Establishing a Health Information Technology for the Vaccination of National Institutes of Health Staff.

Introduction: Healthcare organizations faced unique operational challenges during the COVID-19 pandemic. Assuring the safety of both patients and healthcare workers in hospitals has been the primary focus during the COVID-19 pandemic. Methods: The NIH Vaccine Program (VP) with the Vaccine Management System (VMS) was created based on the commitment of NIH leadership, program leadership, the development team, and the program team; defining Key Performance Indicators (KPIs) of the VP and the VMS; and the NIH Clinical Center's (NIH CC) interdisciplinary approach to deploying the VMS. Results: This article discusses the NIH business requirements of the VP and VMS, the target KPIs of the VP and the VMS, and the NIH CC interdisciplinary approach to deploying an organizational VMS for vaccinating the NIH workforce. The use of the DCRI Spiral-Agile Software Development Life Cycle enabled the development of a system with stakeholder involvement that could quickly adapt to changing requirements meeting the defined KPIs for the program and system. The assessment of the defined KPIs through a survey and comments from the survey support that the VP and VMS were successful. Conclusion: A comprehensive program to maintain a healthy workforce includes asymptomatic COVID testing, symptomatic COVID testing, contact tracing, vaccinations, and policy-driven education. The need to develop systems during the pandemic resulted in changes to build software quickly with the input of many more users and stakeholders then typical in a decreased amount of time.

Marijuana Use and the Risk of Early Ischemic Stroke: The Stroke Prevention in Young Adults Study.

BACKGROUND AND PURPOSE: Few studies have examined the dose-response and temporal relationships between marijuana use and ischemic stroke while controlling for important confounders, including the amount of tobacco smoking. The purpose of our study was to address these knowledge gaps. METHODS: A population-based case-control study with 1090 cases and 1152 controls was used to investigate the relationship of marijuana use and early-onset ischemic stroke. Cases were first-ever ischemic stroke between the ages of 15 and 49 identified from 59 hospitals in the Baltimore-Washington region. Controls obtained by random digit dialing from the same geographic region were frequency-matched to cases by age, sex, region of residence and, except for the initial study phase, race. After excluding subjects with cocaine and other vasoactive substance use, the final study sample consisted of 751 cases and 813 controls. All participants underwent standardized interviews to characterize stroke risk factors and marijuana use. Unconditional logistic regression analysis was used to assess the relationships between marijuana use and risk of ischemic stroke, adjusting for age, sex, race, study phase, the amount of current tobacco smoking, current alcohol use, hypertension, and diabetes. RESULTS: After adjusting for other risk factors, including the amount of current tobacco smoking, marijuana use was not associated with ischemic stroke, regardless of the timing of use in relationship to the stroke, including ever use, use within 30 days, and use within 24 hours. There was a nonsignificant trend towards increased stroke risk among those who smoked marijuana at least once a week (odds ratio, 1.9 [95% CI, 0.8-4.9]). CONCLUSIONS: These analyses do not demonstrate an association between marijuana use and an increased risk of early-onset ischemic stroke, although statistical power was limited for assessing the association among very heavy users.

Unveiling the silent threat among us: leveraging health information technology in the search for asymptomatic COVID 19 healthcare workers.

Assuring the safety of both patients and healthcare workers (HCWs) in hospitals has been the primary focus of every healthcare organization during the COVID 19 pandemic. This article discusses the NIH Clinical Center's interdisciplinary approach to deploying an organizational Asymptomatic Staff Testing System.

Neurobiological research with suicidal participants: A framework for investigators.

