Notes

DNA-Mediated Au-Au Dimer-Based Surface area Plasmon Direction Electrochemiluminescence Warning pertaining to BRCA1 Gene Discovery.
28; 95% CI, 1.14-1.44) and rise (HR, 1.18; 95% 1.05-1.32) in SUA were related to risk of all-cause mortality. These associations were similar across different baseline SUA categories. Consistent results were observed in alternative measures of SUA variability. Moreover, individuals with higher variability in SUA were more related to common risk factors than those with stable SUA.

Higher variability in SUA was independently associated with the risk of all-cause mortality irrespective of baseline SUA and direction of variability in the general population.
Higher variability in SUA was independently associated with the risk of all-cause mortality irrespective of baseline SUA and direction of variability in the general population.
Multiple myeloma (MM) is a type of hematological malignancy affecting the functions of plasma cells. The treatment of MM patients has changed dramatically with the use of new agents. However, unfortunately, it is still incurable. Therefore, a new approach for treating MM is still needed to improve patient outcomes.

Because the histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) pathway is a key signal in cancer cell biology, we investigated whether dual HDAC and PI3K inhibitors could suppress the myeloma cells.

Gene expression of HDACs is high in myeloma cells. CUDC-907, a dual inhibitor of PI3K and HDAC, inhibits HDAC activity. Akt activity and expression of BCL-XL, MCL-1, and NF-κB p65 were reduced by CUDC-907 in a dose-dependent manner. The number of apoptotic and caspase 3/7-positive cells also increased in the myeloma cells. Combined treatment of myeloma cells with carfilzomib and CUDC-907 increased cytotoxicity compared to that observed with each drug alone.

Data from this study suggested that the administration of CUDC-907 might be a powerful strategy against myeloma cells, to enhance the cytotoxic effects of proteasome inhibitors.
Data from this study suggested that the administration of CUDC-907 might be a powerful strategy against myeloma cells, to enhance the cytotoxic effects of proteasome inhibitors.
MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models.

Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel.

ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent.

The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.
The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.
Pretreatments are commonly used to facilitate the deconstruction of lignocellulosic biomass to its component sugars and aromatics. Previously, we showed that iron ions can be used as co-catalysts to reduce the severity of dilute acid pretreatment of biomass. Transgenic iron-accumulating Arabidopsis and rice plants exhibited higher iron content in grains, increased biomass yield, and importantly, enhanced sugar release from the biomass.

In this study, we used intracellular ferritin (FerIN) alone and in combination with an improved version of cell wall-bound carbohydrate-binding module fused iron-binding peptide (IBPex) specifically targeting switchgrass, a bioenergy crop species. The FerIN switchgrass improved by 15% in height and 65% in yield, whereas the FerIN/IBPex transgenics showed enhancement up to 30% in height and 115% in yield. The FerIN and FerIN/IBPex switchgrass had 27% and 51% higher in planta iron accumulation than the empty vector (EV) control, respectively, under normal growth conditions. Improved pretreatability was observed in FerIN switchgrass (~ 14% more glucose release than the EV), and the FerIN/IBPex plants showed further enhancement in glucose release up to 24%.

We conclude that this iron-accumulating strategy can be transferred from model plants and applied to bioenergy crops, such as switchgrass. The intra- and extra-cellular iron incorporation approach improves biomass pretreatability and digestibility, providing upgraded feedstocks for the production of biofuels and bioproducts.
We conclude that this iron-accumulating strategy can be transferred from model plants and applied to bioenergy crops, such as switchgrass. The intra- and extra-cellular iron incorporation approach improves biomass pretreatability and digestibility, providing upgraded feedstocks for the production of biofuels and bioproducts.
Measuring access to medicines has often been limited to assessing availability and affordability, while little is known regarding other dimensions of access including geographical accessibility. Our study aims to provide a systematic review of literature on the accessibility of medicines by studying the geographical distribution of pharmacies using Spatial Analytical methods.

As systematic review of scientific peer-reviewed literature between 2000 and 2018 was carried out using PubMed, Web of Science, Google Scholar, Google and the Preferred Reporting items for Systematic Reviews and Meta-Analyses (PRISMA). Data regarding pharmacy density, distance to pharmacies in relation of pharmacy to sociodemographic factors and pharmacy characteristics were extracted from studies that meet the inclusion criteria.

Twenty papers fulfilled our inclusion criteria, of which only three were from middle income countries and rest from high-income economies. Pharmacy density per population was reported in 15 studies. Although geographical information was utilized in all studies, only 14 studies reported distance to pharmacies represented as Euclidean (straight line) distance. Disparities in accessibility was reported according to population income and rural or urban location. Seven studies described additional pharmacy characteristics including opening hours, presence of a pharmacist and delivery services.

Geographical accessibility is a key dimension of access to medicines. Pharmacy density per population is a relevant indicator to assess geographical accessibility which should be complemented by an equity analysis using socio-demographic information and population perception of accessibility.
Geographical accessibility is a key dimension of access to medicines. Pharmacy density per population is a relevant indicator to assess geographical accessibility which should be complemented by an equity analysis using socio-demographic information and population perception of accessibility.
Dangguixu-san (DS), a herbal extract, is widely used in Korean medicine to treat pain and swelling caused by ankle sprain. However, there is insufficient evidence regarding the effects of DS on ankle sprains. Accordingly, we assessed the efficacy and safety of DS for the treatment of acute lateral ankle sprain (ALAS).

