Pharmacological Factors Research Articles

Herbal infusion – processing techniques, bioactivity, quality, and safety

Botanical remedy, including herbal infusion or tisane, is getting attention from the healthconscious consumer to provide dietary polyphenol/dietary antioxidants. However, some quality and pharmacological aspects of dried herbs used in the tisane or herbal tea are taken for granted and can place the consumer's health and safety at risk. The purpose of this review is to investigate pre-harvesting and post-harvesting aspects of herbal tea that implicate the quality, i.e., therapeutic properties and safety, i.e., toxicity. Selection of botanical origin, agricultural practice, and pharmacological background (pharmacodynamic and pharmacokinetic aspects) of botanical material are the identified vital factors in the pre-harvesting aspects that should be considered before introducing the monoherbal or polyherbal preparation to ensure optimum benefits and safety. Besides the herbal blending preparation, the tea processing standard and drying technique are vital in ensuring the stability of herbal tea and consequently determining the quality of herbal infusion. The variation of processing techniques used and the pharmacological factors of herbal sources have laced on the quality and authenticity issues of herbal infusion and still need further studies to identify the potential health risks to the consumer.

Age, Sex, Metabolic and Pharmacologic Factors May Predict Nonresponse Status to Rheumatoid Arthritis Therapies.

A real challenge for patients with rheumatoid arthritis (RA) and rheumatologists is primary nonresponse status (PNRS) or secondary nonresponse status (SNRS) to various therapies. Despite their detrimental influence on patient life quality, PNRS and SNRS have no accurate definition and no early predictive criteria for their development exist. Patients with RA under 40 years of age are rare, hence PNRS and SNRS data for this age group are scarce. This study examined the PNRS and SNRS according to sex, age, BMI, therapy type, and duration. Retrospectively, 115 patients with RA having PNRS and/or SNRS were stratified by age (22-39, 40-59, and 60-81). The association between body mass index (BMI), proinflammatory cytokines inhibitors, JAK inhibitors, and TNF-alpha inhibitors, sex, age, and PNRS and SNRS was examined. All three proinflammatory cytokine inhibitors (rituximab, tocilizumab, and abatacept) were associated with PNRS and SNRS in women with a high BMI aged 40-59 years. Abatacept-related PNRS and SNRS was significant in women with normal BMI aged 60-81 years. Adalimumab, infliximab, and golimumab affected SNRS differently in women with normal BMI aged 22-39 years and women with high BMI aged 60-81 years. Etanercept and infliximab were associated with SNRS status in men with high-BMI aged 40-59 years. PNRS and SNRS development in patients with RA is significantly influenced by age, sex, and BMI, but most importantly is closely and differentially related to therapy type and duration.

Schooling and Occupational Outcomes in Adults with ADHD: Predictors of Success and Support Strategies for Effective Learning

Attention Deficit Hyperactivity Disorder (ADHD) is a neurobehavioral disorder that is usually diagnosed in childhood. It is characterized by attention deficits, hyperactivity, and impulsivity leading to significant impairment in academic, occupational, familiar, and social functioning. Most of the literature has been focusing on the impact of this condition on infancy and preadolescence, but little is known on its consequences in adulthood. This narrative review addresses this gap by focusing on the studies regarding the schooling outcomes of this population. After identifying the specific clinical and neuropsychological profile of ADHD in adults, this study analyzes their precise needs for effective learning and presents evidence on their academic and occupational achievements. Pharmacological, educational, and rehabilitative factors predicting a positive scholastic and career success are critically reviewed. Finally, this study focuses on the strategies that can improve the learning processes in adults with ADHD by expanding the analysis on executive functions, metacognition, and emotional dysregulation. Schooling outcomes in adults with ADHD, therefore, are conceptualized as a complex measure depending on several variables, like early pharmacological treatment, educational support, neuropsychological intervention, and targeted strategies for life-long learning.

The role of ethnicity, biological sex, and psychotropic agents in early and late onset Alzheimer's disease.