OBJECTIVE: Suicide is a public health threat. Nevertheless, the research literature on actively suicidal participants is relatively sparse, in part because they are often excluded from medical, psychiatric, and psychological research for a host of logistical, ethical, and safety concerns. These obstacles to research participation and enrollment may contribute to our lack of understanding regarding the neurobiology of the suicidal crisis as well as to the dearth of evidence concerning both risk prediction and treatment. METHOD: In order to directly investigate neurobiological markers of acute suicide risk, the National Institute of Mental Health Intramural Research Program (NIMH-IRP) implemented the Neurobiology of Suicide protocol. In this protocol, actively suicidal individuals consent to research for both neurobiological assessment and potential rapid-acting interventions. RESULTS AND CONCLUSIONS: This article reviews lessons learned from implementing this protocol in the hopes of assisting future research on the neurobiology of suicide. Areas of specific discussion include the Failure Modes and Effects Analysis (FMEA), recruitment and informed consent, participant monitoring, and the safety of the physical environment.

Factors Considered by Clinicians when Prognosticating Intracerebral Hemorrhage Outcomes.

BACKGROUND: The early subjective clinical judgment of clinicians outperforms formal prognostic scales for accurate determination of outcome after intracerebral hemorrhage (ICH), with the judgment of physicians and nurses having equivalent accuracy. This study assessed specific decisional factors that physicians and nurses incorporate into early predictions of functional outcome. METHODS: This prospective observational study enrolled 121 ICH patients at five US centers. Within 24 h of each patient's admission, one physician and one nurse on the clinical team were each surveyed to predict the patient's modified Rankin Scale (mRS) at 3 months and to list up to 10 subjective factors used in prognostication. Factors were coded and compared between (1) physician and nurse and (2) accurate and inaccurate surveys, with accuracy defined as an exact prediction of mRS. RESULTS: Aside from factors that are components of the ICH or FUNC scores, surveys reported pre-existing comorbidities (40.0%), other clinical or radiographic factors not in clinical scales (43.0%), and non-clinical/radiographic factors (21.9%) as important. Compared to physicians, nurses more frequently listed neurologic examination components (Glasgow Coma Scale motor, 27.3 vs. 5.8%, p < 0.0001; GCS verbal, 12.4 vs. 0.0%, p < 0.0001) and non-clinical/radiographic factors (31.4 vs. 12.4%, p = 0.0005). Physicians more frequently listed neuroimaging factors (ICH location, 33.9 vs. 7.4%, p < 0.0001; intraventricular hemorrhage, 13.2 vs. 2.5%, p = 0.003). There was no difference in listed factors between accurate versus inaccurate surveys. CONCLUSIONS: Clinicians frequently utilize factors outside of the components of clinical scales for prognostication, with physician and nurses focusing on different factors despite having similar accuracy.

Association of Comorbid and Metabolic Factors with Optimal Control of Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a poorly controlled epidemic worldwide that demands active research into mitigation of the factors that are associated with poor control. AIMS: The study was to determine the factors associated with suboptimal glycemic control. MATERIALS AND METHODS: Electronic medical records of 263 adult patients with T2DM in our suburban internal medicine office were reviewed. Patients were divided into two groups: Group 1 [optimal diabetes control with glycosylated hemoglobin (HbA1c) of 7% or less] and Group 2 (suboptimal diabetes control with HbA1c greater than 7%). The influence of factors such as age, gender, race, social history, comorbid conditions, gestational diabetes, family history of diabetes, diabetes management, statin use, aspirin use, angiotensin convertase enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) use, body mass index (BMI), blood pressures, lipid profile, and urine microalbumin level were analyzed in the two groups. RESULTS: In the suboptimal diabetes control group (N = 119), the majority (86.6%) of the patients were 41-80 years old. Factors associated with the suboptimal control were male gender [odds ratio (OR) 2.6, 95% confidence interval (CI), 1.579-4.321], Asian ethnicity (OR 1.4, 95% CI, 0.683-3.008), history of peripheral arterial disease (PAD; OR 3.9, 95% CI, 1.017-14.543), history of congestive heart failure (CHF; OR 3.9, 95% CI, 1.017-14.543), elevated triglycerides (OR 1.004, 95% CI, 1.000-1.007), and elevated urine microalbumin level of 30 mg/24 h or above (OR 4.5, 95% CI, 2.446-8.380). Patients with suboptimal diabetes control had a 3.8 times greater odds (95% CI, 1.493-6.885) of receiving the insulin and oral hypoglycemic agent together. CONCLUSIONS: In adult patients with T2DM, male gender, Asian ethnicity, CHF, PAD, management with insulin along with oral hypoglycemic agents, hypertriglyceridemia, and microalbuminuria were associated with suboptimal control.