This study was a multicenter (two Korean hospitals), randomized, double-blind, placebo-controlled, parallel-arm clinical trial with a 11 allocation ratio that included a per-protocol analysis and sub-analysis based on symptom severity. Forty-eight participants (n = 28 at Semyung University Korean Medicine Hospital in Chungju; n = 20 at DongShin University Gwangju Korean Medicine Hospital) with grade I or II ALAS that occurred within 72 h before enrollment were randomized to a DS (n = 24) or placebo (n = 24) group. Both groups received acupuncture treatment once daily for 5 consecutive days and the trial medication (DS/placebo capsule) three times a day for 7 consecutive days. Primary (visual and symptom alleviation in patients with grade I or II ALAS.

Clinical Research Information Service KCT0002374 . Registered on July 11, 2017; retrospectively registered.
Clinical Research Information Service KCT0002374 . Registered on July 11, 2017; retrospectively registered.
Whether elevated blood pressure (BP) is a modifiable risk factor for atrial fibrillation (AF) is not established. We tested (1) whether the association between BP and risk of AF is causal, (2) whether it varies according to individual's genetic susceptibility for AF, and (3) the extent to which specific BP-lowering drugs are expected to reduce this risk.

First, causality of association was assessed through two-sample Mendelian randomization, using data from two independent genome-wide association studies that included a population of one million Europeans in total. Second, the UK Biobank data of 329,237 participants at baseline was used to study the effect of BP on AF according to genetic susceptibility of developing AF. Third, a possible treatment effect with major BP-lowering drug classes on AF risk was predicted through genetic variants in genes encode the therapeutic targets of each drug class. Estimated drug effects were compared with effects on incident coronary heart disease, for which direct trialin AF prevention. However, average effects masked clinically important variations, with a more pronounced effect in individuals with high genetic susceptibility risk for AF.
The effect of elevated BP on the risk of AF is likely to be causal, suggesting that BP-lowering treatment may be effective in AF prevention. However, average effects masked clinically important variations, with a more pronounced effect in individuals with high genetic susceptibility risk for AF.
Central precocious puberty is a condition characterized by precocious activation of the hypothalamic-pituitary-gonadal axis. It may be idiopathic or secondary to organic causes, including syndromes such as Neurofibromatosis type 1 (NF1).

We presented a girl of 6 years and 10 months with almost 11 café-au-lait skin macules, without other clinical or radiological signs typical of NF1, and with a central precocious puberty. Genetic analysis evidenced the new variant NM-152594.2c.304delAp. (Thr102Argfs*19) in SPRED1 gene, which allowed to diagnose Legius syndrome.

We report for the first time a case of central precocious puberty in a girl with Legius syndrome. The presence of central precocious puberty in a child with characteristic café-au-lait macules should suggest pediatricians to perform genetic analysis in order to reach a definitive diagnosis. Further studies on timing of puberty in patients with RASopathies are needed to better elucidate if this clinical association is casual or secondary to their clinical condition.
We report for the first time a case of central precocious puberty in a girl with Legius syndrome. The presence of central precocious puberty in a child with characteristic café-au-lait macules should suggest pediatricians to perform genetic analysis in order to reach a definitive diagnosis. Further studies on timing of puberty in patients with RASopathies are needed to better elucidate if this clinical association is casual or secondary to their clinical condition.
In recent years, the popularity of multi-arm multi-stage, seamless adaptive, and platform trials has increased. However, many design-related questions and questions regarding which operating characteristics should be evaluated to determine the potential performance of a specific trial design remain and are often further complicated by the complexity of such trial designs.

A systematic search was conducted to review existing software for the design of platform trials, whereby multi-arm multi-stage trials were also included. The results of this search are reported both on the literature level and the software level, highlighting the software judged to be particularly useful.

In recent years, many highly specialized software packages targeting single design elements on platform studies have been released. Only a few of the developed software packages provide extensive design flexibility, at the cost of limited access due to being commercial or not being usable as out-of-the-box solutions.

We believe that both an open-source modular software similar to OCTOPUS and a collaborative effort will be necessary to create software that takes advantage of and investigates the impact of all the flexibility that platform trials potentially provide.
We believe that both an open-source modular software similar to OCTOPUS and a collaborative effort will be necessary to create software that takes advantage of and investigates the impact of all the flexibility that platform trials potentially provide.
Before the deposition of amyloid-beta plaques and the onset of learning memory deficits, patients with Alzheimer's disease (AD) experience olfactory dysfunction, typified by a reduced ability to detect, discriminate, and identify odors. Rodent models of AD, such as the Tg2576 and APP/PS1 mice, also display impaired olfaction, accompanied by aberrant in vivo or in vitro gamma rhythms in the olfactory pathway. However, the mechanistic relationships between the electrophysiological, biochemical and behavioral phenomena remain unclear.

