Miracle-dz/UniFAR-FTUs huggingface dataset:
Relationship, difference, and diagnostic discordance between blood ionized and total calcium concentrations in client-owned chelonians.

OBJECTIVE To determine (1) the relationship, (2) the difference, and (3) the diagnostic discordance between blood total calcium concentration (tCa) and ionized calcium concentration (iCa) in a population of client-owned chelonian patients. ANIMALS 161 consecutively admitted client-owned chelonians. PROCEDURES Results for tCa, iCa, and other variables were extracted from records. Bound calcium concentration (tCa - iCa) was calculated. General linear models were developed to evaluate factors affecting tCa, iCa and bound calcium concentrations. Diagnostic discordance between tCa and iCa was assessed. RESULTS iCa decreased with increasing albumin concentration, it was not influenced by sex, and it was lower in chelonians with disorders of the reproductive tract than in those with disorders of the endocrine/hemopoietic and urinary systems. Total calcium and bound calcium concentrations increased with increasing albumin concentration; they were higher in females and in chelonians with disorders of the reproductive tract. Of the 161 chelonians, 93 (57.7%; 95% CI, 49.7% to 65.5%) would have had a different diagnosis of calcium status based on tCa and iCa results (ie, diagnostic discordance). A 2.2 mmol/L cutoff value for bound calcium could differentiate chelonians with and without disorders of the reproductive tract with a sensitivity (95% CI) of 81.8% (64.5% to 93.0%) and specificity of 76.4% (68.0% to 83.5%). CLINICAL RELEVANCE tCa and iCa were related and were associated with albumin concentrations in chelonians. Evaluation of tCa or iCa alone is likely to result in underdiagnosis of alterations of the calcium status. Calculation of bound calcium concentration could help identify chelonians with reproductive disorders.
Service Users’ Views and Experiences of Alcohol Relapse Prevention Treatment and Adherence: New Role for Pharmacists?

Abstract Aims To understand service users' views and experiences of alcohol relapse prevention medication, views of a telephone behavioural modification intervention delivered by pharmacists and the use of Contingency Management (CM) to support acamprosate adherence following assisted alcohol withdrawal. Methods Four focus groups were conducted within four alcohol treatment and recovery groups across England (UK), with service users with lived experience of alcohol dependence (26 participants). Semi-structured topic guide was used to explore participants' views and experiences of alcohol relapse prevention medication, a telephone behavioural modification medication intervention delivered by pharmacists, and the use of CM to support acamprosate adherence. These were audio-recorded, transcribed verbatim and thematically analysed inductively and deductively. Results Four themes were identified: concerns about support and availability of alcohol relapse prevention medication; lack of knowledge and understanding about acamprosate treatment; positive perceptions of acamprosate adherence telephone support from pharmacists; and negative perceptions of CM to support acamprosate adherence. There were misunderstandings about acamprosate's mode of action and strong negative beliefs about CM. However, most were positive about pharmacists' new role to support acamprosate adherence. Conclusion This study highlighted challenges service users face to commence alcohol relapse prevention medication. It appears service users could benefit from a pharmacist-led telephone intervention to improve understanding about acamprosate medication, particularly, if delivered in an engaging and motivating way.
Context‐dependent integrated stress resistance promotes a global invasive pest

In nature, insects concurrently face multiple environmental stressors, a scenario likely increasing with climate change. Integrated stress resistance (ISR) thus often improves fitness and could drive invasiveness, but how physiological mechanisms influence invasion has lacked examination. Here, we investigated cross‐tolerance to abiotic stress factors which may influence range limits in the South American tomato pinworm—a global invader that is an ecologically and socially damaging crop pest. Specifically, we tested the effects of prior rapid cold‐ and heat‐hardening (RCH and RHH), fasting, and desiccation on cold and heat tolerance traits, as well as starvation and desiccation survivability between T. absoluta life stages. Acclimation effects on critical thermal minima (CTmin) and maxima (CTmax) were inconsistent, showing significantly deleterious effects of RCH on adult CTmax and CTmin and, conversely, beneficial acclimation effects of RCH on larval CTmin. While no beneficial effects of desiccation acclimation were recorded for desiccation tolerance, fasted individuals had significantly higher survival in adults, whereas fasting negatively affected larval tolerances. Furthermore, fasted and desiccation acclimated adults had significantly higher starvation tolerance, showing strong evidence for cross‐tolerance. Our results show context‐dependent ISR traits that may promote T. absoluta fitness and competitiveness. Given the frequent overlapping occurrence of these divergent stressors, ISR reported here may thus partly elucidate the observed rapid global spread of T. absoluta into more stressful environments than expected. This information is vital in determining the underpinnings of multistressor responses, which are fundamental in forecasting species responses to changing environments and management responses.
Increasing Cases of Chronic Nonbacterial Osteomyelitis in Children: A Series of 215 Cases From a Single Tertiary Referral Center