Cocaine Use and Risk of Ischemic Stroke in Young Adults.

BACKGROUND AND PURPOSE: Although case reports have long identified a temporal association between cocaine use and ischemic stroke (IS), few epidemiological studies have examined the association of cocaine use with IS in young adults, by timing, route, and frequency of use. METHODS: A population-based case-control study design with 1090 cases and 1154 controls was used to investigate the relationship of cocaine use and young-onset IS. Stroke cases were between the ages of 15 and 49 years. Logistic regression analysis was used to evaluate the association between cocaine use and IS with and without adjustment for potential confounders. RESULTS: Ever use of cocaine was not associated with stroke with 28% of cases and 26% of controls reporting ever use. In contrast, acute cocaine use in the previous 24 hours was strongly associated with increased risk of stroke (age-sex-race adjusted odds ratio, 6.4; 95% confidence interval, 2.2-18.6). Among acute users, the smoking route had an adjusted odds ratio of 7.9 (95% confidence interval, 1.8-35.0), whereas the inhalation route had an adjusted odds ratio of 3.5 (95% confidence interval, 0.7-16.9). After additional adjustment for current alcohol, smoking use, and hypertension, the odds ratio for acute cocaine use by any route was 5.7 (95% confidence interval, 1.7-19.7). Of the 26 patients with cocaine use within 24 hours of their stroke, 14 reported use within 6 hours of their event. CONCLUSIONS: Our data are consistent with a causal association between acute cocaine use and risk of early-onset IS.

Clinician judgment vs formal scales for predicting intracerebral hemorrhage outcomes.

OBJECTIVE: To compare the performance of formal prognostic instruments vs subjective clinical judgment with regards to predicting functional outcome in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: This prospective observational study enrolled 121 ICH patients hospitalized at 5 US tertiary care centers. Within 24 hours of each patient's admission to the hospital, one physician and one nurse on each patient's clinical team were each asked to predict the patient's modified Rankin Scale (mRS) score at 3 months and to indicate whether he or she would recommend comfort measures. The admission ICH score and FUNC score, 2 prognostic scales selected for their common use in neurologic practice, were calculated for each patient. Spearman rank correlation coefficients (r) with respect to patients' actual 3-month mRS for the physician and nursing predictions were compared against the same correlation coefficients for the ICH score and FUNC score. RESULTS: The absolute value of the correlation coefficient for physician predictions with respect to actual outcome (0.75) was higher than that of either the ICH score (0.62, p = 0.057) or the FUNC score (0.56, p = 0.01). The nursing predictions of outcome (r = 0.72) also trended towards an accuracy advantage over the ICH score (p = 0.09) and FUNC score (p = 0.03). In an analysis that excluded patients for whom comfort care was recommended, the 65 available attending physician predictions retained greater accuracy (r = 0.73) than either the ICH score (r = 0.50, p = 0.02) or the FUNC score (r = 0.42, p = 0.004). CONCLUSIONS: Early subjective clinical judgment of physicians correlates more closely with 3-month outcome after ICH than prognostic scales.

Obesity increases risk of ischemic stroke in young adults.

