Notes

Creating along with imagining pore openings within gelatin-based hydrogel foam.
The primary goal of precision medicine is to maximize the benefit-risk relationships for individual patients by delivering the right drug to the right patients at the right dose. To achieve this goal, it has become increasingly important to assess gene-drug interactions (GDIs) in clinical settings. The US Food and Drug Administration (FDA) periodically updates the table of pharmacogenetic/genomic (PGx) biomarkers in drug labeling on their website. As described herein, an effort was made to categorize various PGx biomarkers covered by the FDA-PGx table into certain groups. There were 2 major groups, oncology molecular targets (OMT) and drug-metabolizing enzymes and transporters (DMETs), which constitute ~70% of all biomarkers (~33% and ~35%, respectively). These biomarkers were further classified whether their labeling languages could be actionable in clinical practice. For OMT biomarkers, ~70% of biomarkers are considered actionable in clinical practice as they are critical for the selection of appropriate drugs to individual patients. In contrast, ~30% of DMET biomarkers are considered actionable for the dose adjustments or alternative therapies in specific populations, such as CYP2C19 and CYP2D6 poor metabolizers. In addition, the GDI results related to some of the other OMT and DMET biomarkers are considered to provide valuable information to clinicians. However, clinical GDI results on the other DMET biomarkers can possibly be used more effectively for dose recommendation. As the labels of some drugs already recommend the precise doses in specific populations, it will be desirable to have clear language for dose recommendation of other (or new) drugs if appropriate.Mechanical ventilation (MV) is a life-saving instrument used to provide ventilatory support for critically ill patients and patients undergoing surgery. Unfortunately, an unintended consequence of prolonged MV is the development of inspiratory weakness due to both diaphragmatic atrophy and contractile dysfunction; this syndrome is labeled ventilator-induced diaphragm dysfunction (VIDD). VIDD is clinically important because diaphragmatic weakness is an important contributor to problems in weaning patients from MV. Investigations into the pathogenesis of VIDD reveal that oxidative stress is essential for the rapid development of VIDD as redox disturbances in diaphragm fibers promote accelerated proteolysis. Currently, no standard treatment exists to prevent VIDD and, therefore, developing a strategy to avert VIDD is vital. Guided by evidence indicating that activation of the classical axis of the renin-angiotensin system (RAS) in diaphragm fibers promotes oxidative stress and VIDD, we hypothesized that activation of the nonclassical RAS signaling pathway via angiotensin 1-7 (Ang1-7) will protect against VIDD. Using an established animal model of prolonged MV, our results disclose that infusion of Ang1-7 protects the diaphragm against MV-induced contractile dysfunction and fiber atrophy in both fast and slow muscle fibers. Further, Ang1-7 shielded diaphragm fibers against MV-induced mitochondrial damage, oxidative stress, and protease activation. Collectively, these results reveal that treatment with Ang1-7 protects against VIDD, in part, due to diminishing oxidative stress and protease activation. These important findings provide robust evidence that Ang1-7 has the therapeutic potential to protect against VIDD by preventing MV-induced contractile dysfunction and atrophy of both slow and fast muscle fibers.Inhibitor of apoptosis proteins (IAPs) regulate apoptosis and modulate NF-κB signalling thereby driving expression of genes involved in immune/inflammatory responses. The orally available IAP antagonist Debio 1143 has potential to enhance tumor response to chemoradiotherapy and/or immunotherapy. Patients with pre-operative squamous cell carcinomas of the head and neck (SCCHN) received Debio 1143 monotherapy (200 mg/day D1-15 +/-2); Debio 1143 (200 mg/day D1-15 +/-2) plus cisplatin (40 mg/m2 D-1 and 8); cisplatin alone (40 mg/m2 D-1 and 8) (EudraCT 2014-004655-31). Pharmacokinetic/pharmacodynamic effects were assessed in plasma and resected tumors. Primary endpoint; effect of Debio 1143 on cellular IAP-1 (cIAP-1). Levels of cIAP-1/-2, X-linked inhibitor of apoptosis protein (XIAP), tumor infiltrating lymphocytes (TILs) including CD8+ T cells, programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) and gene expression were also analyzed. Twenty-three of 26 patients completed treatment. In the Debio 1143 monotherapy cohort (n=13), mean tumor concentrations of Debio 1143 were 18-fold (maximum 55.2-fold) greater than in plasma, exceeding the IC50 for cIAPs and XIAP by 100 to 1000-fold, with significant engagement/degradation of cIAP-1 (p less then 0.05). Overall, levels of CD8+ TILs, PD-1 and PD-L1 positive immune cells increased significantly (p less then 0.05) following Debio 1143 treatment. Changes were observed in the expression of genes related to NF-κB signalling. Treatments were well tolerated. Debio 1143 penetrated SCCHN tumors, engaged cIAP-1 and induced immune inflammatory changes in the tumor microenvironment. Based on the mode of action demonstrated here and in previous studies, these data support future combinations of Debio 1143 with immune-checkpoint agents.Thyroid-associated ophthalmopathy (TAO) is a serious, progressive, vision-threatening and difficult-to-treat organ-specific autoimmune disease. The course, therapeutic effects and prognosis of moderate to severe TAO vary greatly. High-dose intravenous glucocorticoid (IVGC) therapy is considered a first-line treatment for active moderate-to-severe TAO, but there is still insufficient evidence regarding the treatment duration. Long-term IVGC therapy can influence the metabolism of glucose, lipids, and bone. This study was designed to compare changes in metabolic and immunological indexes as well as the magnetic resonance imaging apparent diffusion coefficient (ADC) of the extraocular muscles after 4 and 12 weeks of IVGC therapy. Forty-eight patients with active moderate-to-severe TAO were included in this retrospective cohort study. Metabolism and immunological indexes were measured before and after therapy. The ADC and clinical activity score (CAS) were used to evaluate the efficacy of treatment in these patients. We found that the patients in the 12-week group had increased fasting plasma glucose (p = 0.004), glycated hemoglobin (p = 0.028), total cholesterol (p less then 0.001), and low-density lipoprotein (p less then 0.001) after therapy. The patients in both groups had reduced bone metabolism markers after therapy. Thyroid peroxidase antibody and thyrotropin receptor antibody levels decreased after treatment in both groups (p less then 0.001). A significant decrease in thyroglobulin antibody levels was found in the 4-week group (p = 0.006). The change in the ADC was higher in the 4-week group than in the 12-week group (p = 0.014). However, there were no significant differences in CAS values between the two groups. Therefore, 4-week IVGC therapy was recommended for patients with TAO with glucose and lipid disorders.RO6870868 is an oral prodrug of the toll-like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a first-in-human, phase I, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200-2000 mg). Single oral doses were generally well-tolerated with a predictable safety profile associated with dose-dependent increases in systemic interferon. No serious adverse events (AEs) were reported and no subject withdrew from the study due to an AE. No clinically significant changes were observed in vital signs, electrocardiograms, or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half-life ranging 2-6 h across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC0-∞ ) increasing proportionally with dose. A pattern of dose and time-dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose-dependent manner with adequate safety and tolerability. Single-dose data in healthy volunteers are useful to evaluate safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B.
This comprehensive meta-analysis aimed to combine data from different studies and to estimate the association between FKBP5 polymorphisms and depression.