Objective Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disease that is gaining recognition from clinicians and researchers. We aim to publish data from our cohort of patients with CNO living in the northwestern United States to increase the awareness of specific demographics, characteristics, and presentation of this rare disease. Methods A retrospective chart review was performed of our electronic medical records. Patients with complete chart records who met criteria for a diagnosis of CNO from 2005 to 2019 were included. Extracted data including patient demographics, bone biopsy results, and lesion locations on advanced imaging were analyzed. King County census data were used to calculate the annual new case rate within our center. Results A total of 215 CNO cases were diagnosed at our large tertiary pediatric hospital. The majority of cases were of White race residing in Washington’s most populous county, King County. Most cases were diagnosed in 2016 to 2019, showing a significant increase in the annual case rate from 8 to 23 per million children in King County, though there did not appear to be a seasonal predilection. Biopsy rate decreased from 75% to 52%. One hundred fifty-two (71%) children had family history of autoimmunity. With increasing use of whole-body magnetic resonance imaging (WB-MRI), results showed 68% had multiple lesions. Conclusion CNO has been diagnosed at an increased rate in recent years. WB-MRI may assist in identifying other lesions that may be asymptomatic on presentation. Bone biopsy is still required in some children at the time of diagnosis.
Clathrin heavy chain is essential for the development and reproduction of Locusta migratoria

Clathrin heavy chain (Chc) is a constituent of clathrin‐coated vesicles and serves important functions in endocytosis and intracellular membrane trafficking but appears to have physiological roles also at the organismal level. Most of what we know about Chc functions originates from studies performed in fungal or vertebrate cells. However, the physiological functions of Chc in insects remain poorly understood. Here, we identified a Chc ortholog from a Locusta migratoria transcriptome database. RT‐qPCR revealed that LmChc was constitutively expressed in fifth‐instar nymphs. In this developmental stage, LmChc showed the highest expression in the ovary followed by hemolymph, testis, hindgut, midgut, and foregut. In isolated hemocytes, we detected the Chc protein in patches at the plasma membrane. To examine the role of LmChc in L. migratoria during development, RNA interference was performed by injecting dsRNA into the early fifth‐instar nymphs. Silencing of LmChc caused a lethal phenotype with molting defect from nymph to adult. In addition, silencing of LmChc resulted in abnormal development of the ovaries, the size of which was significantly smaller than that in controls. Taken together, our results suggest that LmChc is a vital gene in L. migratoria that plays an important role in growth, development, and reproduction. LmChc may be used as an efficient RNAi target gene for developing dsRNA‐based biological insecticides to manage insect pests.
Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy

Abstract Voltage-gated calcium (CaV) channels form three subfamilies (CaV1–3). The CaV1 and CaV2 channels are heteromeric, consisting of an α1 pore-forming subunit, associated with auxiliary CaVβ and α2δ subunits. The α2δ subunits are encoded in mammals by four genes, CACNA2D1–4. They play important roles in trafficking and function of the CaV channel complexes. Here we report biallelic variants in CACNA2D1, encoding the α2δ-1 protein, in two unrelated individuals showing a developmental and epileptic encephalopathy. Patient 1 has a homozygous frameshift variant c. 818_821dup/p.(Ser275Asnfs*13) resulting in nonsense-mediated mRNA decay of the CACNA2D1 transcripts, and absence of α2δ-1 protein detected in patient-derived fibroblasts. Patient 2 is compound heterozygous for an early frameshift variant c. 13_23dup/p.(Leu9Alafs*5), highly probably representing a null allele and a missense variant c.626G>A/p.(Gly209Asp). Our functional studies show that this amino-acid change severely impairs the function of α2δ-1 as a calcium channel subunit, with strongly reduced trafficking of α2δ-1G209D to the cell surface and a complete inability of α2δ-1G209D to increase the trafficking and function of CaV2 channels. Thus, biallelic loss-of-function variants in CACNA2D1 underlie the severe neurodevelopmental disorder in these two patients. Our results demonstrate the critical importance and non-interchangeability of α2δ-1 and other α2δ proteins for normal human neuronal development.
Association of Screen Time With Internalizing and Externalizing Behavior Problems in Children 12 Years or Younger: A Systematic Review and Meta-analysis.

Importance Currently, there is a lack of consensus in the literature on the association between screen time (eg, television, video games) and children's behavior problems. Objective To assess the association between the duration of screen time and externalizing and internalizing behavior problems among children 12 years or younger. Data Sources For this systematic review and meta-analysis, MEDLINE, Embase, and PsycINFO databases were searched for articles published from January 1960 to May 2021. Reference lists were manually searched for additional studies. Study Selection Included studies measured screen time (ie, duration) and externalizing or internalizing behavior problems in children 12 years or younger, were observational or experimental (with baseline data), were available in English, and had data that could be transformed into an effect size. Studies conducted during the COVID-19 pandemic were excluded. Of 25 196 nonduplicate articles identified and screened for inclusion, 595 met the selection criteria. Data Extraction and Synthesis The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Extracted variables were child age, sex, and socioeconomic status; informants and measurement type for screen time and behavior problems; study publication year; and study design and quality. Data were extracted by 2 independent coders and were pooled using a random-effects model. Main Outcomes and Measures The primary outcome was the association of screen time duration with externalizing (eg, aggression, attention deficit/hyperactivity disorder symptoms) and internalizing (eg, depression, anxiety) behaviors or diagnoses. Results Of the 595 full-text articles assessed for eligibility, 87 studies met all inclusion criteria, comprising 98 independent samples and 159 425 participants (mean [SD] age, 6.07 [2.89] years; 83 246 [51.30%] male). Increased duration of screen time had a small but significant correlation with more externalizing problems (90 samples; r, 0.11; 95% CI, 0.10-0.12) and internalizing problems (43 samples; r, 0.07; 95% CI, 0.05-0.08) in children. Several methodological moderators explained between-study heterogeneity. There was evidence of significant between study heterogeneity (I2 = 87.80). Conclusions and Relevance This systematic review and meta-analysis found small but significant correlations between screen time and children's behavior problems. Methodological differences across studies likely contributed to the mixed findings in the literature.
Gene variants previously associated with reduced soft tissue injury risk: Part 1 – independent associations with elite status in rugby

ABSTRACT There is growing evidence of genetic contributions to tendon and ligament pathologies. Given the high incidence and severity of tendon and ligament injuries in elite rugby, we studied whether 13 gene polymorphisms previously associated with tendon/ligament injury were associated with elite athlete status. Participants from the RugbyGene project were 663 elite Caucasian male rugby athletes (RA) (mean (standard deviation) height 1.85 (0.07) m, mass 101 (12) kg, age 29 (7) yr), including 558 rugby union athletes (RU) and 105 rugby league athletes. Non-athletes (NA) were 909 Caucasian men and women (56% female; height 1.70 (0.10) m, mass 72 (13) kg, age 41 (23) yr). Genotypes were determined using TaqMan probes and groups compared using Χ2 and odds ratio (OR). COLGALT1 rs8090 AA genotype was more frequent in RA (27%) than NA (23%; P = 0.006). COL3A1 rs1800255 A allele was more frequent in RA (26%) than NA (23%) due to a greater frequency of GA genotype (39% vs 33%). For MIR608 rs4919510, RA had 1.7 times the odds of carrying the CC genotype compared to NA. MMP3 rs591058 TT genotype was less common in RA (25.1%) than NA (31.2%; P < 0.04). For NID1 rs4660148, RA had 1.6 times the odds of carrying the TT genotype compared to NA. It appears that elite rugby athletes have an inherited advantage that contributes to their elite status, possibly via resistance to soft tissue injury. These data may, in future, assist personalised management of injury risk amongst athletes. Highlights The elite rugby athletes we studied had differing genetic characteristics to non-athletes regarding genetic variants previously associated with soft-tissue injury risk. COLGALT1 rs8090, COL3A1 rs1800255, MIR608 rs4919510, MMP3 rs591058 and NID1 rs4660148 were all associated with elite status in rugby. We propose that elite rugby athletes might possess an inherited resistance to soft tissue injury, which has enabled them to achieve elite status despite exposure to the high-risk environment of elite rugby.
P.063 Endovascular Treatment of Acute Ischemic Stroke in Patients with Pre-morbid Disability: A Meta-analysis