To address the above issues in AD models, we conducted in vivo measurement of local field potential (LFP) with a combination of in vitro electro-olfactogram (EOG), whole-cell patch and field recordings to evaluate oscillatory and synaptic function and pharmacological regulation in the olfactory pathway, particularly in the olfactory bulb (OB). Levels of protein involved in excitation and inhibition of the OB were investigated by western blotting and fluorescence staining, whileerlying aberrant gamma activity in the OB.

This study suggests that the concomitant dysfunction of both olfactory behavior and gamma oscillations have important implications for early AD diagnosis in particular, awareness of aberrant GABAergic signaling mechanisms might both aid diagnosis and suggest therapeutic strategies for olfactory damage in AD.
This study suggests that the concomitant dysfunction of both olfactory behavior and gamma oscillations have important implications for early AD diagnosis in particular, awareness of aberrant GABAergic signaling mechanisms might both aid diagnosis and suggest therapeutic strategies for olfactory damage in AD.
Heterotrophic single-cell oils (SCOs) are one potential replacement to lipid-derived biofuels sourced from first-generation crops such as palm oil. However, despite a large experimental research effort in this area, there are only a handful of techno-economic modelling publications. As such, there is little understanding of whether SCOs are, or could ever be, a potential competitive replacement. To help address this question, we designed a detailed model that coupled a hypothetical heterotroph (using the very best possible biological lipid production) with the largest and most efficient chemical plant design possible.

Our base case gave a lipid selling price of $1.81/kg for ~ 8,000 tonnes/year production, that could be reduced to $1.20/kg on increasing production to ~ 48,000 tonnes of lipid a year. A range of scenarios to further reduce this cost were then assessed, including using a thermotolerant strain (reducing the cost from $1.20 to $1.15/kg), zero-cost electricity ($ 1.12/kg), using non-sterile cond a low molecular weight, bulk chemical, alongside the lipid. All other research areas will only ever give incremental gains rather than leading towards an economically competitive, sustainable, microbial oil.
The model presented here represents an ideal case that which while not achievable in reality, importantly would not be able to be improved on, irrespective of the scientific advances in this area. From the scenarios explored, it is possible to produce lower cost SCOs, but research must start to be applied in three key areas, firstly designing products where the whole cell is used. Secondly, further work on the product systems that produce lipids extracellularly in a continuous processing methodology or finally that create an effective biorefinery designed to produce a low molecular weight, bulk chemical, alongside the lipid. All other research areas will only ever give incremental gains rather than leading towards an economically competitive, sustainable, microbial oil.
A few literatures reported that the outcomes of total knee replacement (TKR) in posttraumatic osteoarthritis (PTOA) were lower compared to TKR in primary osteoarthritis (primary OA). The study's purpose was to compare the comorbidity and outcome of TKR among fracture PTOA, ligamentous PTOA, and primary OA. The secondary aim was to identify the effect of postoperatively lower limb mechanical axis on an 8-year survivorship after TKR between PTOA and primary OA.

Seven hundred sixteen patients with primary OA, 32 patients with PTOA (knee fracture subgroup), and 104 PTOA (knee ligamentous injury subgroup) were recruited. Demography, comorbidities, Charlson Comorbidity Index (CCI), operative parameters, mechanical axis, functional outcome assessed by WOMAC, and complications were compared among the three groups.

PTOA group was significantly younger (p<0.0001) with a higher proportion of men (p=0.001) while the primary OA group had higher comorbidities than the PTOA group, including anticoagulant usage (p=0.0002), ASA class ≥3 (p<0.0001), number of diseases ≥ 4 (p<0.0001), and CCI (p<0.0001). Both the fracture PTOA group (p<0.0001) and ligamentous PTOA group (p = 0.009) had a significantly longer operative time than the primary OA group. The fracture PTOA group had significantly lower pain components and stiffness components than the primary OA group. There was no significant difference in the rate of an aligned group, outlier group, and an 8-year survivorship in both groups.

The outcome following TKR in the fracture PTOA was poorer compared to primary knee OA in the midterm follow-up. However, no difference was detected between the ligamentous PTOA and primary knee OA. The mechanical axis alignment within the neutral axis did not affect the 8-year survivorship after TKR in both groups.

Level III; retrospective cohort study.
Level III; retrospective cohort study.
Nicotine replacement therapy (NRT) has proven effect in assisting smoking cessation. However, its effectiveness varies across studies and population groups. This may be due to differences in the rate of adherence. Hence, this review aims to examine the level of adherence to NRT and to assess if the level of adherence to NRT affects success of smoking cessation.

A systematic review and meta-analysis was conducted using studies retrieved from five electronic databases (MEDLINE, Scopus, EMBASE, Web of science, and PsycINFO) and grey literature. Pooled analysis was conducted using Stata version 16 software. Methodological quality and risk of bias were assessed using the NIH Quality Assessment Tool. Analyses were done among those studies that used similar measurements to assess level of adherence and successful smoking cessation. Heterogeneity of studies was assessed using the Higgins' I
statistical test. Funnel plots and Egger's regression asymmetry test were used to affirm presence of significant publicatice. Health programs and policies are recommended to integrate the issue of adherence to NRT as a core component of smoking cessation interventions.