BACKGROUND AND PURPOSE: Body mass index has been associated with ischemic stroke in older populations, but its association with stroke in younger populations is not known. In light of the current obesity epidemic in the United States, the potential impact of obesity on stroke risk in young adults deserves attention. METHODS: A population-based case-control study design with 1201 cases and 1154 controls was used to investigate the relationship of obesity and young onset ischemic stroke. Stroke cases were between the ages of 15 and 49 years. Logistic regression analysis was used to evaluate the association between body mass index and ischemic stroke with and without adjustment for comorbid conditions associated with stroke. RESULTS: In analyses adjusted for age, sex, and ethnicity, obesity (body mass index >30 kg/m(2)) was associated with an increased stroke risk (odds ratio, 1.57; 95% confidence interval, 1.28-1.94) although this increased risk was highly attenuated and not statistically significant after adjustment for smoking, hypertension, and diabetes mellitus. CONCLUSIONS: These results indicate that obesity is a risk factor for young onset ischemic stroke and suggest that this association may be partially mediated through hypertension, diabetes mellitus, or other variables associated with these conditions.

Correction of Low Vitamin D Improves Fatigue: Effect of Correction of Low Vitamin D in Fatigue Study (EViDiF Study).

BACKGROUND: Fatigue is a common presenting complaint of patients in the primary care offices. Low levels of vitamin D have been associated with fatigue in cancer patients. Normalization of vitamin D level improves their fatigue. Whether low vitamin D plays a role in fatigue in medically stable patients is not known. AIMS: This prospective non-randomized therapeutic study observed the prevalence of low vitamin D in fatigue and the effect of normalization of vitamin D on fatigue. MATERIAL AND METHODS: One hundred and seventy four adult patients, who presented in our primary care office with fatigue and stable chronic medical conditions,completed fatigue assessment questionnaires. Patients with low vitamin D levels received ergocalciferol therapy for 5 weeks. Scores of pre- and post-treatment fatigue assessment questionnaires were compared. RESULTS: Prevalence of low vitamin D was 77.2% in patients who presented with fatigue. After normalization of vitamin D levels fatigue symptom scores improved significantly (P < 0.001) in all five subscale categories of fatigue assessment questionnaires. CONCLUSION: The prevalence of low vitamin D is high in patients who present with fatigue and stable chronic medical conditions, if any. Normalization of vitamin D levels with ergocalciferol therapy significantly improves the severity of their fatigue symptoms.

Prothrombin G20210A mutation is associated with young-onset stroke: the genetics of early-onset stroke study and meta-analysis.

BACKGROUND AND PURPOSE: Although the prothrombin G20210A mutation has been implicated as a risk factor for venous thrombosis, its role in arterial ischemic stroke is unclear, particularly among young adults. To address this issue, we examined the association between prothrombin G20210A and ischemic stroke in a white case-control population and additionally performed a meta-analysis. METHODS: From the population-based Genetics of Early Onset Stroke (GEOS) study, we identified 397 individuals of European ancestry aged 15 to 49 years with first-ever ischemic stroke and 426 matched controls. Logistic regression was used to calculate odds ratios (ORs) in the entire population and for subgroups stratified by sex, age, oral contraceptive use, migraine, and smoking status. A meta-analysis of 17 case-control studies (n=2305 cases <55 years) was also performed with and without GEOS data. RESULTS: Within GEOS, the association of the prothrombin G20210A mutation with ischemic stroke did not achieve statistical significance (OR=2.5; 95% confidence interval [CI]=0.9-6.5; P=0.07). However, among adults aged 15 to 42 years (younger than median age), cases were significantly more likely than controls to have the mutation (OR=5.9; 95% CI=1.2-28.1; P=0.03), whereas adults aged 42 to 49 years were not (OR=1.4; 95% CI=0.4-5.1; P=0.94). In our meta-analysis, the mutation was associated with significantly increased stroke risk in adults ≤55 years (OR=1.4; 95% CI=1.1-1.9; P=0.02), with significance increasing with addition of the GEOS results (OR=1.5; 95% CI=1.1-2.0; P=0.005). CONCLUSIONS: The prothrombin G20210A mutation is associated with ischemic stroke in young adults and may have an even stronger association among those with earlier onset strokes. Our finding of a stronger association in the younger young adult population requires replication.