We performed a meta-analysis of observational studies. An electronic search was conducted on four databases for articles published before July 1, 2020.

A total of 5125 patients with depression and 8399 controls from 16 independent studies were included in the analysis. The results showed that FKBP5 rs1360780 was associated with the risk of depression in the codominant model (CT vs. CC; OR = 1.10, 95% CI = 1.00-1.20, P = .04); rs4713916 polymorphism was associated with depression in the codominant model (AG vs. GG; OR = 1.19, 95% CI = 1.05-1.34, P = .008) and recessive model (AA vs. AG + GG; OR = 0.74, 95% CI = 0.56-0.99, P = .04); a significant association between rs3800373 and depression was found in the codominant genetic model (AC vs. AA; OR = 1.18, 95% CI = 1.05-1.34, P = .007) and dominant model (CC + AC vs. AA; OR = 1.15, 95% CI = 1.03-1.30, P = d dominant model.Upon infection of host cells, Salmonella enterica serovar Typhimurium resides in a modified-endosomal compartment referred to as the Salmonella-containing vacuole (SCV). SCV biogenesis is driven by multiple effector proteins translocated through two type III secretion systems (T3SS-1 and T3SS-2). While many host proteins targeted by these effector proteins have been characterised, the role of host lipids in SCV dynamics remains poorly understood. Previous studies have shown that S. Typhimurium infection in macrophages leads to accumulation of intracellular cholesterol, some of which concentrates in and around SCVs; however, the underlying mechanisms remain unknown. Here, we show that S. Typhimurium utilises the T3SS-2 effector SseJ to downregulate expression of the host cholesterol transporter ABCA1 in macrophages, leading to a ~45% increase in cellular cholesterol. Mechanistically, SseJ activates a signalling cascade involving the host kinases FAK and Akt to suppress Abca1 expression. Mutational inactivation of SseJ acyltransferase activity, silencing FAK, or inhibiting Akt prevents Abca1 downregulation and the corresponding accumulation of cholesterol during infection. Importantly, RNAi-mediated silencing of ABCA1 rescued bacterial survival in FAK-deficient macrophages, suggesting that Abca1 downregulation and cholesterol accumulation are important for intracellular survival.Vincristine (VCR) is one of the most widely prescribed medications for treating solid tumors and acute lymphoblastic leukemia (ALL) in children and adults. However, its major dose-limiting toxicity is peripheral neuropathy that can disrupt curative therapy. Peripheral neuropathy can also persist into adulthood, compromising quality of life of childhood cancer survivors. Reducing VCR-induced neurotoxicity without compromising its anticancer effects would be ideal. Here, we show that low expression of NHP2L1 is associated with increased sensitivity of primary leukemia cells to VCR, and that concomitant administration of VCR with inhibitors of NHP2L1 increases VCR cytotoxicity in leukemia cells, prolongs survival of ALL xenograft mice, but decreases VCR effects on human-induced pluripotent stem cell-derived neurons and mitigates neurotoxicity in mice. These findings offer a strategy for increasing VCR's antileukemic effects while reducing peripheral neuropathy in patients treated with this widely prescribed medication.Individuals that disperse long distances from their natal site must select breeding patches with no prior knowledge of patch suitability. Despite decades of theoretical studies examining which cues dispersing individuals should use to select breeding patches, few empirical studies have tested the predictions of these theories at spatial scales relevant to long-distance dispersal in wild animal populations. Here, we use a novel assignment model based on multiple intrinsic markers to quantify natal dispersal distances of Wood Thrush (Hylocichla mustelina) breeding in forest fragments. We show that long-distance natal dispersal in this species is more frequent than commonly assumed for songbirds and that habitat selection by these individuals is driven by density-dependence and patch quality but not the amount of habitat surrounding breeding patches. These results represent an important contribution to understanding habitat selection by dispersing individuals, especially with regards to long-distance dispersal.Nintedanib is a multi-target receptor tyrosine kinase inhibitor that reduces the decline in forced vital capacity (FVC) and prevents acute exacerbations in idiopathic pulmonary fibrosis (IPF), which is a risk factor for lung cancer. However, it remains unclear whether nintedanib is an effective treatment for lung cancer in patients with IPF. Here, we describe an 82-year-old man with non-small cell lung carcinoma complicated by IPF who was treated with nintedanib. High-resolution computed tomography (HRCT) showed a subpleural basal-predominant reticular shadow and traction bronchiectasis with a honeycomb pattern. His FVC decreased over time, and his 6-min walk test showed oxygen desaturation. Furthermore, an enlarged nodular lesion was detected after 6 months of referral. Biopsy confirmed non-small cell carcinoma. Because of the risk of acute exacerbation of IPF by chemotherapy, supportive care was selected. Nintedanib was started as treatment for the IPF. Nine months later, HRCT revealed partial remission without exacerbation of IPF. This case indicates the possibility of nintedanib monotherapy in suppressing lung cancer complicated by IPF. Patients with lung cancer complicated by IPF in whom treatment is effective remain unknown. Additional research is needed to identify effective therapy for lung cancer with IPF.The main objective of this study was to determine whether Eltrombopag, a synthetic thrombopoietin receptor agonist, could improve peripheral blood counts in the three hematopoietic lineages and achieve transfusion independence in children with poor graft function (PGF) after allogenic hematopoietic stem cell transplantation (HSCT). Retrospective study of patients under 18 years who developed PGF post-HSCT in a large tertiary institution between January 2013 and March 2019. Out of 198 allogeneic HSCT, five patients met PGF criteria and were treated with eltrombopag. Median time from HSCT to eltrombopag initiation was 120 days. The median starting dose was 50 mg/day and the maximum dose reached was 75 mg/day. Median treatment duration was 9 months. Three patients achieved complete response and one partial response. The median dose among responders was 75 mg/day and the median time to response 8 weeks. Responses were sustained in three patients and two required a booster dose of CD34+ -selected cells from the original donor. None of the patients had to stop treatment due to adverse effects. The use of eltrombopag in children with PGF achieved responses in 80% of cases and demonstrated to be an effective and safe therapeutic option in pediatric patients with PGF.
This study aimed to evaluate the anti-adiposity effect of heat-killed Lactobacillus brevis KB290 originating from traditional Japanese fermented pickles in mice fed a high-fat diet (HFD).