PROSPERO registration number CRD42020176749 . Registered on 28 April 2020.
PROSPERO registration number CRD42020176749 . Registered on 28 April 2020.
Necrotizing enterocolitis (NEC) is the most frequent life-threatening gastrointestinal disease experienced by premature infants in neonatal intensive care units all over the world. The objective of the present study was to take advantage of RNA-Seq data from the analysis of intestinal specimens of preterm infants diagnosed with NEC. Function enrichments with Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes were used to analyse previous data in order to identify biological and functional processes, which could provide more insight into the pathogenesis of NEC in infants.

Gene set enrichment analysis indicated that the most significant biological pathways over-represented in NEC neonates were closely associated with innate immune functions. One of the striking observations was the highly modulated expression of inflammatory genes related to the IL-17 pathway including such as pro-inflammatory cytokines (CXCL8), chemokines (CXCL5 and CXCL10) and antimicrobials (DEF5A, DEF6A, LCN2, NOS2) in the i its downstream targets in NEC.
Goatpox is a viral disease caused by infection with goatpox virus (GTPV) of the genus Capripoxvirus, Poxviridae family. Capripoxviruses cause serious disease to livestock and contribute to huge economic losses. Goatpox and sheeppox are endemic to Africa, particularly north of the Equator, the Middle East and many parts of Asia. GTPV and sheeppox virus are considered host-specific; however, both strains can cause clinical disease in either goats or sheep with more severe disease in the homologous species and mild or sub-clinical infection in the other. Goatpox has never been reported in Morocco, Algeria or Tunisia despite the huge population of goats living in proximity with sheep in those countries. To evaluate the susceptibility and pathogenicity of indigenous North African goats to GTPV infection, we experimentally inoculated eight locally bred goats with a virulent Vietnamese isolate of GTPV. Two uninfected goats were kept as controls. Clinical examination was carried out daily and blood was sampled for t can be applied in GTPV vaccine efficacy studies.
Clinical signs of goatpox were reproduced in indigenous North African goats and confirmed a high susceptibility of the North African goat breed to GTPV infection. A clinical scoring system is proposed that can be applied in GTPV vaccine efficacy studies.Fowl cholera caused by Pasteurella multocida exerts a massive economic burden on the poultry industry. Lipopolysaccharide (LPS) is essential for the growth of P. multocida genotype L1 strains in chickens and specific truncations to the full length LPS structure can attenuate bacterial virulence. Here we further dissected the roles of the outer core transferase genes pcgD and hptE in bacterial resistance to duck serum, outer membrane permeability and virulence in ducks. Two P. multocida mutants, ΔpcgD and ΔhptE, were constructed, and silver staining confirmed that they all produced truncated LPS profiles. Inactivation of pcgD or hptE did not affect bacterial susceptibility to duck serum and outer membrane permeability but resulted in attenuated virulence in ducks to some extent. After high-dose inoculation, ΔpcgD showed remarkably reduced colonization levels in the blood and spleen but not in the lung and liver and caused decreased injuries in the spleen and liver compared with the wild-type strain. In contrast, the ΔhptE loads declined only in the blood, and ΔhptE infection caused decreased splenic lesions but also induced severe hepatic lesions. Furthermore, compared with the wild-type strain, ΔpcgD was significantly attenuated upon oral or intramuscular challenge, whereas ΔhptE exhibited reduced virulence only upon oral infection. Therefore, the pcgD deletion caused greater virulence attenuation in ducks, indicating the critical role of pcgD in P. multocida infection establishment and survival.
Pseudohypoparathyroidism (PHP) represents a heterogeneous group of rare endocrine disorders caused by (epi) genetic abnormalities affecting the GNAS locus. It is mainly characterized by resistance to PTH and TSH, and by peculiar clinical features such as short stature, obesity, cognitive impairment, subcutaneous ossifications and brachydactyly. Delayed puberty, GHRH and calcitonin resistances have also been described. The healthcare-pathway recently proposed by the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) has provided a standardized clinical approach to these conditions. The purpose of the present study was to evaluate its application in clinical practice, and to collect data for setting future specific studies.

Through a semi-structured survey, based on the indications of the care-pathway, data on PHP clinical management were collected. The compilation of each data in the survey was read as an index of the adoption of the healthcare-pathway in clinical practice.

In addition toese patients and increasing knowledge on PHP.
The presented data show that the ISPED healthcare-pathway could represent a valid tool both to confirm the clinical approach to PHP patients and to allow homogeneous data collection; however, it has not yet been fully adopted. The strengthening of the network among the major Italian Endocrine Centers will contribute to improve its application in clinical practice, optimizing the follow-up of these patients and increasing knowledge on PHP.
Tissue oxygenation index (TOI) using the near infrared spectroscopy (NIRS) has been demonstrated as a useful indicator to predict return of spontaneous circulation (ROSC) among out-of-hospital cardiac arrest (OHCA) patients in hospital setting. However, it has not been widely examined based on pre-hospital setting.