Prevention opportunities for oral contraceptive-associated ischemic stroke.

BACKGROUND AND PURPOSE: Literature suggests a small increased risk of ischemic stroke with oral contraception (OC) use. We evaluated the association of stroke and OC use in women on the basis of whether they recalled being advised by a physician not to use OC or to discontinue OC use because of the presence of stroke risk modifiers, and whether such advice resulted in behavioral change. METHODS: A total of 572 women (224 strokes and 348 controls) aged 15 to 49 years were interviewed about OC use and risk modifiers, including cigarette smoking and headaches, among others. RESULTS: The adjusted odds ratio for OC use and stroke was 2.00 (95% confidence interval, 1.29-3.09). The association of OC use with stroke was stronger in women that reported receiving doctor's advice against OC use because of the presence of other stroke risk modifiers (odds ratio, 3.12; 95% confidence interval, 1.62-6.00) than in women who did not recall receiving such advice (odds ratio, 1.31; 95%confidence interval, 0.71-2.43). Of 256 women who recalled being advised by their doctor not to start OC or to discontinue OC use because of the presence of other stroke risk modifiers, 24% were still on OC at the time of stroke or interview. CONCLUSIONS: We confirm that certain medical conditions increase the risk of stroke during OC use and demonstrate the importance of physician counseling in those using OC in the setting of concurrent high-risk conditions and the need for improved patient compliance with such counseling.

Factor V leiden and ischemic stroke risk: the Genetics of Early Onset Stroke (GEOS) study.

BACKGROUND: Factor V Leiden (FVL) has been associated with ischemic stroke in children but not in adults. Although the FVL mutation is associated with increased risk for venous thrombosis, its association with ischemic stroke in young adults remains uncertain. Therefore, we examined the association between FVL and ischemic stroke in participants of the Genetics of Early Onset Stroke (GEOS) study. METHODS: A population-based case control study identified 354 women and 476 men 15 to 49 years of age with first-ever ischemic stroke and 907 controls. Participant-specific data included vascular risk factors, FVL genotype and, for cases, the ischemic stroke subtype by modified Trial of ORG 10172 in Acute Stroke criteria. Logistic regression was used to calculate odds ratios for the entire population and for subgroups stratified by risk factors and ischemic stroke subtype. RESULTS: The frequency of the FVL mutation was similar between ischemic stroke patients (3.6%; 95% confidence interval [CI] 2.5%-5.1%) and nonstroke controls (3.8%; 95% CI 2.7%-5.2%). This frequency did not change significantly when cases were restricted to patients with stroke of undetermined etiology (4.1%; 95% CI 2.6%-6.4%). CONCLUSIONS: Among young adults, we found no evidence for an association between FVL and either all ischemic stroke or the subgroup with stroke of undetermined etiology.

Murine typhus: endemic Rickettsia in southwest Texas.

Murine Typhus is a zoonosis caused by the organism Rickettsia typhi and is transmitted to humans by fleas. It is endemic in several areas of Texas, California and Hawaii where the vector is supported predominantly by rodents in addition to opossums, domestic and feral cats and domestic dogs. We present a typical case in an adult from Corpus Christi, located in one of the four endemic areas in Texas. Included is an overview of the organism's pathogenicity and our host responses, both influencing the milder clinical course seen with this species of Rickettsia.

Genome-wide association analysis of ischemic stroke in young adults.