C57BL/6J mice were fed a normal-fat diet, HFD or HFD supplemented with heat-killed KB290 for 8weeks. Epididymal and renal adipose tissue weights, as well as areas of epididymal adipocytes, were significantly lower in the mice fed a HFD supplemented with KB290 than in those fed an unsupplemented HFD. Mice whose diets were supplemented with KB290 had elevated adiponectin and β3-adrenergic receptor expression in epididymal adipose tissue and an accompanying higher serum free fatty acid level. Furthermore, the HFD-induced elevations in serum glucose, insulin and HOMA-IR were significantly suppressed by dietary supplementation with KB290. Amplicon sequencing of 16S rRNA genes revealed that KB290 ingestion altered the composition of the intestinal microbiota.

Heat-killed L. brevis KB290 suppressed diet-induced visceral fat accumulation and ameliorated diet-induced metabolic symptoms and intestinal gut microbiota modifications, suggesting possibility of novel paraprobiotic.

Heat-killed L. brevis KB290 is useable as a material to develop functional foods that attenuate visceral fat accumulation.
Heat-killed L. brevis KB290 is useable as a material to develop functional foods that attenuate visceral fat accumulation.
The Italian Society of Interventional Cardiology (GIse) registry Of Transcatheter treatment of mitral valve regurgitaTiOn (GIOTTO) was conceived in order to assess the safety and efficacy of MitraClip therapy in Italy. The aim of this study was to assess procedural and mid-term outcomes, and clinical and echocardiographic predictors of mid-term mortality after MitraClip therapy, stratifying the results according to the diagnosis of functional and degenerative mitral regurgitation (FMR vs. DMR).