In this prospective observational study, we measured TOI in pre-hospital setting among OHCA patients receiving cardio-pulmonary resuscitation (CPR) during ambulance transportation between 2017 and 2018. Throughout the pre-hospital CPR procedure, TOI was continuously measured. The study population was divided into two subgroups ROSC group and non-ROSC group.

Of the 81 patients included in the final analysis, 26 achieved ROSC and 55 did not achieve ROSC. Patients in the ROSC group were significantly younger, had higher ∆TOI (changes in TOI) (5.8 % vs. 1.3 %; p < 0.01), and were more likely to have shockable rhythms and event witnessed than patients in the non-ROSC group. ∆TOI cut-off value of 5 % had highest sensitivity (65.4 %) and specificity (89.3 %) for ROSC. Patients with a cut-off value ≤-2.0 % did not achieve ROSC and while all OHCA patient with a cut-off value ≥ 8.0 % achieved ROSC. In addition, ROSC group had stronger positive correlation between mean chest compression rate and ∆TOI (r = 0.82) than non-ROSC group (r = 0.50).

This study suggests that ∆ TOI could be a useful indicator to predict ROSC in a pre-hospital setting.
This study suggests that ∆ TOI could be a useful indicator to predict ROSC in a pre-hospital setting.
Hip fracture is common and carries high morbidity and mortality; thus, it has become a vital concern. We aim to analyse the present status, worldwide trends in hip fracture and state of clinical research.

Publications from 2000 to 2019 were retrieved from the Web of Science database and analysed using a bibliometric methodology. VOSviewer software was utilised for analysis.

In total, 6139 publications were included, and publications increased annually from 152 in 2000 to 592 in 2019. U.S. researchers have produced the most publications, the highest H-index and the greatest number of citations. Osteoporosis International has published the most papers on the topic. Leading researchers, contributing institutions, their cooperative relationships and scientific masterpieces have been identified. The publications can be divided into five clusters 'mortality', 'surgical management', 'rehabilitation', 'osteoporosis' and 'epidemiology'. A clear developing trend was described, which began with fracture epidemiology and prevention, transitioned to perioperative management, orthogeriatric care and patient safety and then to functional recovery, disease burden and national audits in recent times.

Hip fractures result in conditions that extend far beyond orthopaedics concerning epidemiology and preventive medicine, internal medicine and endocrinology, as well as critical care and gerontology. Interest, research and publications are on the rise.
Hip fractures result in conditions that extend far beyond orthopaedics concerning epidemiology and preventive medicine, internal medicine and endocrinology, as well as critical care and gerontology. Interest, research and publications are on the rise.
Many neurodegenerative diseases develop only later in life, when cells in the nervous system lose their structure or function. In many forms of neurodegenerative diseases, this late-onset phenomenon remains largely unexplained.

Analyzing single-cell RNA sequencing from Alzheimer's disease (AD) and Huntington's disease (HD) patients, we find increased transcriptional heterogeneity in disease-state neurons. We hypothesize that transcriptional heterogeneity precedes neurodegenerative disease pathologies. To test this idea experimentally, we use juvenile forms (72Q; 180Q) of HD iPSCs, differentiate them into committed neuronal progenitors, and obtain single-cell expression profiles. We show a global increase in gene expression variability in HD. Autophagy genes become more stable, while energy and actin-related genes become more variable in the mutant cells. Knocking down several differentially variable genes results in increased aggregate formation, a pathology associated with HD. We further validate the increased transcriptional heterogeneity in CHD8+/- cells, a model for autism spectrum disorder.

Overall, our results suggest that although neurodegenerative diseases develop over time, transcriptional regulation imbalance is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value.
Overall, our results suggest that although neurodegenerative diseases develop over time, transcriptional regulation imbalance is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value.
The Tight Control of psoriatic arthritis (TICOPA) trial confirmed improved clinical outcomes with a treat to target (T2T) strategy in psoriatic arthritis (PsA). This consisted of 4-weekly review and escalation of 'step up' therapy (single disease modifying therapy (DMARD), combination DMARDs and then biologics) based on remission criteria. Based on this, a T2T approach is supported by European PsA treatment recommendations. However, it is not commonly implemented in routine care primarily due to feasibility and cost concerns. In the TICOPA trial, the same treatment regime was used for all participants regardless of their disease profile. Despite the recognition of PsA as a highly heterogeneous condition, no studies have tailored which drugs are used depending on disease severity. The cohort will establish real world outcomes for the T2T approach in PsA and also form the basis of a trials within cohorts (TWiCs) design to test alternative therapeutic approaches within embedded clinical trials providing an eviT2T approach. The TWiCs design allows robust generalizability to routine healthcare, avoids disappointment bias, aids recruitment and in future will allow assessment of longer-term outcomes.

