IMPORTANCE: Low-density lipoprotein cholesterol (LDL-C)–lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as ...proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes. OBJECTIVE: To investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: The associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50 775 individuals with type 2 diabetes and 270 269 controls and 60 801 individuals with coronary artery disease and 123 504 controls. Data collection took place in Europe and the United States between 1991 and 2016. EXPOSURES: Low-density lipoprotein cholesterol–lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) for type 2 diabetes and coronary artery disease. RESULTS: Low-density lipoprotein cholesterol–lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L 38.7-mg/dL reduction in LDL-C of 0.61 95% CI, 0.42-0.88; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 95% CI, 1.70-3.43; P < .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0% for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles. CONCLUSIONS AND RELEVANCE: In this meta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.
Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic ...regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.
On June 24, 2022, the US Supreme Court ended constitutional protections for abortion, resulting in wide variability in access from severe restrictions in many states and fewer restrictions in others. ...Healthcare institutions capture information about patients' pregnancy and abortion care and, due to interoperability, may share it in ways that expose their providers and patients to social stigma and potential legal jeopardy in states with severe restrictions. In this article, we describe sources of risk to patients and providers that arise from interoperability and specify actions that institutions can take to reduce that risk. Institutions have significant power to define their practices for how and where care is documented, how patients are identified, where data are sent or hosted, and how patients are counseled, and thus should protect patients' privacy and ability to receive medical care that is safe and legal where it is performed.
Germline mutations in telomere biology genes cause dyskeratosis congenita (DC), an inherited bone marrow failure and cancer predisposition syndrome. DC is a clinically heterogeneous disorder ...diagnosed by the triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia; Hoyeraal-Hreidarsson syndrome (HH), a clinically severe variant of DC, also includes cerebellar hypoplasia, immunodeficiency, and intrauterine growth retardation. Approximately 70% of DC cases are associated with a germline mutation in one of nine genes, the products of which are all involved in telomere biology. Using exome sequencing, we identified mutations in Adrenocortical Dysplasia Homolog (ACD) (encoding TPP1), a component of the telomeric shelterin complex, in one family affected by HH. The proband inherited a deletion from his father and a missense mutation from his mother, resulting in extremely short telomeres and a severe clinical phenotype. Characterization of the mutations revealed that the single-amino-acid deletion affecting the TEL patch surface of the TPP1 protein significantly compromises both telomerase recruitment and processivity, while the missense mutation in the TIN2-binding region of TPP1 is not as clearly deleterious to TPP1 function. Our results emphasize the critical roles of the TEL patch in proper stem cell function and demonstrate that TPP1 is the second shelterin component (in addition to TIN2) to be implicated in DC.
Risk-standardized hospital readmission rates are used as publicly reported measures reflecting quality of care. Valid risk-standardized models adjust for differences in patient-level factors across ...hospitals. We conducted a systematic review of peer-reviewed literature to identify models that compare hospital-level poststroke readmission rates, evaluate patient-level risk scores predicting readmission, or describe patient and process-of-care predictors of readmission after stroke.
Relevant studies in English published from January 1989 to July 2010 were identified using MEDLINE, PubMed, Scopus, PsycINFO, and all Ovid Evidence-Based Medicine Reviews. Authors of eligible publications reported readmission within 1 year after stroke hospitalization and identified ≥ 1 predictors of readmission in risk-adjusted statistical models. Publications were excluded if they lacked primary data or quantitative outcomes, reported only composite outcomes, or had < 100 patients.
Of 374 identified publications, 16 met the inclusion criteria for this review. No model was specifically designed to compare risk-adjusted readmission rates at the hospital level or calculate scores predicting a patient's risk of readmission. The studies providing multivariable models of patient-level and/or process-of-care factors associated with readmission varied in stroke definitions, data sources, outcomes (all-cause and/or stroke-related readmission), durations of follow-up, and model covariates. Few characteristics were consistently associated with readmission.
This review identified no risk-standardized models for comparing hospital readmission performance or predicting readmission risk after stroke. Patient-level and system-level factors associated with readmission were inconsistent across studies. The current literature provides little guidance for the development of risk-standardized models suitable for the public reporting of hospital-level stroke readmission performance.
A prescribing cascade occurs when a drug is prescribed to manage the often unrecognised side effect of another drug; these cascades are of particular concern for older adults who are at heightened ...risk for drug-related harm. It is unknown whether, and to what extent, gender bias influences physician decision-making in the context of prescribing cascades. The aim of this transnational study is to explore the potential impact of physician implicit gender biases on prescribing decisions that may lead to the initiation of prescribing cascades in older men and women in two countries, namely: Canada and Italy.