Between January 2016 and March 2020, 1659 patients were prospectively included in the GIOTTO registry (FMR 59.4% vs. DMR 40.6%). Acute Mitral Valve Academic Research Consortium (MVARC) technical success was achieved in 97.2% of patients, without differences between FMR and DMR and with sustained results at 30 days. In the study population, all-cause mortality was 4.0%, 17.5% and 34.6% at 30 days, 1 year and 2 years, respectively. Cardiovascular death was the most frequent cause of mortality. Overall hospitalizationrved within 2 years. Optimal rMR 1+ was correlated to a more favourable mid-term outcome, particularly in FMR.Plants often adjust their leaf mitochondrial ("dark") respiration (Rd ) measured at a standardized temperature such as 20°C (R20 ) downward after experiencing warmer temperatures and upward after experiencing cooler temperatures. These responses may help leaves maintain advantageous photosynthetic capacity and/or be a response to recent photosynthate accumulation, and can occur within days after a change in thermal regime. It is not clear, however, how the sensitivity and magnitude of this response change over time, or which time period prior to a given measurement best predicts R20 . Nor is it known whether nighttime, daytime, or 24-hour temperatures should be most influential. To address these issues, we used data from 1620 Rd temperature response curves of 10 temperate and boreal tree species in a long-term field experiment in Minnesota, USA to assess how the observed nearly complete acclimation of R20 was related to past temperatures during periods of differing lengths. We hypothesized that R20 would be b temporal acclimation responsiveness in some species were all results that were unanticipated.Reliability generalization (RG) is a meta-analytic approach that aims to characterize how reliability estimates from the same test vary across different applications of the instrument. With this purpose RG meta-analyses typically focus on a particular test and intend to obtain an overall reliability of test scores and to investigate how the composition and variability of the samples affect reliability. Although several guidelines have been proposed in the meta-analytic literature to help authors improve the reporting quality of meta-analyses, none of them were devised for RG meta-analyses. The purpose of this investigation was to develop REGEMA (REliability GEneralization Meta-Analysis), a 30-item checklist (plus a flow chart) adapted to the specific issues that the reporting of an RG meta-analysis must take into account. Based on previous checklists and guidelines proposed in the meta-analytic arena, a first version was elaborated by applying the nominal group methodology. The resulting instrument was submitted to a list of independent meta-analysis experts and, after discussion, the final version of the REGEMA checklist was reached. In a pilot study, four pairs of coders applied REGEMA to a random sample of 40 RG meta-analyses in Psychology, and results showed satisfactory inter-coder reliability. REGEMA can be used by (a) meta-analysts conducting or reporting an RG meta-analysis and aiming to improve its reporting quality; (b) consumers of RG meta-analyses who want to make informed critical appraisals of their reporting quality, and (c) reviewers and editors of journals who are considering submissions where an RG meta-analysis was reported for potential publication.
Recently, dipeptidyl peptidase 3 (DPP3) has been discovered as the peptidase responsible for cleavage of angiotensin (1-7) [Ang (1-7)]. Ang (1-7) is part of the angiotensin-converting enzyme-Ang (1-7)-Mas pathway which is considered to antagonize the renin-angiotensin-aldosterone system (RAAS). Since DPP3 inhibits the counteracting pathway of the RAAS, we hypothesize that DPP3 might be deleterious in the setting of heart failure. However, no data are available on DPP3 in chronic heart failure. We therefore investigated the clinical characteristics and outcome related to elevated DPP3 concentrations in patients with worsening heart failure.

Dipeptidyl peptidase 3 was measured in 2156 serum samples of patients with worsening heart failure using luminometric immunoassay (DPP3-LIA) by 4TEEN4 Pharmaceuticals GmbH, Hennigsdorf, Germany. Predictors of DPP3 levels were selected using multiple linear regression with stepwise backward selection. Median DPP3 concentration was 11.45 ng/mL with a range from 2.8 to 84.ibody against DPP3, might be a potential future treatment option for patients with heart failure.
In patients with worsening heart failure, DPP3 is a marker of more severe disease with higher RAAS activity. It may be deleterious in heart failure by counteracting the Mas receptor pathway. Procizumab, a specific antibody against DPP3, might be a potential future treatment option for patients with heart failure.Combined liver-kidney transplantation is a therapeutic option for children affected by type 1 primary hyperoxaluria. Persistently high plasma oxalate levels may lead to kidney graft failure. It is debated whether pre-emptive liver transplantation, followed by kidney transplantation, might be a better strategy to reduce kidney graft loss. Our experience of 6 pediatric combined liver-kidney transplants for primary hyperoxaluria type 1 in pediatric recipients was retrospectively analyzed. Plasma oxalate levels were monitored before and after transplantation. All the recipients were on hemodialysis at transplantation. Median [IQR] recipient's age at transplantation was 11 [1-14] years; in all cases, a compatible graft from a pediatric brain-dead donor aged 8 [2-16] years was used. In a median follow-up of 7 [2-19] years after combined liver-kidney transplantation, no child died and no liver graft failure was observed; three kidney grafts were lost, due to chronic rejection, primary non-function, and early renal oxalate accumulation. Liver and kidney graft survival remained stable at 1, 3, and 5 years, at 100% and 85%, respectively. Kidney graft loss was the major complication in our series. Risk is higher with very young, low-weight donors. The impact of treatment with glyoxalate pathway enzyme inhibitors treatment in children with advanced disease as well as of donor kidney preservation by ex vivo machine perfusion needs to be evaluated. At present, a case-by-case discussion is needed to establish an optimal treatment strategy.Despite the highly strained nature of cyclopropanes possessing three vicinal quaternary carbon stereocenters, the regio- and diastereoselective copper-catalyzed carbomagnesiation reaction of cyclopropenes provides an easy and efficient access to these novel persubstituted cyclopropyl cores with a complete regio- and diastereoselectivity.Evidence for the extrapulmonary benefits of (CFTR) modulators is rapidly expanding. The use of CFTR modulators in CF patients who have undergone lung transplantation is not clear without guidance published in the medical literature to assist clinicians in the care of these patients. We discuss the potential benefits of CFTR modulators and provide insight into their use based on our experience in a small cohort of CF LTx recipients. We present pros and cons of CFTR modulator therapy for LTx recipients with CF. CFTR modulators should be considered in CF patients after lung transplantation for the time being until further research defines how to best use these therapies in transplant recipients.
Shared decision-making (SDM) processes, combining patients' and professionals' perspectives, are especially necessary for patients with complex needs (CNs) during their care transitions. In 2016, we started implementing interprofessional and interinstitutional SDM processes (IIPs) for patients admitted to a short-stay unit (SSU) for inpatient care and then followed-up by primary care providers. Two types of IIPs were identified (a) iterative IIPs, and (b) meeting IIPs. These differed in terms of the timing of SDM processes whereas the former were multilateral and iterative, meeting IIPs were simultaneous. However, the two processes had similar outcomes and participants had similar characteristics. The intervention included other components, such as CNs assessment and a care coordinator position. The present study aimed to assess the feasibility of the intervention's implementation.

