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e can be made on gene therapy for sickle cell disease. learn more This systematic review has identified the need for well-designed, randomised controlled trials to assess the benefits and risks of gene therapy for sickle cell disease.

Quetiapine and aripiprazole are currently prescribed for pregnant women to treat schizophrenia and bipolar disorder. A dramlatic decline in the plasma concentrations of these two drugs was observed if the doses remained fixed throughout pregnancy. This study aims to develop physiologically based pharmacokinetic(PBPK) models to predict the pharmacokinetics of quetiapine, aripiprazole, and the active aripiprazole metabolite dehydroaripiprazole during pregnancy.

We developed models using a combined 'bottom-up' and 'top-down' strategy. Models were verified by assessing goodness-of-fit plots and ratios of predicted-to-observed pharmacokinetic parameters. To extrapolate to pregnancy, we considered anatomical, physiological, and metabolic alterations. The in silico models were applied to predict steady-state pharmacokinetics in the three stages of pregnancy and to inform dose selection.

We successfully constructed PBPK models that accurately predicted the pharmacokinetics of drugs in the adult population. Predictions suggested that the area under the concentration-time curve at steady state in the first, second, and third trimesters, respectively, decreased by 8.7%, 35.0%, and 49.1% for quetiapine and 12.6%, 38.8%, and 60.9% for the active moiety of aripiprazole. The third-trimester plasma concentrations of quetiapine were below the lower limit of the therapeutic range (100 ng/mL) for most of the time interval, and aripiprazole was entirely unable to reach its effective concentration (150 ng/mL).

According to PBPK predictions, the doses should be increased in the latter two trimesters. We generally recommend that women during late pregnancy take at least 2.5- and 2-times their baseline doses of quetiapine and aripiprazole, respectively.

According to PBPK predictions, the doses should be increased in the latter two trimesters. We generally recommend that women during late pregnancy take at least 2.5- and 2-times their baseline doses of quetiapine and aripiprazole, respectively.

New treatments and interventions are in development to address clinical needs in heart failure. To support decision making on reimbursement, cost-effectiveness analyses are frequently required. A systematic literature review was conducted to identify and summarize heart failure utility values for use in economic evaluations.

Databases were searched for articles published until June 2019 that reported health utility values for patients with heart failure. Publications were reviewed with specific attention to study design; reported values were categorized according to the health states, 'chronic heart failure', 'hospitalized', and 'other acute heart failure'. Interquartile limits (25th percentile 'Q1', 75th percentile 'Q3') were calculated for health states and heart failure subgroups where there were sufficient data.

The systematic literature review identified 161 publications based on data from 142 studies. Utility values for chronic heart failure were reported by 128 publications; 39 publications publio ensure a robust economic analysis.Antibiotic resistance has brought into question the efficiency of clarithromycin which is a vital component of eradication therapy for Helicobacter pylori infection. The point mutations within the 23S rRNA sequence of H. pylori isolates which contribute to clarithromycin resistance have yet to be fully characterized. This study was aimed to detect clarithromycin resistance-associated mutations and assess the prevalence of key virulence factors of H. pylori among Iranian patients. Amplification of 16S rRNA and glmM genes were done to identify H. pylori. Minimal inhibitory concentration (MIC) of clarithromycin in 82 H. pylori clinical isolates was determined by agar dilution method. Subsequently, various virulence markers including cagA, vacA, sabA, babA, and dupA of H. pylori were identified by PCR. PCR-sequencing was applied to detect point mutations in the 23S rRNA gene. Based on MIC values, 43.9% of H. pylori isolates showed resistance to clarithromycin. The babA and cagA genes were detected in 92.7% and 82.9% of isolates, assigned to be higher than other virulence factors. No significant relationship was found between the H. pylori virulence genotypes and clarithromycin susceptibility (P > 0.05). Analyzing the 23S rRNA sequences revealed A2143G (4/48, 8.3%) and A2142G (3/48, 6.2%) as the most prevalent mutations in clarithromycin-resistant isolates. Additionally, several novel mutations including G2220T, C2248T, A2624C, G2287A, T2188C, G2710C, C2248T, G2269A, and G2224T were also detected among either resistant or susceptible isolates. Our findings revealed the presence of several point mutations in the 23S rRNA gene of H. pylori isolates which may be associated with resistance to clarithromycin.

Prolonged systemic non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with adverse renal outcomes among older adults. However, there is scant data regarding the renal safety of topical and short-course systemic NSAIDs. We aimed to evaluate the risk of acute adverse renal outcomes among older adults prescribed topical and short-term systemic NSAIDs.