Background: Practice-changing trials of endovascular thrombectomy (EVT) for acute stroke excluded patients with pre-morbid disability. Observational studies may inform the role of EVT in this population. We performed a meta-analysis to estimate the effect of EVT in patients with pre-morbid disability. Methods: We adhered to PRISMA guidelines and searched Medline and Embase for studies describing EVT in adults with and without pre-morbid disability with stroke. Random-effects meta-analysis was used to pool outcomes, including favorable outcomes (mRS=0-2 or return to baseline), no increase in disability at 90 days, symptomatic ICH (sICH) and 90-day mortality. Results: We included 8 studies with 5570 patients (mRS 3-5=863, mRS 0-2=4,707). Patients with pre-morbid disability were more likely to return to their baseline mRS (aOR 2.53, 95% CI=1.47-4.36), although they had higher 90-day mortality (aOR=2.21, 95% CI=1.66-2.93). aOR for favorable outcome (aOR=0.83, 95% CI=0.67-1.03) or sICH (aOR=1.07, 95% CI=0.74-1.54) was not significantly different between groups. Conclusions: Observational studies suggest that EVT is safe in patients with pre-stroke disability and may result in comparable return to pre-stroke status as in patients without such disability. These findings argue against the routine exclusion of patients with pre-morbid disability from EVT and merit validation with randomized controlled trials.
MYPT1/PP1‐Mediated EZH2 Dephosphorylation at S21 Promotes Epithelial–Mesenchymal Transition in Fibrosis through Control of Multiple Families of Genes

The methyltransferase EZH2 plays an important role in regulating chromatin conformation and gene transcription. Phosphorylation of EZH2 at S21 by AKT kinase suppresses its function. However, protein phosphatases responsible for the dephosphorylation of EZH2‐S21 remain elusive. Here, it is demonstrated that EZH2 is highly expressed in the ocular lens, and AKT‐EZH2 axis is important in TGFβ‐induced epithelial‐mesenchymal transition (EMT). More importantly, it is identified that MYPT1/PP1 dephosphorylates EZH2‐S21 and thus modulates its functions. MYPT1 knockout accelerates EMT, but expression of the EZH2‐S21A mutant suppresses EMT through control of multiple families of genes. Furthermore, the phosphorylation status and gene expression modulation of EZH2 are implicated in control of anterior subcapsular cataracts (ASC) in human and mouse eyes. Together, the results identify the specific phosphatase for EZH2‐S21 and reveal EZH2 dephosphorylation control of several families of genes implicated in lens EMT and ASC pathogenesis. These results provide important novel information in EZH2 function and regulation.
Bioavailability, safety and tolerability of intravenous brivaracetam in healthy Japanese participants