The intervention's feasibility was assessed using fidelity and coverage indicators. We collected data from the patients' recolisability.
These results showed that an intervention targeting the implementation of formalized IIPs for SDM in transitional care was feasible. However, to improve the evaluation of such interventions, other methods should be used to measure their appropriateness and acceptability. Additionally, assessing the effects of IIPs would legitimize their funding, supporting their sustainability and generalisability.Within the Open Science project entitled 'Botanic Garden, factory of molecules', a multidisciplinary study approach was applied to Ballota acetabulosa (L.) Benth., at the Ghirardi Botanic Garden (Toscolano Maderno, BS, Italy). Micromorphological and histochemical investigations were performed on the secreting structures of the vegetative and reproductive organs under light, fuorescence and electronic microscopy. Concurrently the characterization of the volatiles spontaneously emitted from leaves and flowers were examined. Four trichome morphotypes were identified peltate and short-stalked, medium-stalked and long-stalked capitate trichomes, each with a specific distribution pattern. The histochemical analysis was confirmed using ultrastructural observations, with the peltates and long-stalked capitates as the main sites responsible for terpene production. The head-space characterization revealed that sesquiterpene hydrocarbons dominated both in leaves and flowers, with γ-muurolene, β-caryophyllene and (E)-nerolidol as the most abundant compounds. Moreover, a comparison with literature data concerning the ecological roles of the main compounds suggested their dominant roles in defence, both at the leaf and flower level. Hence, we correlated the trichome morphotypes with the production of secondary metabolites in an attempt to link these data to their potential ecological roles. Finally, we made the obtained scientific knowledge available to visitors of the Botanic Garden through the realization of new labelling dedicated to B. acetabulosa that highlights the 'invisible', microscopic features of the plant.Tenofovir disoproxil fumarate (TDF) in combination with emtricitabine (FTC) is the backbone for both human immunodeficiency virus (HIV) treatment and pre-exposure prophylaxis (PrEP) worldwide. Tenofovir alafenamide (TAF) with FTC is increasingly used in HIV treatment and was recently approved for PrEP among men-who-have-sex-with-men. TDF and TAF are both metabolized into tenofovir (TFV). Antiretrovirals in plasma are taken up into hair over time, with hair levels providing a long-term measure of adherence. Here, we report a simple, robust, highly sensitive, and validated high-performance liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS)-based analytical method for analyzing TFV and FTC from individuals on either TDF/FTC or TAF/FTC in small hair samples. TFV/FTC are extracted from ~5 mg hair and separated on a column using a gradient elution. The lower quantification limits are 0.00200 (TFV) and 0.0200 (FTC) ng/mg hair; the assay is linear up to 0.400 (TFV) and 4.00 (FTC) ng/mg hair. The intra-day and inter-day coefficients of variance (CVs) are 5.39-12.6% and 6.40-13.5% for TFV and 0.571-2.45% and 2.45-5.16% for FTC. TFV concentrations from participants on TDF/FTC-based regimens with undetectable plasma HIV RNA were 0.0525 ± 0.0295 ng/mg, whereas those from individuals on TAF/FTC-based regimens were 0.0426 ± 0.0246 ng/mg. Despite the dose of TFV in TDF being 10 times that of TAF, hair concentrations of TFV were not significantly different for those on TDF versus TAF regimens. Pharmacological enhancers (ritonavir and cobicistat) did not boost TFV concentrations in hair. In summary, we developed and validated a sensitive analytical method to analyze TFV and FTC in hair and found that hair concentrations of TFV were essentially equivalent among those on TDF and TAF.
Fatty liver disease (FLD) is a surrogate condition for glucose intolerance development. FLD may involve normal or abnormal liver enzyme levels. Whether FLD is a risk factor for glucose intolerance, regardless of liver enzyme levels, remains unknown. We assessed relationships between the development of impaired fasting glucose (IFG) and FLD, liver enzyme abnormalities, and alcohol consumption.

We retrospectively evaluated 8,664 participants with more than two annual health check-ups. Participants were classified according to sex, alcohol consumption, alanine aminotransferase (ALT) levels, and fatty liver status.

In univariate analyses, IFG onset among men was related to normal or high ALT levels with FLD in the nonalcoholic and alcoholic groups (P-trend<0.01). In multivariate analyses, IFG onset among nonalcoholic men was associated with normal or high ALT levels with FLD, independent of potential confounding factors (P-trend<0.01). However, IFG onset was non-independently associated with any condition among alcoholic men. In univariate analyses, IFG onset among women was related to normal or high ALT levels with FLD in the nonalcoholic group (P-trend<0.01) and high ALT levels with FLD in the alcoholic group (P-trend<0.05). In multivariate analyses, IFG onset was independently associated with only normal ALT levels in nonalcoholic FLD women.