Male and female primary care physicians at each site will be randomised 1:1 to a case vignette that features either a male or female older patient who presents with concerns consistent with the side effect of a medication they are taking. During individual interviews, while masked to the true purpose of the study, participants will read the vignette and use the think-aloud method to describe their ongoing thought processes as they consider the patient's concerns and determine a course of action. Interviews will be recorded, transcribed verbatim and thematic analysis will be conducted to highlight differences in decisions in the interviews/transcripts, using a common analytical framework across the sites.
This study has received ethics approval at each study site. Verbal informed consent will be received from participants prior to data collection and all data will be deidentified and stored on password-protected servers. Results of this study will be disseminated through peer-reviewed journal articles and presented at relevant national and international conferences.
Patients with severe aplastic anemia (SAA) can have an unrecognized inherited bone marrow failure syndrome (IBMFS) because of phenotypic heterogeneity. We curated germline genetic variants in 104 ...IBMFS-associated genes from exome sequencing performed on 732 patients who underwent hematopoietic cell transplant (HCT) between 1989 and 2015 for acquired SAA. Patients with pathogenic or likely pathogenic (P/LP) variants fitting known disease zygosity patterns were deemed unrecognized IBMFS. Carriers were defined as patients with a single P/LP variant in an autosomal recessive gene or females with an X-linked recessive P/LP variant. Cox proportional hazard models were used for survival analysis with follow-up until 2017. We identified 113 P/LP single-nucleotide variants or small insertions/deletions and 10 copy number variants across 42 genes in 121 patients. Ninety-one patients had 105 in silico predicted deleterious variants of uncertain significance (dVUS). Forty-eight patients (6.6%) had an unrecognized IBMFS (33% adults), and 73 (10%) were carriers. No survival difference between dVUS and acquired SAA was noted. Compared with acquired SAA (no P/LP variants), patients with unrecognized IBMFS, but not carriers, had worse survival after HCT (IBMFS hazard ratio HR, 2.13; 95% confidence intervalCI, 1.40-3.24; P = .0004; carriers HR, 0.96; 95% CI, 0.62-1.50; P = .86). Results were similar in analyses restricted to patients receiving reduced-intensity conditioning (n = 448; HR IBMFS = 2.39; P = .01). The excess mortality risk in unrecognized IBMFS attributed to death from organ failure (HR = 4.88; P < .0001). Genetic testing should be part of the diagnostic evaluation for all patients with SAA to tailor therapeutic regimens. Carriers of a pathogenic variant in an IBMFS gene can follow HCT regimens for acquired SAA.
•The detection of unrecognized inherited disorders in severe aplastic anemia calls for genetic testing in the diagnosis of all patients.•Patients with IBMFS, but not carriers, may need disease-specific transplant regimens to improve their outcomes.
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Blue intratissue refractive index shaping (blue-IRIS) is a method with potential to correct ocular refraction noninvasively in humans. To date, blue-IRIS has only ever been applied to cat corneas and ...hydrogels. To test the comparability of refractive index change achievable in cat and human tissues, we used blue-IRIS to write identical phase gratings in ex vivo feline and human corneas. Femtosecond pulses (400 nm) were focused ∼300 μm below the epithelial surface of excised cat and human corneas and scanned to write phase gratings with lines ∼1 μm wide, spaced 5 μm apart, using a scan speed of 5 mm/s. Additional cat corneas were used to test writing at 3 and 7 mm/s in order to document speed dependence of the refractive index change magnitude. The first-order diffraction efficiency was immediately measured and used to calculate the refractive index change attained. Our data show that blue-IRIS induces comparable refractive index changes in feline and human corneas, an essential requirement for further developing its use as a clinical vision correction technique.
Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. ...We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near
(rs9942471,
= 4.5 × 10
) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at
and
, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
Estimates suggest that 10-40% of lumbar spine surgery patients experience persistent post-surgical pain (PPSP). PPSP is associated with 50% greater healthcare costs, along with risks of emotional ...distress and impaired quality of life. In 2019, U.S. Health and Human Services identified brief and digital behavioral treatments as important for pain management after surgery. Indeed, brief behavioral pain treatments delivered in the perioperative period may offer patients a low burden opportunity to acquire essential pain coping strategies for enhanced surgical recovery. Additionally, the COVID-19 pandemic has diminished in-person pain treatment access during extended perioperative time frames, thus underscoring the need for on-line options and home based care. This report describes the integration of an online, live-instructor delivered single-session pain self-management intervention (Empowered Relief) into the standard of care for lumbar spine surgery. Here, we apply the RE-AIM framework; describe systems implementation of the Empowered Relief intervention in a large, academic medical center during the COVID-19 pandemic; describe operational challenges and financial considerations; and present patient engagement data. Finally, we discuss the scalable potential of Empowered Relief and other single-session interventions in surgical populations, their importance during extended perioperative periods, practical and scientific limitations, and new directions for future research on this topic.
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