Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Missing signposts on the roadmap to quality: a call to improve medication adherence indicators in data collection for population research

Purpose: Poor adherence to prescribed medicines is associated with increased rates of poor outcomes, including hospitalization, serious adverse events, and death, and is also associated with increased healthcare costs. However, current approaches to evaluation of medication adherence using real-world electronic health records (EHRs) or claims data may miss critical opportunities for data capture and fall short in modeling and representing the full complexity of the healthcare environment. We sought to explore a framework for understanding and improving data capture for medication adherence in a population-based intervention in four U.S. counties.Approach: We posited that application of a data model and a process matrix when designing data collection for medication adherence would improve identification of variables and data accessibility, and could support future research on medication-taking behaviors. We then constructed a use case in which data related to medication adherence would be leveraged to support improved healthcare quality, clinical outcomes, and efficiency of healthcare delivery in a population-based intervention for persons with diabetes. Because EHRs in use at participating sites were deemed incapable of supplying the needed data, we applied a taxonomic approach to identify and define variables of interest. We then applied a process matrix methodology, in which we identified key research goals and chose optimal data domains and their respective data elements, to instantiate the resulting data model.Conclusions: Combining a taxonomic approach with a process matrix methodology may afford significant benefits when designing data collection for clinical and population-based research in the arena of medication adherence. Such an approach can effectively depict complex real-world concepts and domains by mapping the relationships between disparate contributors to medication adherence and describing their relative contributions to improved outcomes

Electron Leak From the Mitochondrial Electron Transport Chain Complex I at Site IQ Is Crucial for Oxygen Sensing in Rabbit and Human Ductus Arteriosus

Background As partial pressure of oxygen (pO2) rises with the first breath, the ductus arteriosus (DA) constricts, diverting blood flow to the pulmonary circulation. The DA's O2 sensor resides within smooth muscle cells. The DA smooth muscle cells’ mitochondrial electron transport chain (ETC) produces reactive oxygen species (ROS) in proportion to oxygen tension, causing vasoconstriction by regulating redox‐sensitive ion channels and enzymes. To identify which ETC complex contributes most to DA O2 sensing and determine whether ROS mediate O2 sensing independent of metabolism, we used electron leak suppressors, S1QEL (suppressor of site IQ electron leak) and S3QEL (suppressor of site IIIQo electron leak), which decrease ROS production by inhibiting electron leak from quinone sites IQ and IIIQo, respectively. Methods and Results The effects of S1QEL, S3QEL, and ETC inhibitors (rotenone and antimycin A) on DA tone, mitochondrial metabolism, O2‐induced changes in intracellular calcium, and ROS were studied in rabbit DA rings, and human and rabbit DA smooth muscle cells. S1QEL's effects on DA patency were assessed in rabbit kits, using micro computed tomography. In DA rings, S1QEL, but not S3QEL, reversed O2‐induced constriction (P=0.0034) without reducing phenylephrine‐induced constriction. S1QEL did not inhibit mitochondrial metabolism or ETC‐I activity. In human DA smooth muscle cells, S1QEL and rotenone inhibited O2‐induced increases in intracellular calcium (P=0.02 and 0.001, respectively), a surrogate for DA constriction. S1QEL inhibited O2‐induced ROS generation (P=0.02). In vivo, S1QEL prevented O2‐induced DA closure (P<0.0001). Conclusions S1QEL, but not S3QEL, inhibited O2‐induced rises in ROS and DA constriction ex vivo and in vivo. DA O2 sensing relies on pO2‐dependent changes in electron leak at site IQ in ETC‐I, independent of metabolism. S1QEL offers a therapeutic means to maintain DA patency

The Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study Community Registry and Biorepository

Current understanding of chronic diseases is based on crude clinical characterization, imaging studies, and laboratory testing that has evolved over decades. The Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study is a multi-tiered, longitudinal study designed to enable classification of chronic diseases using clinically annotated biospecimen collections, -omic technologies, electronic health records, and standard epidemiological methods. We expect that detailed molecular classification will improve mechanistic understanding of chronic diseases, augmenting discovery and testing of new treatments, and allowing refined selection of prevention and treatment strategies. The MURDOCK Study Community Registry and Biorepository will serve as a bridge for validation of initial exploratory studies, a platform for future prospective studies in targeted populations, and a resource of both data (analytical and clinical) and samples for cross-registry meta-analyses and comparative population studies. Participation of local health care providers and the Cabarrus County/Kannapolis, NC, community will facilitate future medical research and provide the opportunity to educate and inform the public about genomic research, actively engaging them in shaping the future of medical discovery and treatment of chronic diseases. We present the rationale and study design for the MURDOCK Community Registry and Biorepository and baseline characteristics of the first 6000 participants