Among nonalcoholic men and women, FLD was a risk factor for IFG onset, including normal ALT concentrations. Care is needed for individuals with nonalcoholic FLD, regardless of liver injury, possibly helping reduce glucose intolerance risk.
Among nonalcoholic men and women, FLD was a risk factor for IFG onset, including normal ALT concentrations. Care is needed for individuals with nonalcoholic FLD, regardless of liver injury, possibly helping reduce glucose intolerance risk.Multiple-resonance (MR) organic emitters bearing small full-width at half-maximum (FWHMs) are of general interest in organic light-emitting diodes. Indolo[3,2,1-jk]carbazole (ICz) embedded MR-fluorophors have demonstrated extremely small FWHMs, yet in the violet region with low electroluminescence efficiency. Herein, a strategic implementation of ICz subunits into MR fluorophors is proposed by taking advantage of the synergetic effect of para-positioned nitrogen atoms to enhance electronic coupling to decrease emitting energy gap. Deep blue emitters peaking at 441 and 447 nm with FWHMs of only 18 and 21 nm are thereof obtained, respectively, accompanied by ≈90 % photo-luminance quantum yields. With the assistance of a thermally activated delayed fluorescence sensitizer to recycle excitons, the corresponding narrowband electroluminescent devices show unprecedent high maximum external quantum efficiencies of 32.0 % and 34.7 % with CIEy of 0.10 and 0.085, respectively.Discrete molecular soft cages integrate multiple functionalities in one molecule. They express their functions from the confined space in their cavity, functional groups in the cavity interior wall and exterior wall, and the chelating nodes in many chelating cages. Such functional integrity render cage molecules special applications in material engineering. Increasing applications of cage molecules in material design have been reported in recent years. Compared with other cavity-rich molecular structures such as metal-organic framework (MOF) or covalent organic frameworks (COF), discrete soft cages present the unique advantage of material design flexibility, that they can easily composite with nanoparticles or polymers and exist in materials of various forms. We document the development of cage-based materials in recent years and expect to further inspire materials engineering to integrate contribution from the functionality specificity of cage molecules and ultimately promote the development of functional materials and thus human life qualities.The caregivers of people with schizophrenia might suffer from various problems. We investigated the prevalence of depression, anxiety, and stress among them, and factors associated with their quality of life. A cross-sectional study in communities of rural areas was conducted. We found that the prevalence of depression, anxiety, and stress were 14.2%, 25.5%, and 6.6%, respectively. Their quality of life was independently associated with family functioning (affective responsiveness, problem solving, communication) and the presence of depressive symptoms (p  less then  .05). Schizophrenia caregivers need more supports from health care professionals to improve their skills in problem solving.
This study aimed to evaluate prognostic value of quantitative flow ratio (QFR) in drug-coated balloon (DCB) angioplasty for in-stent restenosis (ISR).

There is a high incidence of recurrent ISR after DCB angioplasty. QFR is a novel method for fast computation of fractional flow reserve for the target vessel based on quantitative coronary angiography (QCA) and fluid dynamics algorithms.

Patients participating in the RESTORE ISR China randomized trial were enrolled and classified into the recurrent restenosis group and the non-recurrent restenosis group. The binary classifications followed the QCA standards of ISR. Clinical and angiographic characteristics of the groups were analyzed, and the QFRs before and after lesion preparation and after final DCB angioplasty were measured and compared.

A total of 208 patients who underwent follow-up angiography were enrolled in the study, with 226 lesions measured in total. QFR value after DCB angioplasty (odds ratio [OR] 0.88; 95% confidence interval [CI] 0.83-0.93; p < .0001 for 1 mm increase), lesion length (OR 1.08; 95% CI 1.01-1.15; p = .017), and vessel caliber lumen diameter (OR 0.35; 95% CI 0.13-0.89; p = .027) were independently associated with recurrent restenosis after DCB angioplasty. The optimal QFR cut-off value was determined to be 0.90 with a sensitivity of 0.94, specificity of 0.56, and accuracy of 0.79 in predicting recurrent restenosis.

The QFR value after DCB angioplasty is a promising predictor of DES ISR.
The QFR value after DCB angioplasty is a promising predictor of DES ISR.
Although digital health tools (DHTs) are a promising alternative and effective strategy to deliver cancer care and support, their role in health promotion among cancer survivors remains relatively unexplored. We aimed to investigate the acceptability and impact of DHT for health promotion in cancer survivors.

Data was pooled from cycle three of the fifth edition of the Health Information National Trends Survey. Logistic regressions were conducted to evaluate differences between cancer survivors and the general population regarding ownership, usage, and perceived usefulness of DHT for health management. Regression models were used to identify sociodemographic predictors of DHT usage among cancer survivors.

Overall, cancer survivors were as likely as the general population to own and use DHT (e.g., health apps, wearable devices) for their care and they were likely to find these tools beneficial in tracking their health and communicating with healthcare providers. Cancer survivors who had health applications installed on their mobile device were more likely to meet national recommendations for diet (fruit and vegetable consumption) and strength training than those without health apps. Age, income, and education level were significant sociodemographic predictors of DHT ownership and usage.