ClinicalTrials.gov NCT03531073 . Retrospectively registered on 21 May 2018.
ClinicalTrials.gov NCT03531073 . Retrospectively registered on 21 May 2018.
The use of plants in rituals is a little explored corner of biocultural diversity which has developed through time within a complex socio-ecological system. Indeed, rituals are complex interactions between humans and biodiversity shaped by history, culture, and ethnic belonging. Yet, in Western Ukraine, such rituals were forbidden for over 50 years (1939-1991). The current revival of rituals by rural inhabitants is an untapped reservoir of local ecological knowledge. The aim of the present study was to identify the ritual use of wild and cultivated plants in two regions of Western Ukraine, Bukovina and Roztochya, and to compare the findings with historical data. Moreover, we analyzed attitudes toward the ritual use of plants and interactions with the local environment.

We conducted 31 in-depth semi-structured interviews among Orthodox Hutsuls of Bukovina and 16 interviews among Greek Catholic rural inhabitants of Roztochya during summer 2018 focusing on the ritual uses of plants.

We documented 28 plant l.
The nosocomial pathogen, Acinetobacter baumannii, has acquired clinical significance due to its ability to persist in hospital settings and survive antibiotic treatment, which eventually resulted in the rapid spread of this bacterium with antimicrobial resistance (AMR) phenotypes. This study used a multidrug-resistant A. baumannii (strain ATCC BAA1605) as a model to study the genomic features of this pathogen.

One circular chromosome and one circular plasmid were discovered in the complete genome of A. baumannii ATCC BAA1605 using whole-genome sequencing. The chromosome is 4,039,171bp long with a GC content of 39.24%. Many AMR genes, which confer resistance to major classes of antibiotics (beta-lactams, aminoglycosides, tetracycline, sulphonamides), were found on the chromosome. Two genomic islands were predicted on the chromosome, one of which (Genomic Island 1) contains a cluster of AMR genes and mobile elements, suggesting the possibility of horizontal gene transfer. A subtype I-F CRISPR-Cas system wasference for future studies on A. baumannii. The genome of A. baumannii ATCC BAA1605 has been deposited at GenBank under accession no. CP058625 and CP058626.Single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) identifies regulated chromatin accessibility modules at the single-cell resolution. Robust evaluation is critical to the development of scATAC-seq pipelines, which calls for reproducible datasets for benchmarking. We hereby present the simATAC framework, an R package that generates scATAC-seq count matrices that highly resemble real scATAC-seq datasets in library size, sparsity, and chromatin accessibility signals. simATAC deploys statistical models derived from analyzing 90 real scATAC-seq cell groups. simATAC provides a robust and systematic approach to generate in silico scATAC-seq samples with known cell labels for assessing analytical pipelines.
The purpose of this study was to compare the charges and payments associated with bone marrow aspiration and biopsies performed by hematology/oncology specialists versus interventional radiology specialists at Bassett Medical Center located in a rural area of New York State. Charges pertained to what the hospital charged for the procedure and payment refers to the reimbursement the hospital received. Our secondary objectives were to compare specimen quality by procedure and to determine whether body mass index was associated with which specialist performed the procedure.

The median charge was significantly higher in the interventional radiology group ($5254 USD) compared to the hematology/oncology group ($413 USD), p < 0.0001. Median payments were also higher in the interventional radiology ($1392 USD) compared to the hematology/oncology group ($1109 USD), p < 0.0001. Adequacy of the samples obtained by either profession was similar. Disease process was not associated with adequacy of the sample. Thhematology/oncology group (28.6), p = 0.0014.
Physiological disturbances in cortical network excitability and plasticity are established and widespread in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those harbouring the C9ORF72 repeat expansion (C9ORF72
) mutation - the most common genetic impairment causal toALS and FTD. Noting that perturbations in cortical function are evidenced pre-symptomatically, and that the cortex is associated with widespread pathology, cortical dysfunction is thought to be an early driver of neurodegenerative disease progression. However, our understanding of how altered network function manifests at the cellular and molecular level is not clear.

To address this we have generated cortical neurons from patient-derived iPSCs harbouring C9ORF72
mutations, as well as from their isogenic expansion-corrected controls. We have established a model of network activity in these neurons using multi-electrode array electrophysiology. We have then mechanistically examined the physiologicaication of previously unidentified defects in pre and postsynaptic compartments affecting synaptic plasticity, synaptic vesicle stores, and network propagation, which directly impact upon cortical function.
These findings suggest synaptic pathophysiology is widespread in ALS-FTD and has an early and fundamental role in driving altered network function that is thought to contribute to neurodegenerative processes in these patients. The overall importance is the identification of previously unidentified defects in pre and postsynaptic compartments affecting synaptic plasticity, synaptic vesicle stores, and network propagation, which directly impact upon cortical function.
Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC.

A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded.

Twenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0-2). Fifty percent of patients were Caucasian, 45% African-American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug-drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders.

Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed.

ClinicalTrials.gov , NCT02158507 . Registered on 12 September 2014.
ClinicalTrials.gov , NCT02158507 . Registered on 12 September 2014.
Falls in older Emergency Department (ED) patients may indicate underlying frailty. Geriatric follow-up might help improve outcomes in addition to managing the direct cause and consequence of the fall. We aimed to study whether fall characteristics and the result of geriatric screening in the ED are independently related to adverse outcomes in older patients with fall-related ED visits.