This study investigates differences in pharmacological and demographic factors among male and female patients with Late-onset Alzheimer's disease (LOAD) and Early-onset Alzheimer's disease (EOAD). Data are from 10,126 AD patients, 9,290 were diagnosed with LOAD, while 836 were diagnosed with EOAD. Data were collected from the Prisma Health Upstate Alzheimer's patients' registry between 2016 and 2021. The logistic regression analysis was used to assess the association between pharmacological and demographic factors in males and females with LOAD and EOAD. In the adjusted analysis for males, patients that were administered memantine [odd ratio (OR) = 1.588, 95% CI, 1.175-2.145, p = 0.003], and buspirone [OR = 1.971, 95% CI, 1.221-3.183, p = 0.006] were more likely to be associated with EOAD, while increasing age [OR = 0.816, 95% CI, 0.799-0.834, p < 0.001] was associated with LOAD. Female patients with a history of alcohol (ETOH) use were more likely to be associated with EOAD while increasing age [OR = 0.845, 95% CI, 0.834-0.857, p < 0.001], treatment with memantine [OR = 0.774, 95% CI, 0.627-0.956, p = 0.017], African Americans [OR = 0.621, 95% CI, 0.462-0.835, p = 0.002] and tobacco use [OR = 0.529, 95% CI, 0.424-0.660, p < 0.001] were associated with LOAD. Our findings identified specific demographic and pharmacological factors associated with males and females with LOAD and EOAD. These findings suggest the need to develop strategies to eliminate disparity in the care of LOAD or EOAD patients.

Preventing falls in older people on mental health inpatient wards: a quality improvement project.

Older people on mental health inpatient wards are at high risk of falls due to a combination of physiological, pathophysiological and pharmacological factors. Falls prevention should therefore be a priority for nursing staff caring for this patient group. This article describes a quality improvement project conducted on four older adult mental health inpatient wards in Scotland. The project aimed to reduce the number of falls, increase staff's adherence to person-centred falls prevention care planning, and ensure every fall would prompt a post-fall review. Nursing staff participated in a falls prevention training session and registered nurses received, in addition, one-to-one coaching sessions on person-centred care planning. Despite the challenges faced by mental healthcare professionals at the time of the project, staff responded positively and there was a decrease in the number of falls, including falls resulting in harm.

The Burden of Postoperative Delirium After Shoulder Arthroplasty and Modifiable Pharmacological Perioperative Risk Factors: A Retrospective Nationwide Cohort Study.

Background: Increasing demand for shoulder arthroplasty and an aging population may increase the rate of complications associated with advanced age such as postoperative delirium, but little is known on its burden in this cohort. Purpose: We sought to answer the following questions: (1) What is the epidemiology of postoperative delirium after shoulder arthroplasty? (2) What modifiable risk factors can be identified for postoperative delirium after shoulder arthroplasty? (3) Do risk factors differ in those younger than and in those older than 70 years of age? Methods: In a retrospective nationwide cohort study, we extracted data from the Premier Healthcare database on inpatient total and reverse shoulder arthroplasties from 2006 to 2016. The primary outcome was postoperative delirium; modifiable risk factors of interest were perioperative opioid use (high, medium, or low), peripheral nerve block use, and perioperative prescription medications. Mixed-effects models assessed associations between risk factors and postoperative delirium. Odds ratios and confidence intervals are reported. We applied a cutoff of 70 years of age because it was the median age of the cohort, as well as the age at which we observed that delirium prevalence increased. Results: A total of 92,429 total and reverse shoulder arthroplasties were identified (age range: 14-89 years). Overall delirium prevalence was 3.1% (n = 2909). Age-specific prevalence of postoperative delirium was lower in patients aged 50 to 70 years and higher in those aged 70 years and older, up to 8% among those older than 88 years. After adjusting for relevant covariates, only long-acting and combined short-acting and long-acting benzodiazepines (compared with no benzodiazepines) were associated with increased odds of postoperative delirium. Corticosteroids were associated with decreased odds of postoperative delirium. Conclusion: Our retrospective cohort study demonstrated that benzodiazepine use and older patient age were significantly associated with postoperative delirium in shoulder arthroplasty patients. The relationship between benzodiazepine use and delirium was particularly notable among those 70 years of age and older. Further investigation is indicated, given the known adverse effects of benzodiazepines in older adults and our findings of higher than expected use of these medications in this surgical cohort.

Withdrawal: Rink-Jan Lohman, Karnaker Reddy Tupally, Ajit Kandale, Peter J. Cabot, Harendra S. Parekh (2022) Design and development of novel, short, stable dynorphin-based opioid agonists for safer analgesic therapy. Br J Pharmacol; https://doi.org/10.1111/bph.15862.