Cancer survivors own and use DHT at similarly high rates to the general population, highlighting the potential for utilizing DHT to expand access and continuity of care in the growing and vulnerable oncology population. With increasing use of DHT in healthcare, future research that targets digital access disparities in cancer survivors from low SES is essential.
Cancer survivors own and use DHT at similarly high rates to the general population, highlighting the potential for utilizing DHT to expand access and continuity of care in the growing and vulnerable oncology population. With increasing use of DHT in healthcare, future research that targets digital access disparities in cancer survivors from low SES is essential.Horizontal gene transfer is an important evolutionary mechanism not only for bacteria but also for eukaryotes. In the domestic silkworm Bombyx mori, a model species of lepidopteran insects, some enzymes are known to have been acquired by horizontal transfer; however, the enzymatic features of protein BmNag31, belonging to glycoside hydrolase family 31 (GH31) and whose gene was predicted to be transferred from Enterococcus sp. are unknown. In this study, we reveal that the transcription of BmNag31 increases significantly during the prepupal to pupal stage, and decreases in the adult stage. The full-length BmNag31 and its truncated mutants were heterologously expressed in Escherichia coli and characterized. Its catalytic domain exhibits α-N-acetylgalactosaminidase activity and the carbohydrate-binding module family 32 domain shows binding activity towards N-acetylgalactosamine, similar to the Enterococcus faecalis homolog, EfNag31A. Gel filtration chromatography and blue native polyacrylamide gel electrophoresis analyses indicate that BmNag31 forms a hexamer whereas EfNag31A is monomeric. These results provide insights into the function of lepidopteran GH31 α-N-acetylgalactosaminidase.The experiment was designed to study the use of rambutan (Nephelium lappaceum) fruit peel powder (RP) with urea (U) supplementation on rumen fermentation, digestibility, methane (CH4 ) production, milk production and composition in lactating dairy cows. Four Holstein crossbred lactating dairy cows, with starting liveweight of 450 ± 15 kg with 130 ± 10 DIM (days-in-milk), were randomly allocated to respective treatments without supplementation (control; T1), supplementation of urea (U) at 90 g/hd/day (T2), supplementation of RP at 450 g/hd/day (T3) and supplementation of RPU (RP at 450 g/hd/day and U 90 g/hd/day) (T4), respectively, using a 4 × 4 Latin square design. The results showed that the U, RP and RPU supplementation did not change feed intakes (p > 0.05) and digestibilities of DM and OM were similar. However, digestibilities of CP and NDF were increased in the U and RPU groups (p 0.05). Supplementation of either U or RPU significantly improved fibre digestibilities, rumen fermentation, microbial protein synthesis, reduced protozoal population, mitigated CH4 production and enhanced milk yield and milk composition.
Extended half-life (EHL) factor VIII (FVIII) products may decrease the burden of prophylactic treatment in haemophilia A by reducing infusion frequency. However, these products still exhibit wide inter-patient variability and benefit from pharmacokinetic (PK) tailoring.

Identify limited sampling strategies for rFVIIIFc, an EHL FVIII product, that produce accurate estimates of PK parameters and relevant troughs.

We performed a limited sampling analysis on simulated populations of adults, adolescents, and children based on published population PK data. Sampling strategies were evaluated by comparing the error in estimates of half-life, clearance, and trough levels, to a full 6-sample design. Furthermore, we assessed the impact of incorporating knowledge about prior doses, and the day of the PK study within the regimen. We also evaluated the potential inappropriate dose adjustment rate (IDAR) among the modelled sampling strategies.

Many sampling strategies, including several 2-sample designs, accurately predicted the PK and exposure measures (median absolute error <10%). When samples are only collected during a single visit (i.e., predose+peak), inclusion of prior dose information reduces median half-life error from >20% to ~5% for adults/adolescents. In this same scenario, appropriate scheduling of the PK study decreases likelihood of unmeasurable predose samples, reducing median error on the 72-h trough from 25% to <12% in the youngest population.

The PK of rFVIIIFc can be accurately estimated using only peak and trough samples, provided that knowledge of prior doses is incorporated and the PK study is planned on an appropriate day within the dosing regimen.
The PK of rFVIIIFc can be accurately estimated using only peak and trough samples, provided that knowledge of prior doses is incorporated and the PK study is planned on an appropriate day within the dosing regimen.Time series of vegetation indices derived from satellite imagery are useful in measuring vegetation response to climate warming in remote northern regions. These indices show that productivity is generally declining in the boreal forest, but it is unclear which components of boreal vegetation are driving these trends. We aimed to compare trends in the normalized difference vegetation index (NDVI) to forest growth and demographic data taken from a 10 ha mapped plot located in a spruce-dominated boreal peatland. We used microcores to quantify recent growth trends and tree census data to characterize mortality and recruitment rates of the three dominant tree species. We then compared spatial patterns in growth and demography to patterns in Landsat-derived maximum NDVI trends (1984-2019) in 78 pixels that fell within the plot. We found that NDVI trends were predominantly positive (i.e., "greening") in spite of the ongoing loss of black spruce (the dominant species; 80% of stems) from the plot. The magnitude of these trends correlated positively with black spruce growth trends, but was also governed to a large extent by tree mortality and recruitment. Greening trends were weaker (lower slope) in areas with high larch mortality, and high turnover of spruce and birch, but stronger (higher slope) in areas with high larch recruitment. Larch dominance is currently low (~11% of stems), but it is increasing in abundance as permafrost thaw progresses and will likely have a substantial influence on future NDVI trends. Our results emphasize that NDVI trends in boreal peatlands can be positive even when the forest as a whole is in decline, and that the magnitude of trends can be strongly influenced by the demographics of uncommon species.The gut-microbiota-brain axis is the most important complex and bidirectional pathway between the gastrointestinal tract and the central nervous system. This study investigated the potential of microbe-induced gut-to-brain signaling to modulate the effect of stress on depressive-like behavior, intestinal barrier, and neuroinflammation. Result showed that fecal microbiota transplantation increased the consumption of sucrose solutions and decreased the immobility time in forced swimming test. This treatment also increased Firmicutes and decreased Bacteroidetes and Desulfobacterota at phylum levels; reduced the loss of villi and epithelial cells; suppressed the inflammatory cell infiltration in the ileum; increased the expression of ZO-1, occludin; protected the mucosal layer function; and suppressed the high levels of inflammasomes (NLRP3, ASC, caspase-1, and IL-1β) in rat brain. In summary, fecal microbiota transplantation improves the depressive-like behavior, alters the gut microbiota imbalance, and alleviates the intestinal tract inflammation, intestinal mucosa disruption, and neuroinflammation in rats induced by chronic unpredictable mild stress.
To develop a model for predicting renal recovery in cardiac surgery patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT).