This was a secondary analysis of the observational multicenter Acutely Presenting Older Patient (APOP) study, of which a subset of patients aged ≥70 years with fall-related ED visits were prospectively included in EDs of two Dutch hospitals. Fall characteristics (cause and location) were retrospectively collected. The APOP-screener was used as a geriatric screening tool. The outcome was 3- and 12-months functional decline and mortality. We assessed to what extent fall characteristics and the geriatric screening result were independent predictors of the outcome, using multivariable logistic regression analysis.

We includedated with adverse outcomes in older ED patients, suggesting that information on both should be evaluated to guide follow-up geriatric assessment and interventions in clinical care.
Ankylosing spondylitis (AS), as a common inflammatory rheumatic disease, often causes depression and impaired health-related quality of life (QoL). Although positive effects of patient education have been demonstrated, limited studies explored the benefits of education via mobile applications for AS patients. This study aimed to evaluate the effects of the WeChat-based educational intervention on depression, health-related QoL, and other clinical outcomes in AS patients.

We conducted a single-blind randomized controlled trial from March to December 2017. Patients were recruited and randomized into the intervention group which received a 12-week WeChat-based educational intervention (consisting of four individual online educational sessions, online educational materials) or the control group receiving standard care. Data was collected at baseline and 12 weeks. Outcomes were measured by Beck Depression Inventory-II, the Medical Outcomes Study Short Form 36-item Health Survey (SF-36), Bath Ankylosing Spondylber ChiCTR-IPR-16009293 ).
This study has been approved by the hospital's ethics committee (ID 20160364) in 2016 and registered at the Chinese Clinical Trail Registry (registry number ChiCTR-IPR-16009293 ).
This was a cross-sectional study in China which analyzed the levels of macrophages (Mφ) in semen and evaluated the influence of Mφ levels in semen on sperm quality.

The subjects involves 78 males, 25- to 35-year old. The samples were divided into a low group (Mφ < 6 × 10
/ml) and a high group (Mφ > 6 × 10
/ml). Evaluation included consideration of the influencing factors of male semen quality, macrophage concentration, sperm motility, morphology, membrane integrity DNA fragmentation index (DFI), anti-sperm antibodies (AsAb), IL-10, and IL-12 in semen.

There was no difference in the physical or chemical indices of the semen, sperm concentration, AsAb, IL-10, or IL-12 between the two groups (P > 0.05). The percentage of sperm forward motility (PR%), the rate of normal sperm shape, and the integrity of cell membranes in the low group were higher than those in the high group (P < 0.05), while the percentage of sperm inactivity (IM%), the rate of sperm head deformity, the rate of deformity in tte. There is no significant correlation between the macrophages and the concentration of IL-10 or IL-12.
Prevention of hyperuricaemia (HU) is critical to the prevention of gout. Understanding causal relationships and relative contributions of various risk factors to hyperuricemia istherefore important in the prevention of gout. Here, we use attributable fraction to compare the relative contribution of genetic, dietary, urate-lowering therapy (ULT) and other exposures to HU. We use Mendelian randomisation to test for the causality of diet in urate levels.

Four European-ancestry sample sets, three from the general population (n = 419,060) and one of people with gout (n = 6781) were derived from the Database of Genotypes and Phenotypes (ARIC, FHS, CARDIA, CHS) and UK Biobank. Dichotomised exposures to diet, genetic risk variants, BMI, alcohol, diuretic treatment, sex and age were used to calculate adjusted population and average attributable fractions (PAF/AAF) for HU (≥0.42 mmol/L [≥7 mg/dL]). Exposure to ULT was also assessed in the gout cohort. Two sample Mendelian randomisation was donein the UK Biobank usi use of ULT was the largest attributable fraction tested for HU.
Uganda has one of the highest adolescent pregnancy rates in sub-Saharan Africa. We compared the risk of adverse birth outcomes between adolescents (age 12-19years) and mothers (age 20-34years) in four urban hospitals.

Maternal demographics, HIV status, and birth outcomes of all live births, stillbirths, and spontaneous abortions delivered from August 2015 to December 2018 were extracted from a hospital-based birth defects surveillance database. Differences in the distributions of maternal and infant characteristics by maternal age groups were tested with Pearson's chi-square. Adjusted odds ratios (aORs) and 95% confidence intervals (CI) were calculated using logistic regression to compare the prevalence of adverse birth outcomes among adolescents to mothers 20-34years.

A total of 100,189 births were analyzed, with 11.1% among adolescent mothers and 89.0% among older mothers. Adolescent mothers had an increased risk of preterm delivery (aOR 1.14; CI 1.06-1.23), low birth weight (aOR 1.46; CI 1.34-1.59), and early neonatal deaths (aOR 1.58; CI 1.23-2.02). Newborns of adolescent mothers had an increased risk of major external birth defects (aOR 1.33; CI 1.02-1.76), specifically, gastroschisis (aOR 3.20; CI 1.12-9.13) compared to mothers 20-34years. The difference between the prevalence of gastroschisis among adolescent mothers (7.3 per 10,000 births; 95% CI 3.7-14.3) was statistically significant when compared to mothers 20-34years (1.6 per 10,000 births; 95% CI 0.9-2.6).

