errors or other irregularities in the labelling, but the majority appeared genuine to the eye. Hence, this spot check demonstrates the importance of chemical authenticity analysis of market samples in order to detect fraudulent products. Moreover, we used the same sample set for an evaluation of the Chinese standard method for carbon stable isotope determination of wine ethanol in comparison to the current OIV (International Organisation of Vine and Wine) standard method. The results of a Bland-Altman analysis indicated that the methods can be applied interchangeably. As the two methods differ in their workflow and in the requested equipment, this might eventually enable more laboratories to perform 13C/12C analysis of wine and spirits. Graphical abstract
Abnormal function in dentate nuclei precedes the onset of psychosis: a resting-state fMRI study in high-risk individuals

Objective The cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions. We recently developed a new parcellation of the dentate nuclei (DN), the major output nuclei of the cerebellum, which optimally divides the structure into three functional territories that contribute uniquely to default-mode, motor-salience, and visual processing networks as indexed by resting-state functional connectivity (RsFc). Here we test for the first time whether RsFc differences in the DN precede the onset of psychosis in individuals at risk of developing schizophrenia. Methods We used the MRI dataset from the Shanghai At Risk for Psychosis study that included subjects at high risk to develop schizophrenia (N=144), with longitudinal follow-up to determine which subjects developed a psychotic episode within one year of their fMRI scan (converters N=23). Analysis used the three functional parcels (default-mode, salience-motor, and visual territory) from the DN as seed regions of interest for whole-brain RsFc analysis. Results RsFc analysis revealed abnormalities at baseline in high-risk individuals who developed psychosis, compared to high-risk individuals who did not develop psychosis. The nature of the observed abnormalities was found to be anatomically specific such that abnormal RsFc was localized predominantly in cerebral cortical networks that matched the three functional territories of the DN that were evaluated. Conclusions We show for the first time that abnormal RsFc of the DN may precede the onset of psychosis. This new evidence highlights the role of the cerebellum as a potential target for psychosis prediction and prevention.
Mortality and Neurologic Sequelae in Influenza-Associated Encephalopathy: Retrospective Multicenter PICU Cohort in France

Supplemental Digital Content is available in the text. OBJECTIVES: To describe and estimate the mortality rate of severe influenza-associated encephalopathy/encephalitis among children admitted to PICUs. DESIGN: Multicenter retrospective study. SETTING: Twelve French PICUs. PATIENTS: All children admitted for influenza-associated encephalopathy/encephalitis between 2010 and 2018 with no severe preexisting chronic neurologic disorders and no coinfection potentially responsible for the disease. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We collected the clinical presentation; laboratory, electroencephalographic, and MRI findings; and treatments used in the PICU. The primary outcome was mortality. The secondary outcomes included sequelae at discharge and last follow-up. We included 41 patients with a median (interquartile range) age of 4.7 years (2.5–8.2 yr). The main reasons for admission were altered consciousness (59%) and status epilepticus (34%); 48% of patients had meningitis, and one third had acute necrotizing encephalopathy on MRI. Mechanical ventilation was required in 73% of patients and hemodynamic support in 24%. The use of specific treatments was variable; steroids were given to 49% of patients. Seven patients (17%) died in the PICU. Median (interquartile range) PICU stay length was 7 days (2–13 d), and total hospital length of stay was 23 days (7–33 d). On hospital discharge, 49% (n = 20) had neurologic sequelae, with 27% (n = 11) having severe disabilities defined by modified Rankin Score greater than or equal to 4. CONCLUSIONS: Children requiring PICU admission for influenza-associated encephalopathy/encephalitis have high mortality and morbidity rates. The management remains highly variable due to the lack of guidelines.