Data from a prospective randomized controlled trial, conducted in a tertiary hospital to compare the survival effect of two dosages of hemofiltration for continuous RRT in cardiac surgery patients between 20 March 2012 and 9 August 2015, were used to develop the model. The outcome was renal recovery defined as alive and dialysis-free 90 days after RRT initiation. Multivariate logistic regression with a stepwise backward selection of variables based on Akaike Information Criterion was applied to develop the model, which was internally validated using bootstrapping. Model discrimination, calibration and clinical value were assessed using the concordance index (C-Index), calibration plots and decision curve analysis, respectively.

Totally, 211 patients with AKI requiring RRT (66.8% male) with median age of 57 years were included. The incidence of renal recovery was 33.2% (n=70). The model included six variables body mass index stratification, baseline estimated glomerular filtration rate, hypertension, sepsis, mean arterial pressure and mechanical ventilation. The C-Index for this model was 0.807 (95% CI, 0.744-0.870). After correction by the bootstrap, the C-Index was 0.780 (95% CI, 0.720-0.845). The calibration plots indicated good consistency between actual observations and model prediction of renal recovery. Decision curve analysis demonstrated the model was clinical usefulness.

We developed and validated a model to predict the chance of renal recovery in cardiac surgery patients with AKI requiring RRT.
We developed and validated a model to predict the chance of renal recovery in cardiac surgery patients with AKI requiring RRT.
Synthetic emulsifiers have recently been shown to promote metabolic syndrome and considerably alter gut microbiota. Yet, data are lacking regarding the effects of natural emulsifiers, such as plant lecithins rich in essential α-linolenic acid (ALA), on gut and metabolic health.

For 5 days, male Swiss mice are fed diets containing similar amounts of ALA and 0, 1, 3, or 10% rapeseed lecithin (RL) or 10% soy lecithin (SL). Following an overnight fast, they are force-fed the same oil mixture and euthanized after 90 minutes.The consumption of lecithin significantly increased fecal levels of the Clostridium leptum group (p = 0.0004), regardless of origin or dose, without altering hepatic or intestinal expression of genes of lipid metabolism. 10%-RL increased ALA abundance in plasma triacylglycerols at 90 minutes,reduced cecal bile acid hydrophobicity, and increased their sulfatation, as demonstrated by the increased hepatic RNA expression of Sult2a1 (p = 0.037) and cecal cholic acid-7 sulfate (CA-7S) concentration (p = 0.05) versus 0%-lecithin.

After only 5 days, nutritional doses of RL and SL modified gut bacteria in mice, by specifically increasing C. leptum group. RL also increased postprandial ALA abundance and induced beneficial modifications of the bile acid profile. ALA-rich lecithins, especially RL, may then appear as promising natural emulsifiers.
After only 5 days, nutritional doses of RL and SL modified gut bacteria in mice, by specifically increasing C. leptum group. RL also increased postprandial ALA abundance and induced beneficial modifications of the bile acid profile. ALA-rich lecithins, especially RL, may then appear as promising natural emulsifiers.In the wake of the COVID-19 pandemic, little is known about how university training programs transitioned to teletherapy. This study describes the transition of two university marriage and family therapy (i.e., master's and doctoral) training clinics to teletherapy and presents preliminary analyses of the types of clients and cases that converted to teletherapy. A series of chi-square analyses, a t-test, a logistic regression model, and a multiple linear regression model were employed. Four key findings emerged (1) most cases converted to teletherapy; (2) Hispanic ethnicity was the only demographic characteristic to significantly predict conversion to teletherapy; (3) individual cases were significantly more likely to convert to teletherapy than relational cases; and (4) the number of prior in-person sessions attended significantly predicted conversion to teletherapy. Teletherapy conversion implications are discussed across four systemic levels client, student trainee, supervision, and larger systems.
The arginine-glutamic acid dipeptide repeats gene (RERE) encodes a nuclear receptor coregulator that modulates gene expression through its interaction with transcriptional machinery. In humans, RERE deficiency causes neurodevelopmental disorder with or without structural defects of the brain, eye, heart, and kidney (NEDBEH). Ophthalmological defects are seen in approximately one third of individuals with NEDBEH and in RERE-deficient mice which can serve as a useful animal model.

In mice, RERE is expressed in a subset of retinal ganglion cells (RGC), the lens epithelium, and the ciliary body during the embryonic period. RERE expression expands into the outer nuclear layer and the inner nuclear layer during the postnatal period. RERE-deficient mice have retinal and optic nerve atrophy. We show that RERE deficiency causes progressive loss of retinal cells and apoptosis of retinal cells in the ganglion cell layer as early as E17.5. The number of RGCs is also reduced in RERE-deficient embryos and mice.

We conclude that RERE is required to control the apoptosis of retinal cells in the developing retina, and that RERE deficiency results in the retina atrophy through degeneration of the retinal cells and optic nerve atrophy through the loss of RGCs.
We conclude that RERE is required to control the apoptosis of retinal cells in the developing retina, and that RERE deficiency results in the retina atrophy through degeneration of the retinal cells and optic nerve atrophy through the loss of RGCs.
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