Methods and initial findings from the Durham Diabetes Coalition: Integrating geospatial health technology and community interventions to reduce death and disability

Objective: The Durham Diabetes Coalition (DDC) was established in response to escalating rates of disability and death related to type 2 diabetes mellitus, particularly among racial/ethnic minorities and persons of low socioeconomic status in Durham County, North Carolina. We describe a community-based demonstration project, informed by a geographic health information system (GHIS), that aims to improve health and healthcare delivery for Durham County residents with diabetes. Materials and Methods: A prospective, population-based study is assessing a community intervention that leverages a GHIS to inform community-based diabetes care programs. The GHIS integrates clinical, social, and environmental data to identify, stratify by risk, and assist selection of interventions at the individual, neighborhood, and population levels. Results: The DDC is using a multifaceted approach facilitated by GHIS to identify the specific risk profiles of patients and neighborhoods across Durham County. A total of 22,982 patients with diabetes in Durham County were identified using a computable phenotype. These patients tended to be older, female, African American, and not covered by private health insurance, compared with the 166,041 persons without diabetes. Predictive models inform decision-making to facilitate care and track outcomes. Interventions include: 1) neighborhood interventions to improve the context of care; 2) intensive team-based care for persons in the top decile of risk for death or hospitalization within the coming year; 3) low-intensity telephone coaching to improve adherence to evidence-based treatments; 4) county-wide communication strategies; and 5) systematic quality improvement in clinical care. Conclusions: To improve health outcomes and reduce costs associated with type 2 diabetes, the DDC is matching resources with the specific needs of individuals and communities based on their risk characteristics

Availability of activated CD4+ T cells dictates the level of viremia in naturally SIV-infected sooty mangabeys

Naturally SIV-infected sooty mangabeys (SMs) remain asymptomatic despite high virus replication. Elucidating the mechanisms underlying AIDS resistance of SIV-infected SMs may provide crucial information to better understand AIDS pathogenesis. In this study, we assessed the determinants of set-point viremia in naturally SIV-infected SMs, i.e., immune control of SIV replication versus target cell limitation. We depleted CD4+T cells in 6 naturally SIV-infected SMs by treating with humanized anti-CD4 mAb (Cdr-OKT4A-huIgG1). CD4+T cells were depleted almost completely in blood and BM and at variable levels in mucosal tissues and LNs. No marked depletion of CD14+monocytes was observed. Importantly, CD4+T cell depletion was associated with a rapid, significant decline in viral load, which returned to baseline level at day 30–45, coincident with an increased fraction of proliferating and activated CD4+T cells. Throughout the study, virus replication correlated with the level of proliferating CD4+T cells. CD4+T cell depletion did not induce any changes in the fraction of Tregs or the level of SIV-specific CD8+T cells. Our results suggest that the availability of activated CD4+T cells, rather than immune control of SIV replication, is the main determinant of set-point viral load during natural SIV infection of SMs

New Medical Device and Therapeutic Approvals in Otolaryngology: State of the Art Review of 2022

Abstract Objective To review new drugs and devices relevant to otolaryngology approved by the Food and Drug Administration (FDA) in 2022. Data Sources Publicly available FDA data on drugs and devices approved in 2022. Review Methods A preliminary screen was conducted to identify drugs and devices relevant to otolaryngology. A secondary screen by members of the American Academy of Otolaryngology–Head and Neck Surgery's (AAO‐HNS) Medical Devices and Drugs Committee differentiated between minor updates and new approvals. The final list of drugs and devices was sent to members of each subspecialty for review and analysis. Conclusion A total of 1251 devices and 37 drugs were identified on preliminary screening. Of these, 329 devices and 5 drugs were sent to subspecialists for further review, from which 37 devices and 2 novel drugs were selected for further analysis. The newly approved devices spanned all subspecialties within otolaryngology. Many of the newly approved devices aimed to enhance patient experience, including over‐the‐counter hearing aids, sleep monitoring devices, and refined CPAP devices. Other advances aimed to improve surgical access, convenience, or comfort in the operating room and clinic. Implications for Practice Many new devices and drugs are approved each year to improve patient care and care delivery. By staying up to date with these advances, otolaryngologists can leverage new innovations to improve the safety and quality of care. Given the recent approval of these devices, further studies are needed to assess long‐term impact within the field of otolaryngology