The kappa opioid receptor has exceptional potential as an analgesic target, seemingly devoid of the many peripheral side-effects of Mu opioid receptors. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally-mediated side effects have limited their clinical translation. Here, we modify an active endogenous dynorphin peptide to improve drug-likeness and develop safer KOPr agonists for clinical use. Using rational, iterative design and modern peptide chemistry, we developed a series of potent, selective and metabolically stable peptides from dynorphin 1-7. Peptides were assessed for cAMP-modulation against Kappa, Mu and Delta opioid receptors, metabolic stability, Kappa receptor specificity and binding, and interrogated for in vitro desensitisation and pERK signalling capability. Finally, lead peptides were evaluated for efficacy in the Freund's complete adjuvant rat model of inflammatory nociception. A library of 70 peptides was synthesised and assessed for pharmacological and metabolic stability factors. At least 10 peptide candidates showed low nanomolar activity (˂50 nM) in a cAMP assay, specificity for Kappa opioid receptor, and plasma half-life >60 min, with 6 candidates also stable in trypsin. None of the selected peptides showed pERK activity, with a bias towards cAMP signalling, and reduced desensitisation, In vivo, KA305 and KA311 showed antinociception opioid receptor-specific activity comparable to morphine and U50844H. These highly potent and metabolically stable peptides are promising opioid analgesic leads for clinical translation. Since they are biased peptide Kappa agonists, it is plausible they lack many of the most significant side effects, such as tolerance, addiction, sedation and euphoria/dysphoria, common to opioid analgesics.

Mechanisms of Cistromic Repositioning of the Transcription Factor PU.1

Aberrant transcriptional networks are a hallmark of cancer, yet our knowledge of the intricacies of transcription factor behavior is poor. PU.1 is an ETS family transcription factor that is essential for hematopoiesis, however more than 50% of AML patients display a disruption of the PU.1 transcriptional network. In this study we implement novel molecular probes to competitively displace PU.1 from canonical DNA binding sites, allowing us to understand PU.1-chromatin binding dynamics, as well as identify the consequences of PU.1 binding site blockade upon PU.1-driven gene transcription and chromatin accessibility. We treated human PU.1low AML cells with a tool PU.1-DNA binding inhibitor, DB2115, and performed PU.1 CUT&Tag, ATAC sequencing and transcriptional profiling. We found, unexpectedly, that DB2115 not only led to inhibition of some canonical PU.1 targets but also mediated concurrent increases of other PU.1 targets. This two-sided response correlated strongly with a robust redistribution of PU.1 chromatin binding rather than a global inhibition - and included losses at regulatory regions of MYC, POMP and gains at CSF1R and TREM2. In fact, most of these redistributed sites (78% of PU.1 gained sites) display subsequent increases in chromatin accessibility and elevated target gene expression, highlighting the pioneering and transcriptional control exerted by repositioned PU.1. Kinetic analyses of PU.1 redistribution reveal that PU.1 losses occur rapidly after DB2115 exposure (1-4hrs), whereas PU.1 gains occur more slowly (4-12hrs) indicative of a loci searching phase prior to novel site binding. Development of an experimental approach combining CLICK-chemistry compound mapping with PU.1 CUT&Tag identified selective drug binding at displaced PU.1 binding sites compared to unchanged/gained sites, with both lost and gained regions being locally enriched for specific and distinct surrounding nucleotide sequences including A/T enrichment. Furthermore, CRISPR-dCas9 blockade and binding site-driven reporter investigations into specific PU.1 cistromic elements revealed important PU.1-mediated direct and rapid control of the POMP, CSF1R and STRAP genes. Overall, PU.1-DNA binding inhibition causes a robust perturbation of PU.1 transcriptional circuits via a novel phenomenon we describe as "Pharmacological transcription factor repositioning". Further investigations with binding site inhibitors such as these represent an unprecedented investigative approach to study complex and fast transcription factor dynamics without disrupting the structure or levels of the factor itself. Furthermore, exploitation of the pharmacological TF repositioning phenomenon may provide novel avenues for therapeutic intervention in PU.1-driven hematologic disorders and other transcriptionally-aberrant diseases.

Gastrocolonic Response.

The gastrocolonic response (GCR), is a physiologic increase in motor activity of the colon, which usually occurs within minutes following meal ingestion. Over the years several triggers that provoke GCR were recognized including gastric dilation, caloric intake, and fat component of the meal. The response is mediated by the vagal nerve and neurohumoral mechanisms, and it can be modified by several pharmacological factors. Assessment of GCR is part of high-resolution colonic manometry studies, performed in patients with suspected colonic dysmotility. This review highlights the physiologic basis of GCR as well as its clinical and diagnostic features and implementation in variable pathological conditions and clinical practice. GCR has a role in patients with constipation, diabetes, dumping syndrome, bowel hyper and hypomotility and irritable bowel syndrome. Novel sensory triggers for GCR were recently recognized. GCR is a physiological response which is evaluated during colonic manometry studies. Abnormal GCR is a marker of an underlying pathology, which can provide a potential target for treatment.

