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Background: Universal spinal muscular atrophy (SMA) newborn screening was implemented in California on June 24, 2020. Objective: We describe California’s experience with the first 18 months of SMA newborn screening, including our assay methodology, timeliness of screening and follow-up milestones, and clinical and epidemiological outcomes observed. Methods: Dried blood spots are screened for SMA using multiplex real time polymerase chain reaction (RT-PCR) to detect deletions of exon 7 in the survival of motor neuron 1 (SMN1) gene. Short-term follow-up data is collected from clinical staff via an online data collection tool. Results: In the first 18 months, 628,791 newborns from California’s diverse population were tested for SMA. Thirty-four screened positive and were confirmed to have the disorder. Infants were referred, diagnosed, and treated at a median of 8, 12, and 33 days of life, respectively. Nearly all infants received the desired treatment modality, and 62% received treatment while still asymptomatic. Conclusions: SMA newborn screening is a highly sensitive and specific test which identifies infants with SMA early when treatment is most effective. Even with newborn screening’s success in facilitating early intervention, there is still work to be done to expedite treatment, especially for infants with the most severe form of the disease.

Carriers of the cystic fibrosis transmembrane conductance regulator (CFTR) gene ("carriers") have been found to have an increased risk of persistent asthma. However, it is unclear at what level of CFTR function this risk exists and whether it is modified by asthmogens, such as air pollution. We conducted a retrospective cohort study of children born in California between July 2007 and December 2013, linking CFTR genotype data from the California newborn screening program to Medicaid claims records through March 17, 2020 to identify asthma cases, and to air pollution data from CalEnviroScreen 3.0 to identify levels of particulate matter with diameter 2.5 microns or smaller (PMsub2.5/sub). Log-binomial regression models for asthma risk were fitted, adjusting for race/ethnicity and sex. Compared to population controls, carriers had higher risk of asthma (adjusted risk ratio (aRR) = 1.29, 95% confidence interval (CI): 0.98, 1.69; p lt; 0.1). Other non-CF-causing variants on the second allele did not appear to further increase risk. Genotypes with the greatest asthma risk were F508del with an intron 10 T7 or (TG)11T5 in trans (aRR=1.52, 95% CI: 1.10, 2.12). This association was higher among children living in areas at or above (aRR = 1.80) versus below (aRR = 1.37) the current national air quality standard for PMsub2.5/sub, though this difference was not statistically significant (psubinteraction/sub gt; 0.2). These results suggest carriers with CFTR functional levels between 25% and 45% of wildtype are at increased risk of asthma. Knowledge of CFTR genotype in asthmatics may be important to open new CFTR-related treatment options for these patients.

The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) variants generally correlates with severity of cystic fibrosis (CF). However, 3 adults bearing the common severe variant p.Phe508del (legacy: F508del) and a deletion variant in an ivacaftor binding region of CFTR (p.Phe312del; legacy: F312del) manifested only elevated sweat chloride concentration (sw[Cl-]; 87-105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl-] (75-123 mEq/L) and variable CF features. F312del occurs at a higher-than-expected frequency in the general population, confirming that individuals with F312del and a CF-causing variant do not consistently develop overt CF features. In primary nasal cells, CFTR bearing F312del and F508del generated substantial chloride transport (66.0% ± 4.5% of WT-CFTR) but did not respond to ivacaftor. Single-channel analysis demonstrated that F312del did not affect current flow through CFTR, minimally altered gating, and ablated the ivacaftor response. When expressed stably in CF bronchial epithelial (CFBE41o-) cells, F312del-CFTR demonstrated residual function (50.9% ± 3.3% WT-CFTR) and a subtle decrease in forskolin response compared with WT-CFTR. F312del provides an exception to the established correlation between CFTR chloride transport and CF phenotype and informs our molecular understanding of ivacaftor response.

Background In 6.5 years of newborn screening for severe combined immunodeficiency in California, 3,252,156 infants had DNA from dried blood spots (DBSs) assayed for T-cell receptor excision circles. Infants with T-cell receptor excision circle values of less than a designated cutoff on a single DBS, 2 DBS samples with insufficient PCR amplification, or known genetic risk of immunodeficiency had peripheral blood complete blood counts and lymphocyte subsets assayed in a single flow cytometry laboratory. Cases in which immune defects were ruled out were available for analysis. Objective We sought to determine reference intervals for lymphocyte subsets in racially/ethnically diverse preterm and term newborns who proved to be unaffected by any T-lymphopenic immune disorder. Methods Effective gestational age (GA) was defined as GA at birth plus postnatal age at the time of sample collection. After determining exclusion criteria, we analyzed demographic and clinical information, complete and differential white blood cell counts, and lymphocyte subsets for 301 infants, with serial measurements for 33 infants. Lymphocyte subset measurements included total T cells, helper and cytotoxic T-cell subsets, naive and memory phenotype of each T-cell subset, B cells, and natural killer cells. Results Reference intervals were generated for absolute numbers and lymphocyte subsets from infants with effective GAs of 22 to 52 weeks. Sex and ethnicity were not significant determinants of lymphocyte subset counts in this population. Lymphocyte counts increased postnatally. Conclusion This study provides a baseline for interpreting comprehensive lymphocyte data in preterm and term infants, aiding clinicians to determine which newborns require further evaluations for immunodeficiency.