We conducted a retrospective cohort study of all older adults, age 60 years and above, who received prescriptions between July 2015 and December 2017 from the largest tertiary hospital and a major public primary care institution in Singapore. Data from 6 months before until 30 days after the first prescription were retrieved from electronic medical records. The primary outcome was the incidence of acute kidney injury (serum creatinine increased >26.5 µmol/L or >50% from baseline) and/or hyperkalemia within 30 days. A multi-variate analysis taking into account age, sex, co-morbidities, baseline-estimated glomerular filtration rate and seru.54, 95% CI 0.37-0.79, p < 0.001), compared with short-course systemic NSAIDs.

NSAIDs increased the risk of acute adverse renal events. Topical NSAIDs, compared with short-course systemic NSAIDs, were associated with a reduced incidence of acute kidney injury and/or hyperkalemia among older adults with additional risk factors.

NSAIDs increased the risk of acute adverse renal events. Topical NSAIDs, compared with short-course systemic NSAIDs, were associated with a reduced incidence of acute kidney injury and/or hyperkalemia among older adults with additional risk factors.

Medication review is an important component of the management of older hospital patients. Deprescribing (supervised withdrawal of inappropriate medicines) is one outcome of review. This study aimed to iteratively develop and test the usability of deprescribing guides, which support multidisciplinary clinicians to reduce inappropriate polypharmacy in older inpatients.

Deprescribing guides for hospital clinicians were developed using a novel mixed-methods, ten-step process. Iterative development and usability testing were applied. This included content development through review of the literature; expert consensus through five rounds of feedback using a modified Delphi approach; and usability testing by 16 multidisciplinary hospital clinicians on hypothetical clinical scenarios involving observations, semi-structured interviews, and administration of the System Usability Scale.

This novel process was used to develop deprescribing guides that facilitate implementation of evidence on deprescribing in routine-based recommendations that support deprescribing in routine hospital care.

The aim of this study was to analyze potential risk factors for early and late dental implant failure (DIF) in a clinical cohort trial. In a private practice, 9080 implants were inserted during a period of 10 years. In case of DIF, data were classified into early and late DIF and compared to each other in regard of gender, age, site of implantation, implant geometry, and patients' systemic diseases.

Three hundred fifty-one implants failed within the observation period (survival rate96.13%). Early DIF occurred in 293 implants (83.48%) compared to late DIF in 58 implants (16.52%). Significant earlier DIF was seen in the mandible (OR = 3.729, p < 0.001)-especially in the posterior area-and in younger patients (p = 0.017), whereas an increased likelihood of late DIF was associated with maxillary implants (OR = 3.729, p < 0.001) and older patients.

Early DIF is about twice as common as late DIF. Main risk factors for early DIF are implant location in the (posterior) mandible as well as younger age. On contrary, late DIF is rather associated with older patients, cancellous bone quality, and longer implants.

Early DIF is about twice as common as late DIF. Main risk factors for early DIF are implant location in the (posterior) mandible as well as younger age. On contrary, late DIF is rather associated with older patients, cancellous bone quality, and longer implants.This review argues that the three popular concepts of design, rationality and reductionism, which guided vaccine research for many years, actually contributed to the inability of vaccinologists to develop an effective HIV vaccine. The strong goal-directed intentionality inherent in the concept of design together with excessive confidence in the power of rational thinking convinced investigators that the accumulated structural knowledge on HIV epitopes, derived from crystallographic studies of complexes of neutralizing antibodies bound to HIV Env epitopes, would allow them to rationally design complementary immunogens capable of inducing anti-HIV protective antibodies. This strategy failed because it was not appreciated that the structures observed in epitope-paratope crystallographic complexes result from mutually induced fit between the two partners and do not represent structures present in the free disordered molecules before they had interacted. In addition, reductionist thinking led investigators to accept that biology could be reduced to chemistry, and this made them neglect the fundamental difference between chemical antigenicity and biological immunogenicity. As a result, they did not investigate which inherent constituents of immune systems controlled the induction of protective antibodies and focused instead only on the steric complementarity that exists between bound epitopes and paratopes.

Comprehensive metabolomic investigations provide a large set of stress-related metabolites and metabolic pathways, advancing crops under heat stress conditions. Metabolomics-assisted breeding, including mQTL and mGWAS boosted our understanding of improving numerous quantitative traits under heat stress. During the past decade, metabolomics has emerged as a fascinating scientific field that includes documentation, evaluation of metabolites, and chemical methods for cell monitoring programs in numerous plant species. A comprehensive metabolome profiling allowed the investigator to handle the comprehensive data groups of metabolites and the equivalent metabolic pathways in an extraordinary manner. Metabolomics, together with transcriptomics, plays an influential role in discovering connections between stress and genes/metabolite, phenotyping, and biomarkers documentation. Further, it helps to decode several metabolic systems connected with heat stress (HS) tolerance in plants. Heat stress is a critical environmental factor that is globally affecting the growth and productivity of plants.