Deiodinases control local cellular and systemic thyroid hormone availability.

Iodothyronine deiodinases (DIO) are a family of selenoproteins controlling systemic and local availability of the major thyroid hormone l-thyroxine (T4), a prohormone secreted by the thyroid gland. T4 is activated to the active 3,3'-5-triiodothyronine (T3) by two 5'-deiodinases, DIO1 and DIO2. DIO3, a 5-deiodinase selenoenzyme inactivates both the prohormone T4 and its active form T3. DIOs show species-specific different patterns of temporo-spatial expression, regulation and function and exhibit different mechanisms of reaction and inhibitor sensitivities. The main regulators of DIO expression and function are the thyroid hormone status, several growth factors, cytokines and altered pathophysiological conditions. Selenium (Se) status has a modest impact on DIO expression and translation. DIOs rank high in the priority of selenium supply to various selenoproteins; thus, their function is impaired only during severe selenium deficiency. DIO variants, polymorphisms, SNPs and rare mutations have been identified. Development of DIO isozyme selective drugs is ongoing. A first X-ray structure has been reported for DIO3. This review focusses on the biochemical characteristics and reaction mechanisms, the relationships between DIO selenoproteins and their importance for local and systemic provision of the active hormone T3. Nutritional, pharmacological, and environmental factors and inhibitors, such as endocrine disruptors, impact DIO functions.

Antibacterial effects of natural compounds on biofilm formation of Streptococcus mutans.

In this study, we surveyed the antibacterial activity of natural compounds in terms of the biofilm production of S. mutans. We extracted the studies related to natural compounds affected on S. mutans biofilm from different databases. Disruption of S. mutans viability in biofilms by a potent new pharmacological factor could inhibit and remove cavities. Various antibacterial agents are needed to destroy biofilms that remove both pathogens and commensal bacteria, and also exert inhibitory effects on many bacterial species. An effective therapeutic agent for dental caries has to be capable of removing pathogens and their biofilms. Specific virulence attributes of S. mutans exist; hence, natural compounds that have excellent properties to combat such pathogens need to be selected.

Evaluation of noise regression techniques in resting-state fMRI studies using data of 434 older adults.

Subject motion is a well-known confound in resting-state functional MRI (rs-fMRI) and the analysis of functional connectivity. Consequently, several clean-up strategies have been established to minimize the impact of subject motion. Physiological signals in response to cardiac activity and respiration are also known to alter the apparent rs-fMRI connectivity. Comprehensive comparisons of common noise regression techniques showed that the "Independent Component Analysis based strategy for Automatic Removal of Motion Artifacts" (ICA-AROMA) was a preferred pre-processing technique for teenagers and adults. However, motion and physiological noise characteristics may differ substantially for older adults. Here, we present a comprehensive comparison of noise-regression techniques for older adults from a large multi-site clinical trial of exercise and intensive pharmacological vascular risk factor reduction. The Risk Reduction for Alzheimer's Disease (rrAD) trial included hypertensive older adults (60-84 years old) at elevated risk of developing Alzheimer's Disease (AD). We compared the performance of censoring, censoring combined with global signal regression, non-aggressive and aggressive ICA-AROMA, as well as the Spatially Organized Component Klassifikator (SOCK) on the rs-fMRI baseline scans from 434 rrAD subjects. All techniques were rated based on network reproducibility, network identifiability, edge activity, spatial smoothness, and loss of temporal degrees of freedom (tDOF). We found that non-aggressive ICA-AROMA did not perform as well as the other four techniques, which performed table with marginal differences, demonstrating the validity of these techniques. Considering reproducibility as the most important factor for longitudinal studies, given low false-positive rates and a better preserved, more cohesive temporal structure, currently aggressive ICA-AROMA is likely the most suitable noise regression technique for rs-fMRI studies of older adults.

Integrating machine learning with electronic health record data to facilitate detection of prolactin level and pharmacovigilance signals in olanzapine-treated patients.

