Investigations into the causal underpinnings of disease processes can be aided by the incorporation of genetic information. Genetic studies require populations varied in both ancestry and prevalent ...disease in order to optimize discovery and ensure generalizability of findings to the global population. Here, we report the genetic determinants of the serum proteome in 466 African Americans with chronic kidney disease attributed to hypertension from the richly phenotyped African American Study of Kidney Disease and Hypertension (AASK) study. Using the largest aptamer-based protein profiling platform to date (6,790 proteins or protein complexes), we identified 969 genetic associations with 900 unique proteins; including 52 novel cis (local) associations and 379 novel trans (distant) associations. The genetic effects of previously published cis-protein quantitative trait loci (pQTLs) were found to be highly reproducible, and we found evidence that our novel genetic signals colocalize with gene expression and disease processes. Many trans- pQTLs were found to reflect associations mediated by the circulating cis protein, and the common trans-pQTLs are enriched for processes involving extracellular vesicles, highlighting a plausible mechanism for distal regulation of the levels of secreted proteins. Thus, our study generates a valuable resource of genetic associations linking variants to protein levels and disease in an understudied patient population to inform future studies of drug targets and physiology.
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Background: Patients with pancreatic ductal adenocarcinoma (PDAC) experience significant functional decline over the course of their treatment, which can negatively impact their quality of life ...(QOL) and clinical outcomes. There are currently no standardized methods to monitor physical function (PF) in PDAC patients outside the clinic setting. The use of wearable technology to obtain continuous and objective activity data combined with routine collection of patient-reported outcomes (PROs) provides an opportunity to monitor PF and intervene in a timely matter. Methods: We conducted a single-site, single-arm prospective study in advanced stage 3 and 4 PDAC patients between 2019 and 2/2022. Patients used a wrist-worn wearable activity monitor (Fitbit) continuously for 8 weeks and completed NIH PROMIS surveys (PF, pain, fatigue, sleep disturbance, and emotional distress) at baseline, week 4 and week 8. ECOG performance status (PS), hand grip strength, and timed 15-foot walk test were also assessed at each timepoint. Pearson correlation coefficients were calculated for activity data (step counts, distance, stairs, time spent sedentary and in light, moderate, or vigorous activity, sleep), PROs, and functional outcomes. Multivariable regression models, adjusted for age, sex, and cancer stage, were fit to evaluate associations between activity metrics, PROs, and functional outcomes. Multivariable cox proportional hazard models were fit to evaluate the impact of activity levels on survival. Results: A total of 40 patients consented onto study: 50% female, median age: 67 years (range 47-85), 92% ECOG 1. Baseline activity data are summarized in Table. Statistically significant correlations between step counts and PF T-scores (coeff: 0.6, p = 0.001) and lower pain scores (coeff: -0.53, p = 0.002) were observed. Increased stairs count and time spent in moderate and high physical activity were also positively correlated with increased PF (p<0.001). No statistically significant correlations were observed between hand grip strength, activity metrics or PROs. Fewer average step counts and worse PF scores were significantly associated with poor survival with hazard ratios (HR) of 1.44 per 1000 steps (95% CI 1.06, 1.97, p = 0.02) and 1.69 (95% CI 1.1-2.56, p = 0.017), respectively, after adjusting for age, sex, stage, and ECOG PS. Conclusions: Findings from this research suggest that the use of wearable technology for remote monitoring of daily activity is feasible and may be used to supplement functional assessment and predict outcomes in PDAC patients. Larger trials are needed to validate findings. Table: see text
Reversible protein phosphorylation on serine, threonine, and tyrosine residues is essential for fast, specific, and accurate signal transduction in cells. Up to now, the identification and ...quantification of phosphorylated amino acids, peptides, and proteins continue to be one of the significant challenges in contemporary bioanalytical research. In this paper, a series of surface grafted monoliths in the capillary format targeting phosphorylated serine has been prepared by first synthesizing a monolithic core substrate material based on trimethylolpropane trimethacrylate, onto which a thin surface-imprinted layer was established by oriented photografting of a variety of mono- and bis-imidazolium host monomers at subzero temperature, using six different continuous or pulsed UV light sources. The imprinted monolith capillaries were evaluated in a capillary liquid chromatographic system connected to a mass spectrometer in order to test the specific retention of phosphorylated peptides. Site-specific recognition selectivity and specificity for phosphorylated serine was demonstrated when separating amino acids and peptides, proving that the optimized materials could be used as novel trapping media in affinity-based phosphoproteomic analysis.
This viewpoint was developed to revisit the burden and risks associated with postpartum depression (PPD) among incarcerated women based on a thematic review of the literature. Around one third of ...incarcerated pregnant women have symptoms of moderate to severe depression perinatally. In particular, PPD negatively impacts the well-being of parents and their children. Mitigating the consequences of PPD through screening, promotion of protective factors, and early identification coupled with treatment may have a substantial impact on the overall well-being of the affected children and postpartum individuals. Important risk factors for PPD in correctional populations include previous mental illness diagnosis, a lack of social support, poor pre- and perinatal care, inability to breastfeed, a lack of skin-to-skin contact, and partner violence. We recommend that correctional facilities promote the development of on-site mother-baby units and streamline the visitation process for newborns to visit parents. Improved access to pre- and postnatal care, education, and doula support is highly recommended, as well as consideration of community-based alternatives to incarceration, particularly in correctional settings with underserved mental health care needs. Future studies are needed to estimate the burden of PPD in correctional settings, identify system-related risk factors, and implement evidence-based guidelines for PPD and associated psychosocial sequelae.