Ischemic stroke (IS) is among the leading causes of death in Western countries. There is a significant genetic component to IS susceptibility, especially among young adults. To date, research to identify genetic loci predisposing to stroke has met only with limited success. We performed a genome-wide association (GWA) analysis of early-onset IS to identify potential stroke susceptibility loci. The GWA analysis was conducted by genotyping 1 million SNPs in a biracial population of 889 IS cases and 927 controls, ages 15-49 years. Genotypes were imputed using the HapMap3 reference panel to provide 1.4 million SNPs for analysis. Logistic regression models adjusting for age, recruitment stages, and population structure were used to determine the association of IS with individual SNPs. Although no single SNP reached genome-wide significance (P < 5 × 10(-8)), we identified two SNPs in chromosome 2q23.3, rs2304556 (in FMNL2; P = 1.2 × 10(-7)) and rs1986743 (in ARL6IP6; P = 2.7 × 10(-7)), strongly associated with early-onset stroke. These data suggest that a novel locus on human chromosome 2q23.3 may be associated with IS susceptibility among young adults.

Ischemic stroke risk, smoking, and the genetics of inflammation in a biracial population: the stroke prevention in young women study.

BACKGROUND: Although cigarette smoking is a well-established risk factor for vascular disease, the genetic mechanisms that link cigarette smoking to an increased incidence of stroke are not well understood. Genetic variations within the genes of the inflammatory pathways are thought to partially mediate this risk. Here we evaluate the association of several inflammatory gene single nucleotide polymorphisms (SNPs) with ischemic stroke risk among young women, further stratified by current cigarette smoking status. METHODS: A population-based case-control study of stroke among women aged 15-49 identified 224 cases of first ischemic stroke (47.3% African-American) and 211 age-comparable control subjects (43.1% African-American). Several inflammatory candidate gene SNPs chosen through literature review were genotyped in the study population and assessed for association with stroke and interaction with smoking status. RESULTS: Of the 8 SNPs (across 6 genes) analyzed, only IL6 SNP rs2069832 (allele C, African-American frequency = 92%, Caucasian frequency = 55%) was found to be significantly associated with stroke using an additive model, and this was only among African-Americans (age-adjusted: OR = 2.2, 95% CI = 1.0-5.0, p = 0.049; risk factor adjusted: OR = 2.5, 95% CI = 1.0-6.5, p = 0.05). When stratified by smoking status, two SNPs demonstrated statistically significant gene-environment interactions. First, the T allele (frequency = 5%) of IL6 SNP rs2069830 was found to be protective among non-smokers (OR = 0.30, 95% CI = 0.11-.082, p = 0.02), but not among smokers (OR = 1.63, 95% CI = 0.48-5.58, p = 0.43); genotype by smoking interaction (p = 0.036). Second, the C allele (frequency = 39%) of CD14 SNP rs2569190 was found to increase risk among smokers (OR = 2.05, 95% CI = 1.09-3.86, p = 0.03), but not among non-smokers (OR = 0.93, 95% CI = 0.62-1.39, p = 0.72); genotype by smoking interaction (p = 0.039). CONCLUSION: This study demonstrates that inflammatory gene SNPs are associated with early-onset ischemic stroke among African-American women (IL6) and that cigarette smoking may modulate stroke risk through a gene-environment interaction (IL6 and CD14). Our finding replicates a prior study showing an interaction with smoking and the C allele of CD14 SNP rs2569190.

Familial aggregation of ischemic stroke in young women: the Stroke Prevention in Young Women Study.

BACKGROUND AND PURPOSE: Stroke occurs infrequently in young adults. While a familial basis for older onset stroke is well established, the extent of familial clustering in young-onset stroke is unknown. To address this issue, we compared the frequency of stroke in relatives of stroke cases to that in relatives of controls across different ages and by stroke subtype. METHODS: Through a population-based case-control study of stroke, we identified 487 women aged 15-49 years with ischemic stroke and 615 women without stroke matched by age and geographic region. Family history of stroke was collected for 5,749 relatives (parents and siblings) of case and control probands by standardized interview. RESULTS: Strokes were reported in 149 relatives of case patients and 119 relatives of controls. Siblings of stroke case patients had more than four times the risk of stroke compared to siblings of controls (OR, 4.17; 95% CI, 1.9-8.8) and mothers of stroke case patients had twice the risk of stroke compared to mothers of control subjects (OR, 2.02; 95% CI, 1.4-3.0). The association between stroke in probands and family history of stroke was strongest among women aged 15-24 years (OR, 2.5; 95% CI, 0.4-15.1), and diminished with increasing proband age (OR, 1.6; 95% CI, 0.8-3.3 among women 25-34 years and OR, 1.5; 95% CI, 1.1-1.9 among women 35-49 years; P<0.0001 for trend). CONCLUSIONS: We conclude that young-onset stroke aggregates in families and that the magnitude of aggregation increases with decreasing proband age.