Background and aimAvailable evidence suggests elevated serum prolactin (PRL) levels in olanzapine (OLZ)-treated patients with schizophrenia. However, machine learning (ML)-based comprehensive evaluations of the influence of pathophysiological and pharmacological factors on PRL levels in OLZ-treated patients are rare. We aimed to forecast the PRL level in OLZ-treated patients and mine pharmacovigilance information on PRL-related adverse events by integrating ML and electronic health record (EHR) data.MethodsData were extracted from an EHR system to construct an ML dataset in 672×384 matrix format after preprocessing, which was subsequently randomly divided into a derivation cohort for model development and a validation cohort for model validation (8:2). The eXtreme gradient boosting (XGBoost) algorithm was used to build the ML models, the importance of the features and predictive behaviors of which were illustrated by SHapley Additive exPlanations (SHAP)-based analyses. The sequential forward feature selection approach was used to generate the optimal feature subset. The co-administered drugs that might have influenced PRL levels during OLZ treatment as identified by SHAP analyses were then compared with evidence from disproportionality analyses by using OpenVigil FDA.ResultsThe 15 features that made the greatest contributions, as ranked by the mean (|SHAP value|), were identified as the optimal feature subset. The features were gender_male, co-administration of risperidone, age, co-administration of aripiprazole, concentration of aripiprazole, concentration of OLZ, progesterone, co-administration of sulpiride, creatine kinase, serum sodium, serum phosphorus, testosterone, platelet distribution width, α-L-fucosidase, and lipoprotein (a). The XGBoost model after feature selection delivered good performance on the validation cohort with a mean absolute error of 0.046, mean squared error of 0.0036, root-mean-squared error of 0.060, and mean relative error of 11%. Risperidone and aripiprazole exhibited the strongest associations with hyperprolactinemia and decreased blood PRL according to the disproportionality analyses, and both were identified as co-administered drugs that influenced PRL levels during OLZ treatment by SHAP analyses.ConclusionsMultiple pathophysiological and pharmacological confounders influence PRL levels associated with effective treatment and PRL-related side-effects in OLZ-treated patients. Our study highlights the feasibility of integration of ML and EHR data to facilitate the detection of PRL levels and pharmacovigilance signals in OLZ-treated patients.

Orgasm and Related Disorders Depend on Neural Inhibition Combined With Neural Excitation.

Prevalent models of sexual desire, arousal and orgasm postulate that they result from an excitatory process, whereas disorders of sexual desire, arousal and orgasm result from an inhibitory process based on psychosocial, pharmacological, medical, and other factors. But neuronal excitation and active neuronal inhibition normally interact at variable intensities, concurrently and continuously. We propose herein that in conjunction with neuronal excitation, neuronal inhibition enables the generation of the intense, non-aversive pleasure of orgasm. When this interaction breaks down, pathology can result, as in disorders of sexual desire, arousal, and orgasm, and in anhedonia and pain. For perspective, we review some fundamental behavioral and (neuro-) physiological functions of neuronal excitation and inhibition in normal and pathological processes. To review evidence that the variable balance between neuronal excitation and active neuronal inhibition at different intensities can account for orgasm and its disorders. We selected studies from searches on PubMed, Google Scholar, Dialnet, and SciELO for terms including orgasm, neuronal development, Wallerian degeneration, prenatal stress, parental behavior, sensorimotor, neuronal excitation, neuronal inhibition, sensory deprivation, anhedonia, orgasmic disorder, hypoactive sexual desire disorder, persistent genital arousal disorder, sexual pain. We provide evidence that the intensity of neuronal inhibition dynamically covaries concurrently with the intensity of neuronal excitation. Differences in these relative intensities can facilitate the understanding of orgasm and disorders of orgasm. Neuronal excitation and neuronal inhibition are normal, continuously active processes of the nervous system that are necessary for survival of neurons and the organism. The ability of genital sensory stimulation to induce concurrent neuronal inhibition enables the stimulation to attain the pleasurable, non-aversive, high intensity of excitation characteristic of orgasm. Excessive or deficient levels of neuronal inhibition relative to neuronal excitation may account for disorders of sexual desire, arousal and orgasm.

Determinants of Antibody Responses to SARS-CoV-2 Vaccines: Population-Based Longitudinal Study (COVIDENCE UK).