OBJECTIVES: Newborn screening for severe combined immunodeficiency (SCID) was instituted in California in 2010. In the ensuing 6.5 years, 3 252 156 infants in the state had DNA from dried blood spots assayed for T-cell receptor excision circles (TRECs). Abnormal TREC results were followed-up with liquid blood testing for T-cell abnormalities. We report the performance of the SCID screening program and the outcomes of infants who were identified. METHODS: Data that were reviewed and analyzed included demographics, nursery summaries, TREC and lymphocyte flow-cytometry values, and available follow-up, including clinical and genetic diagnoses, treatments, and outcomes. RESULTS: Infants with clinically significant T-cell lymphopenia (TCL) were successfully identified at a rate of 1 in 15 300 births. Of these, 50 cases of SCID, or 1 in 65 000 births (95% confidence interval 1 in 51 000–1 in 90 000) were found. Prompt treatment led to 94% survival. Infants with non-SCID TCL were also identified, diagnosed and managed, including 4 with complete DiGeorge syndrome who received thymus transplants. Although no cases of typical SCID are known to have been missed, 2 infants with delayed-onset leaky SCID had normal neonatal TREC screens but came to clinical attention at 7 and 23 months of age. CONCLUSIONS: Population-based TREC testing, although unable to detect immune defects in which T cells are present at birth, is effective for identifying SCID and clinically important TCL with high sensitivity and specificity. The experience in California supports the rapid, widespread adoption of SCID newborn screening.

The current approach to health risk assessment of toxic waste sites in the U.S. may lead to considerable expenditure of resources without any meaningful reduction in population exposure. Risk assessment methods used generally ignore background exposures and consider only incremental risk estimates for maximally exposed individuals. Such risk estimates do not address true public health risks to which background exposures also contribute. The purpose of this paper is to recommend a new approach to risk assessment and risk management concerning toxic waste sites. Under this new approach, which we have called public health risk assessment, chemical substances would be classified into a level of concern based on the potential health risks associated with typical national and regional background exposures. Site assessment would then be based on the level of concern for the particular pollutants involved and the potential contribution of site contaminants to typical background human exposures. While various problems can be foreseen with this approach, the key advantage is that resources would be allocated to reduce the most important sources of human exposure, and site remediation decisions could be simplified by focussing on exposure assessment rather than questionable risk extrapolations.

Goals : Police reports of severely injured pedestrians help identify hazardous traffic areas in San Francisco, but they under-report non-fatal collisions. We set out to: identify injured pedestrians who were missing from police collision reports, see what biases exist in injury reporting and assess the utility of broad categories of police severe injury (including fatal) for mapping and analysis. Methods : We linked data on injured pedestrians from police collision reports listed in the Statewide Integrated Traffic Reporting System (SWITRS, n = 1991) with records of pedestrians treated at San Francisco General Hospital (SFGH, n = 1323) for 2000 and 2001. Data were analyzed using bivariate statistics, logistic regression and mapping. Results : We found that police collision reports underestimated the number of injured pedestrians by 21% (531/2442). Pedestrians treated at SFGH who were African-American were less likely then whites (odds ratio = 0.55, p -value ≤ 0.01), and females were more likely than males (odds ratio = 1.5, p -value ≤ 0.01) to have a police collision report. Over 70% of pedestrians deemed by the police to have a severe injury received treatment at SFGH, regardless of the collision's distance from SFGH. The sensitivity of a police-designated severe injury (including fatal) was 69% and the specificity was 89% when compared with a known SFGH assessment. But, sensitivity declined when we included pedestrians without a SFGH record. Conclusion : Though collision reports have demonstrated limitations, broad categories of police severity may be sensitive enough to map locations where numerous severe injuries occur, for timely countermeasure selection.

To evaluate the effectiveness and limitations of the B notification program for detecting tuberculosis among recent foreign-born arrivals in California.Retrospective cohort study. All foreign-born visa holders with a B notification who arrived in California from January 1992 through September 1995 (n = 27 412) were matched with a listing of foreign-born persons who arrived in the US during the same time period and who were reported to have active tuberculosis in California within one year of their arrival from January 1992 through September 1996 (n = 2547).Overall, 3.5% (95% confidence interval 3.3%, 3.8%) of all persons with a B notification were reported to have active tuberculosis within a year of arrival. Recent arrivals with a B notification and tuberculosis accounted for 38% of all foreign-born cases of tuberculosis reported within one year of arrival. Compared to recent arrivals without a B notification, those with a B notification were more likely to have pulmonary tuberculosis, less likely to have smear-positive pulmonary disease and reported with tuberculosis sooner after their arrival in the US. The B notification program was not able to identify 87% of the smear-positive pulmonary tuberculosis cases in adults, and did not identify 99% of these highly infectious cases among Latin Americans.Although the evaluation of persons who enter the US with B notifications has a high yield for identifying active tuberculosis cases, it was not able to identify the majority of recent arrivals with the most infectious form of tuberculosis.

The target for antituberculosis treatment in the United States is for 90% of patients to complete therapy within 12 months.To assess progress in achieving the US national target for tuberculosis treatment.A comparison of treatment outcome in two cohorts of patients with drug-susceptible tuberculosis in California-those reported in 1993-1994 (8488 patients) and 1995-1996 (7823 patients). Risk factors for delay in treatment completion (more than 12 months) were assessed.The percentage of cases completing treatment within 12 months increased in the 1995-1996 cohort (to 68.2%), primarily due to concomitant reductions in delays in treatment completion (to 11.1%) and defaulting (to 2.4%). Disparities in timely treatment completion narrowed over time and in nearly all subpopulations, especially in groups with lowest treatment completion in the 1993-1994 cohort. Remaining risk factors for delay in treatment completion included AIDS and older ages. A substantial percentage of patients died or moved before treatment completion.Despite recent improvements, completion of antituberculosis treatment in California has not reached the national target. Reaching this target will require further reductions in delays in treatment completion and deaths during treatment, and ensuring that patients who move eventually complete treatment.