Rapid development of glomerular injury and renal failure in mice lacking p53R2.

The Rrm2b gene encodes p53R2, a catalytic subunit of ribonucleotide reductase that is required for DNA repair. Embryonic stem (ES) cells containing a retroviral insertion in the Rrm2b locus were used to generate mutant mice. Analysis of kidney RNA from Rrm2b (-/-) mice showed that the retroviral insertion disrupted expression of Rrm2b transcripts. Rrm2b (-/-) pups were represented at the expected Mendelian ratios at 10-12 days of age and grew normally past weaning. Mice failed to thrive after 6 weeks of age and began to die by 8 weeks of age. Phenotyping revealed that Rrm2b (-/-) mice died from a severe glomerular lesion that led to nephrotic syndrome and chronic renal failure. In kidneys of Rrm2b (-/-) mice, podocytes were enlarged and there was evidence of foot process effacement by 6 weeks of age. By 8 weeks of age, progressive podocyte hypertrophy and loss of foot processes was accompanied by hypertrophy of glomerular capillary endothelial cells that was extensive enough to restrict capillary blood flow. Collapsing glomerulopathy with avascular glomeruli was widespread in mice surviving beyond 9 weeks of age. Additional abnormalities in other organ systems were minor or consistent with secondary effects of renal failure. These findings suggest that lack of p53R2, the protein encoded by Rrm2b, has early and relatively selective detrimental effects on the kidney glomerulus that lead to rapid death from progressive renal failure.

Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.

The availability of both the mouse and human genome sequences allows for the systematic discovery of human gene function through the use of the mouse as a model system. To accelerate the genetic determination of gene function, we have developed a sequence-tagged gene-trap library of >270,000 mouse embryonic stem cell clones representing mutations in approximately 60% of mammalian genes. Through the generation and phenotypic analysis of knockout mice from this resource, we are undertaking a functional screen to identify genes regulating physiological parameters such as blood pressure. As part of this screen, mice deficient for the Wnk1 kinase gene were generated and analyzed. Genetic studies in humans have shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II, an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Consistent with the human genetic studies, Wnk1 heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the Wnk1 mutation died during embryonic development before day 13 of gestation. These results demonstrate that Wnk1 is a regulator of blood pressure critical for development and illustrate the utility of a functional screen driven by a sequence-based mutagenesis approach.

Blindness and auditory impairment caused by loss of the sodium bicarbonate cotransporter NBC3.

Normal sensory transduction requires the efficient disposal of acid (H+) generated by neuronal and sensory receptor activity. Multiple highly sensitive transport mechanisms have evolved in prokaryotic and eukaryotic organisms to maintain acidity within strict limits. It is currently assumed that the multiplicity of these processes provides a biological robustness. Here we report that the visual and auditory systems have a specific requirement for H+ disposal mediated by the sodium bicarbonate cotransporter NBC3 (refs. 7,8). Mice lacking NBC3 develop blindness and auditory impairment because of degeneration of sensory receptors in the eye and inner ear as in Usher syndrome. Our results indicate that in certain sensory organs, in which the requirement to transduce specific environmental signals with speed, sensitivity and reliability is paramount, the choice of the H+ disposal mechanism used is limited.