Antibody responses to SARS-CoV-2 vaccines vary for reasons that remain poorly understood. A range of sociodemographic, behavioural, clinical, pharmacologic and nutritional factors could explain these differences. To investigate this hypothesis, we tested for presence of combined IgG, IgA and IgM (IgGAM) anti-Spike antibodies before and after 2 doses of ChAdOx1 nCoV-19 (ChAdOx1, AstraZeneca) or BNT162b2 (Pfizer-BioNTech) in UK adults participating in a population-based longitudinal study who received their first dose of vaccine between December 2020 and July 2021. Information on sixty-six potential sociodemographic, behavioural, clinical, pharmacologic and nutritional determinants of serological response to vaccination was captured using serial online questionnaires. We used logistic regression to estimate multivariable-adjusted odds ratios (aORs) for associations between independent variables and risk of seronegativity following two vaccine doses. Additionally, percentage differences in antibody titres between groups were estimated in the sub-set of participants who were seropositive post-vaccination using linear regression. Anti-spike antibodies were undetectable in 378/9101 (4.2%) participants at a median of 8.6 weeks post second vaccine dose. Increased risk of post-vaccination seronegativity associated with administration of ChAdOx1 vs. BNT162b2 (adjusted odds ratio (aOR) 6.6, 95% CI 4.2–10.4), shorter interval between vaccine doses (aOR 1.6, 1.2–2.1, 6–10 vs. >10 weeks), poor vs. excellent general health (aOR 3.1, 1.4–7.0), immunodeficiency (aOR 6.5, 2.5–16.6) and immunosuppressant use (aOR 3.7, 2.4–5.7). Odds of seronegativity were lower for participants who were SARS-CoV-2 seropositive pre-vaccination (aOR 0.2, 0.0–0.6) and for those taking vitamin D supplements (aOR 0.7, 0.5–0.9). Serologic responses to vaccination did not associate with time of day of vaccine administration, lifestyle factors including tobacco smoking, alcohol intake and sleep, or use of anti-pyretics for management of reactive symptoms after vaccination. In a sub-set of 8727 individuals who were seropositive post-vaccination, lower antibody titres associated with administration of ChAdOx1 vs. BNT162b2 (43.4% lower, 41.8–44.8), longer duration between second vaccine dose and sampling (12.7% lower, 8.2–16.9, for 9–16 weeks vs. 2–4 weeks), shorter interval between vaccine doses (10.4% lower, 3.7–16.7, for <6 weeks vs. >10 weeks), receiving a second vaccine dose in October–December vs. April–June (47.7% lower, 11.4–69.1), older age (3.3% lower per 10-year increase in age, 2.1–4.6), and hypertension (4.1% lower, 1.1–6.9). Higher antibody titres associated with South Asian ethnicity (16.2% higher, 3.0–31.1, vs. White ethnicity) or Mixed/Multiple/Other ethnicity (11.8% higher, 2.9–21.6, vs. White ethnicity), higher body mass index (BMI; 2.9% higher, 0.2–5.7, for BMI 25–30 vs. <25 kg/m2) and pre-vaccination seropositivity for SARS-CoV-2 (105.1% higher, 94.1–116.6, for those seropositive and experienced COVID-19 symptoms vs. those who were seronegative pre-vaccination). In conclusion, we identify multiple determinants of antibody responses to SARS-CoV-2 vaccines, many of which are modifiable.

Risk factors for SARS-CoV-2 infection after primary vaccination with ChAdOx1 nCoV-19 or BNT162b2 and after booster vaccination with BNT162b2 or mRNA-1273: A population-based cohort study (COVIDENCE UK).

BackgroundLittle is known about how demographic, behavioural, and vaccine-related factors affect risk of post-vaccination SARS-CoV-2 infection. We aimed to identify risk factors for SARS-CoV-2 infection after primary and booster vaccinations.MethodsThis prospective, population-based, UK study in adults (≥16 years) vaccinated against SARS-CoV-2 assessed risk of breakthrough SARS-CoV-2 infection up to February, 2022, for participants who completed a primary vaccination course (ChAdOx1 nCoV-19 or BNT162b2) and those who received a booster dose (BNT162b2 or mRNA-1273). Cox regression models explored associations between sociodemographic, behavioural, clinical, pharmacological, and nutritional factors and test-positive breakthrough infection, adjusted for local weekly SARS-CoV-2 incidence.Findings1051 (7·1%) of 14 713 post-primary participants and 1009 (9·5%) of 10 665 post-booster participants reported breakthrough infection, over a median follow-up of 203 days (IQR 195–216) and 85 days (66–103), respectively. Primary vaccination with ChAdOx1 (vs BNT162b2) was associated with higher risk of infection in both post-primary analysis (adjusted hazard ratio 1·63, 95% CI 1·41–1·88) and after an mRNA-1273 booster (1·26 [1·00–1·57] vs BNT162b2 primary and booster). Lower risk of infection was associated with older age (post-primary: 0·97 [0·96–0·97] per year; post-booster: 0·97 [0·97–0·98]), whereas higher risk of infection was associated with lower educational attainment (post-primary: 1·78 [1·44–2·20] for primary/secondary vs postgraduate; post-booster: 1·46 [1·16–1·83]) and at least three weekly visits to indoor public places (post-primary: 1·36 [1·13–1·63] vs none; post-booster: 1·29 [1·07–1·56]).InterpretationVaccine type, socioeconomic status, age, and behaviours affect risk of breakthrough infection after primary and booster vaccinations.FundingBarts Charity, UK Research and Innovation Industrial Strategy Challenge Fund.