Abstract We characterised the bioavailability, safety, and tolerability of brivaracetam 100 mg intravenous bolus and 15-min infusion versus oral reference tablet in 24 healthy Japanese participants. In this randomised, open-label, three-period crossover study, participants received three 100 mg single doses of brivaracetam, intravenous bolus, infusion, and oral tablets. Maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUCt), and area under the plasma concentration-time curve extrapolated to infinity (AUCinf), were compared using analysis of variance following logarithmic transformation. Bioavailability comparisons were based on the 90% confidence intervals (CIs) around the geometric least squares means ratios (intravenous:oral). Safety and tolerability were monitored throughout the study. The 90% CIs around AUCt and AUCinf ratios were entirely contained within the bioequivalence limits (0.80–1.25), but Cmax was outside the limits (90% CI: 1.77–2.08 and 1.44–1.70 for intravenous bolus and infusion, respectively). All participants completed the study. Brivaracetam was well tolerated. Because response to brivaracetam in epilepsy is related to exposure (AUC), no dose adjustment is warranted when switching from oral to intravenous dosing. However, investigations are needed to assess the safety and tolerability of intravenous administration in Japanese patients with epilepsy.
CD4+ T Cells Control Murine Cytomegalovirus Infection Indirectly

Cytomegalovirus infections commonly cause problems in immunocompromised patients and in pregnancy. We lack effective vaccines. ABSTRACT CD4+ T cells are key to controlling cytomegalovirus infections. Salivary gland infection by murine cytomegalovirus (MCMV) provides a way to identify mechanisms. CD11c+ dendritic cells (DC) disseminate MCMV to the salivary glands, where they transfer infection to acinar cells. Antiviral CD4+ T cells are often considered to be directly cytotoxic for cells expressing major histocompatibility complex class II (MHCII). However, persistently infected salivary gland acinar cells are MHCII− and are presumably inaccessible to direct CD4 T cell recognition. Here, we show that CD4+ T cell depletion amplified infection of MHCII− acinar cells but not MHCII+ cells. MCMV-infected mice with disrupted MHCII on CD11c+ cells showed increased MHCII− acinar infection; antiviral CD4+ T cells were still primed, but their recruitment to the salivary glands was reduced, suggesting that engagement with local MHCII+ DC is important for antiviral protection. As MCMV downregulates MHCII on infected DC, the DC participating in CD4 protection may thus be uninfected. NK cells and gamma interferon (IFN-γ) may also contribute to CD4+ T cell-dependent virus control: CD4 T cell depletion reduced NK cell recruitment to the salivary glands, and both NK cell and IFN-γ depletion equalized infection between MHCII-disrupted and control mice. Taken together, these results suggest that CD4+ T cells protect indirectly against infected acinar cells in the salivary gland via DC engagement, requiring the recruitment of NK cells and the action of IFN-γ. Congruence of these results with an established CD4+ T cell/NK cell axis of gammaherpesvirus infection control suggests a common mode of defense against evasive viruses. IMPORTANCE Cytomegalovirus infections commonly cause problems in immunocompromised patients and in pregnancy. We lack effective vaccines. CD4+ T cells play an important role in normal infection control, yet how they act has been unknown. Using murine cytomegalovirus as an accessible model, we show that CD4+ T cells are unlikely to recognize infected cells directly. We propose that CD4+ T cells interact with uninfected cells that present viral antigens and recruit other immune cells to attack infected targets. These data present a new outlook on understanding how CD4+ T cell-directed control protects against persistent cytomegalovirus infection.
Three‐dimensional thermophotonic image optimization modalities of truncated correlation photothermal coherence tomography

Truncated correlation photothermal coherence tomography (TC‐PCT) is a pulse‐compression, matched‐filter‐based photothermal diffusion‐wave imaging modality with a proven track record in non‐destructive evaluation of biomedical, dental, art‐object and industrial applications. This is a study of the effect thermal transient truncation plays in the TC‐PCT algorithm. It introduces a new phase channel which was coined the name Linear Iso Phase (LIOP) and improves the conventional TC‐PCT phase by redevising its matched‐filter sampling scheme and removing the effect of circular aliasing artifacts introduced in the frequency‐domain‐transformed cross‐correlation (CC) calculations. A previously introduced computationally simplified adaptation to TC‐PCT based on conventional CC signal processing, named enhanced truncated correlation photothermal coherence tomography (eTC‐PCT), which does not utilize thermal transient truncation is also investigated: The TC‐PCT and eTC‐PCT algorithms and the LIOP channel are used to produce three‐dimensional reconstructions of a complex multi‐layered marquetry art sample and a tooth with a bacterial‐induced lesion.