Global impact of COVID-19 on stroke care Mansour, Ossama Yassin; Farhoudi, Mehdi; Siegler, James E. ...
International journal of stroke,
07/2021, Letnik:
16, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Background
The COVID-19 pandemic led to profound changes in the organization of health care systems worldwide.
Aims
We sought to measure the global impact of the COVID-19 pandemic on the volumes for ...mechanical thrombectomy, stroke, and intracranial hemorrhage hospitalizations over a three-month period at the height of the pandemic (1 March–31 May 2020) compared with two control three-month periods (immediately preceding and one year prior).
Methods
Retrospective, observational, international study, across 6 continents, 40 countries, and 187 comprehensive stroke centers. The diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases at participating centers.
Results
The hospitalization volumes for any stroke, intracranial hemorrhage, and mechanical thrombectomy were 26,699, 4002, and 5191 in the three months immediately before versus 21,576, 3540, and 4533 during the first three pandemic months, representing declines of 19.2% (95%CI, −19.7 to −18.7), 11.5% (95%CI, −12.6 to −10.6), and 12.7% (95%CI, −13.6 to −11.8), respectively. The decreases were noted across centers with high, mid, and low COVID-19 hospitalization burden, and also across high, mid, and low volume stroke/mechanical thrombectomy centers. High-volume COVID-19 centers (−20.5%) had greater declines in mechanical thrombectomy volumes than mid- (−10.1%) and low-volume (−8.7%) centers (p < 0.0001). There was a 1.5% stroke rate across 54,366 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.9% (784/20,250) of all stroke admissions.
Conclusion
The COVID-19 pandemic was associated with a global decline in the volume of overall stroke hospitalizations, mechanical thrombectomy procedures, and intracranial hemorrhage admission volumes. Despite geographic variations, these volume reductions were observed regardless of COVID-19 hospitalization burden and pre-pandemic stroke/mechanical thrombectomy volumes.
Obesity is a growing epidemic characterized by excess fat storage in adipocytes. Although lipoprotein receptors play important roles in lipid uptake, their role in controlling food intake and obesity ...is not known. Here we show that the lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis. Conditional deletion of the Lrp1 gene in the brain resulted in an obese phenotype characterized by increased food intake, decreased energy consumption, and decreased leptin signaling. LRP1 directly binds to leptin and the leptin receptor complex and is required for leptin receptor phosphorylation and Stat3 activation. We further showed that deletion of the Lrp1 gene specifically in the hypothalamus by Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results demonstrate that the lipoprotein receptor LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in the adult central nervous system.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
It is poorly understood whether insurance type may be a major contributor to the underuse of oral anticoagulation (OAC) among patients with atrial fibrillation (AF), particularly for novel oral ...anticoagulants (NOACs).
We performed a retrospective cohort registry study of patients with insurance, AF, CHA2DS2-VASc ≥2, and at least one outpatient encounter recorded in the ACC NCDR's PINNACLE Registry between January 1, 2011 and December 31, 2014. We used hierarchical regression, adjusting for patient characteristics and clustering by physician, to evaluate the association of insurance type (Private, Military, Medicare, Medicaid, Other) with receipt of OAC (any OAC, warfarin, or NOAC).
In 363,309 patients (age 75±10; 48% female), we found a significant difference in proportions of OAC and NOAC prescription across insurance types (OAC: Military 53%, Private 53%, Medicare 52%, Other 41%, Medicaid 41%, P<.001; NOAC: Military 24%, Private 19%, Medicare 17%, Other 17%, Medicaid 8%, P<.001). After adjustment for patient characteristics and facility, private, Medicaid, and other insurance were independently associated with a lower odds of OAC prescription relative to Medicare, but military insured patients were not significantly different. After adjustment, military and private insurance were independently associated with a higher odds of NOAC prescription relative to Medicare, while Medicaid and other insurance were associated with a lower odds of NOAC prescription.
In a contemporary US AF population, there was significant variation of OAC prescription across insurance plans, with the highest among private and Medicare insured patients. These differences may indicate that insurance plan, and its associated pharmacy benefits, affect the pace of diffusion of new therapies.
Nanobodies bind a target antigen with a kinetic profile similar to a conventional antibody, but exist as a single heavy chain domain that can be readily multimerized to engage antigen via multiple ...interactions. Presently, most nanobodies are produced by immunizing camelids; however, platforms for animal-free production are growing in popularity. Here, we describe the development of a fully synthetic nanobody library based on an engineered human V
3-23 variable gene and a multispecific antibody-like format designed for biparatopic target engagement. To validate our library, we selected nanobodies against the SARS-CoV-2 receptor-binding domain and employed an on-yeast epitope binning strategy to rapidly map the specificities of the selected nanobodies. We then generated antibody-like molecules by replacing the V
and V
domains of a conventional antibody with two different nanobodies, designed as a molecular clamp to engage the receptor-binding domain biparatopically. The resulting bispecific tetra-nanobody immunoglobulins neutralized diverse SARS-CoV-2 variants with potencies similar to antibodies isolated from convalescent donors. Subsequent biochemical analyses confirmed the accuracy of the on-yeast epitope binning and structures of both individual nanobodies, and a tetra-nanobody immunoglobulin revealed that the intended mode of interaction had been achieved. This overall workflow is applicable to nearly any protein target and provides a blueprint for a modular workflow for the development of multispecific molecules.
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