Risk factors associated with COVID-19 infection and mortality in nursing homes

ObjectiveThe aim of this paper was to analyse the association of demographic, clinical and pharmacological risk factors with the presence of SARS-COV-2 virus infection, as well as to know the variables related to mortality from COVID-19 in nursing home (NH) residents. DesignRetrospective case–control study. The study variables of those residents who acquired the infection (case) were compared with those of the residents who did not acquire it (control). A subgroup analysis was carried out to study those variables related to mortality. SiteNursing homes in the region of Guipúzcoa (Spain). Participants and interventions4 NHs with outbreaks of SARS-CoV-2 between March and December 2020 participated in the study. The infectivity and, secondary, mortality was studied, as well as demographic, clinical and pharmacological variables associated with them. Data were collected from the computerised clinical records. Main measurementsInfection and mortality rate. Risk factors associated with infection and mortality. Results436 residents were studied (median age 87 years (IQR 11)), 173 acquired SARS-CoV-2 (39.7%). People with dementia and Global Deterioration Scale ≥6 were less likely to be infected by SARS-CoV-2 virus [OR=0.65 (95% CI 0.43–0.97; p<.05)]. Overall case fatality rate was 10.3% (a mortality of 26% among those who acquired the infection). COVID-19 mortality was significantly associated with a Global Deterioration Scale ≥6 (OR=4.9 (95% CI 1.5–16.1)), COPD diagnosis (OR=7.8 (95% CI 1.9–31.3)) and antipsychotic use (OR=3.1 (95% CI 1.0–9.0)). ConclusionsAdvanced dementia has been associated with less risk of SARS-CoV-2 infection but higher risk of COVID-19 mortality. COPD and chronic use of antipsychotics have also been associated with mortality. These results highlight the importance of determining the stage of diseases such as dementia as well as maintaining some caution in the use of some drugs such as antipsychotics.

Pharmacologic Enhancement of Rotator Cuff Repair: A Narrative Review.

As rotator cuff repairs (RCRs) are among the most common procedures in upper extremity orthopedics, healing augmentation using pharmacologic enhancement of the repaired rotator cuff muscle is of particular interest. The purpose of this study is to review the current understanding of Matrix Metalloproteinases (MMPs), Doxycycline, Testosterone, Estrogen, Growth hormone/ IGF-1, Vitamin D, and Vitamin C as a means to mitigate deleterious effects and propagate factors that support healing following RCR. A review of English language articles in PubMed and Medline was conducted in December of 2020. All articles describing the current understanding of the aforementioned therapies were reviewed. Studies were excluded if they were non-English or reported incomplete results. Matrix metalloproteinases (MMP's) are fundamental to the healing process after rotator cuff tears through a delicate balance of various proteases that can be modulated by doxycycline through inhibition. While testosterone has shown to induce replication and differentiation of the tendon stem-cells, estrogen agonists have been shown to decrease inflammation and muscle atrophy. Though growth hormone being associated with elevated collagen synthesis and decreased anoxic damage when present, clinical studies have shown inconclusive and adverse effects on rotator cuff healing. Patients with Vitamin D deficiency have shown to have increased fatty infiltration in rotator cuff muscle while Vitamin C functions as an antioxidant that increases collagen and fibroblast proliferation. As manipulation of pharmacologic factors shows potential for enhancing healing following RCRs, future studies are needed to establish a viable augmentation strategy to improve patient outcomes.