This study found that adolescent mothers had an increased risk for several adverse birth outcomes compared to mothers 20-34years, similar to findings in the region and globally. Interventions are needed to improve birth outcomes in this vulnerable population.
This study found that adolescent mothers had an increased risk for several adverse birth outcomes compared to mothers 20-34 years, similar to findings in the region and globally. Interventions are needed to improve birth outcomes in this vulnerable population.
Particulate matter (PM) is strongly linked to human health and has detrimental effects on the eye. Studies have, however, focused on the ocular surface, with limited research on the impact of PM
on intraocular pressure (IOP).

To investigate the impact of PM
on IOP and the associated mechanism, C57BL/6 mouse eyes were topically exposed to a PM
suspension for 3 months, and human trabecular meshwork (HTM) cells were subjected to various PM
concentrations in vitro. Cell viability, NLRP3/caspase-1, IL-1β, and GSDMD expression, reactive oxygen species (ROS) production and cell contractility were measured by western blot, ELISA, cell counting kit-8, ROS assay kit or a cell contractility assay. ROS scavenger N-acetyl-L-cysteine (NAC) and caspase-1 inhibitor VX-765 were used to intervene in PM
-induced damages.

The results revealed that the IOP increased gradually after PM
exposure, and upregulations of the NLRP3 inflammasome, caspase-1, IL-1β, and GSDMD protein levels were observed in outflow tissues subsequent induction of NLRP3 inflammasome mediated pyroptosis in trabecular meshwork cells.Na+(K+)/H+ exchanger 6 (NHE6) on synaptic vesicle (SV) is critical for the presynaptic regulation of quantal size at the glutamatergic synapses by converting the chemical gradient (ΔpH) into membrane potential (Δψ) across the SV membrane. We recently found that NHE6 directly interacts with secretory carrier membrane protein 5 (SCAMP5), and SCAMP5-dependent recruitment of NHE6 to SVs controls the strength of synaptic transmission by modulation of quantal size of glutamate release at rest. It is, however, unknown whether NHE6 recruitment by SCAMP5 plays a role during synaptic plasticity. Here, we found that the number of NHE6-positive presynaptic boutons was significantly increased by the chemical long-term potentiation (cLTP). Since cLTP involves new synapse formation, our results indicated that NHE6 was recruited not only to the existing presynaptic boutons but also to the newly formed presynaptic boutons. Knock down of SCAMP5 completely abrogated the enhancement of NHE6 recruitment by cLTP. Interestingly, despite an increase in the number of NHE6-positive boutons by cLTP, the quantal size of glutamate release at the presynaptic terminals remained unaltered. Together with our recent results, our findings indicate that SCAMP5-dependent recruitment of NHE6 plays a critical role in manifesting presynaptic efficacy not only at rest but also during synaptic plasticity. Since both are autism candidate genes, reduced presynaptic efficacy by interfering with their interaction may underlie the molecular mechanism of synaptic dysfunction observed in autism.
Idiopathic Granulomatous Mastitis (IGM) is a benign chronic inflammatory breast condition that mimics two common breast disorders breast carcinoma and breast abscess. It can form breast masses, fistulae, and fluid collections, resulting in breast disfigurement with retraction and nipple areolar complex (NAC) inversion. IGM most often presents in women of childbearing age within a few years of pregnancy, and can significantly impact lactation. Despite the prevalence of this disease, no current literature describes an approach to managing IGM during breastfeeding.

A 28-year-old G3P2 patient of Native American origin presented to her obstetrician at 7months pregnant with worsening left breast swelling and redness. She underwent a mammogram, ultrasound and core needle biopsy that confirmed the diagnosis of Idiopathic Granulomatous Mastitis. During the postpartum period, she underwent intralesional triamcinolone injections of her left breast. Due to the contraindication of breastfeeding after local steroid injproduction and latch on the affected breast. Individualized care should be provided, with considerations given to the following side effects of systemic steroids, the need to wean a breast being treated with intralesional steroids, and augmentation of milk production on the unaffected breast to promote continued breastfeeding.
The purpose of this study was to assess whether thoracic radiotherapy (TRT) combined with chemotherapy (CHT) showed promising anti-tumour activity in extensive-stage small cell lung cancer (ES-SCLC), to explore practice patterns for the radiation time and dose/fractionation and to identify prognostic factors for patients who would benefit from CHT/TRT.

A total of 492 ES-SCLC patients were included from January 2010 to March 2019, 244 of whom received CHT/TRT. Propensity score matching was performed to minimize bias between the CHT/TRT and CHT-alone groups. Patients in the CHT/TRT group were categorized into four subgroups based on the number of induction CHT cycles. For effective dose fractionation calculations, we introduced the time-adjusted biological effective dose (tBED). Categorical variables were analysed with chi-square tests and Fisher's exact tests. Kaplan-Meier curves were generated to estimate survival rates using the R-project. Multivariate prognostic analysis was performed with Cox proportional hazards models.
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