Gender differences in Parkinson's disease with dementia and dementia with Lewy bodies

BackgroundGender differences for dementia with Lewy bodies (DLB), usually considered an intermediate disease between Alzheimer disease (AD), Parkinson disease (PD), and Parkinson disease with dementia (PDD), is controversial. The present study investigated gender differences in DLB and PDD using demographic and pharmacologic treatment strategies in a retrospective data analysis. MethodData of confirmed cases of DLB and PDD between 2015 and 2020 were collected from the PRISMA dementia data-base registry. Data from 7594 PDD patients and 608 DLB patients were analyzed using logistic regression analysis to determine demographic and pharmacologic factors associated with DLB and PDD patients. ResultIn the adjusted analysis, central acetylcholinesterase inhibitors (ChEIs) including donepezil, galantamine, rivastigmine were associated with DLB. Second generation antipsychotics (SGAs) such as risperidone (odd ratio(OR)=1.900, 95% confidence interval (CI),1.192–3.030, P = 0.007) was associated with females with DLB while aripiprazole (OR=0.195,95% CI,0.06–0.631, P<0.006), and a selective serotonin receptor inhibitor (SSRIs) including escitalopram (OR=0.651, 95% CI,0.468–0.906, P = 0.011), and demographic factors including tobacco use (OR=0.620, 95% CI,0.444–0.866, P<0.005) and increasing age (OR =1.042, 95% CI, 1.025–1.058, P<0.001), were associated with females that present with PDD. Olanzapine (OR=2.871, 95% CI, 1.902–4.334, P<0.001), escitalopram (OR=1.444, 95% CI, 1.079–1.932) and tobacco use (OR=1.424, 95%CI, 1.075–1.887, P = 0.014) were associated with males with DLB. African American males (OR= 0.249, 95% CI, 0.088–0.703, P = 0.009) with a history of ethyl alcohol (ETOH) use (OR= 0.371, 95% CI, 0.260–0.531, P<0.001) treated with aripiprazole (OR=0.581, 95%CI, (0.302–1.118), P = 0.004) were associated with PDD. ConclusionOur findings reveal similarities and differences in demographic and pharmacologic factors associated with DLB and PDD. Investigating the effect of identified factors on DLB or PDD in future studies can help improve the care of DLB and PDD patients.

Risk Factors for Development of Pneumatosis Intestinalis after Pediatric Hematopoietic Stem Cell Transplantation: A Single-Center Case-Control Study

The significance of pneumatosis intestinalis (PI) in pediatric patients following hematopoietic stem cell transplantation (HSCT) is poorly understood. A knowledge gap remains with respect to the etiology, risk factors, and evidence-based treatment of these patients. As a result, management is frequently based on each center's clinical practice, without standardization across treatment centers. In this single-center trial, we aimed to validate both previously proposed and additional risk factors for the development of PI and to examine our management and outcomes for these patients. We performed a retrospective case-control study examining risk factors for the development of PI in pediatric HSCT patients at a single tertiary referral children's hospital. We used univariate and multivariable conditional logistic regression analysis to explore differences in pharmacologic and other transplantation-specific risk factors. Between 2012 and 2019, PI was diagnosed in 212 patients at our pediatric hospital, of whom 42 were HSCT recipients. The majority of patients (88%; n=37 of 42) with PI were diagnosed by X-ray. Eighteen patients (43%) were asymptomatic and diagnosed incidentally after imaging was obtained for standard post-transplantation surveillance or other nonrelated indications. All patients with PI were hospitalized and placed on strict bowel rest while receiving parenteral nutrition and antibiotics. Recurrence of PI occurred in 4 patients (10%) following their initial diagnosis. Increased doses of steroid exposure within 30 days of PI diagnosis (odds ratio [OR], 5.7; 95% confidence interval [CI], 2.1 to 15.3; P=.0006), presence of grade II-IV gastrointestinal acute graft-versus-host disease (GVHD) (OR, 5.3; 95% CI, 1.0 to 28.1; P=.05), and receipt of >50% of total daily nutrition by nasogastric (NG) tube feeds (OR, 22.0; 95% CI, 1.3 to 370.2; P=.03) were identified as independent risk factors for the development of PI. Intensity of the conditioning regimen, exposure to total body irradiation, stem cell source, donor type, HLA matching, use of mycophenolate mofetil, and presence of bacterial or viral infection at the time of PI diagnosis were not demonstrably associated with the development of PI in our study. We conclude that development of asymptomatic PI is a benign condition following HSCT, and that the risk for PI is increased in patients with gastrointestinal GVHD, patients receiving steroid therapy, and patients relying on supplemental NG tube feeds for at least one-half of their total daily nutrition.