Economic Burden of Acute Gastroenteritis among Members of Integrated Healthcare Delivery System, United States, 2014-2016.

We conducted a large surveillance study among members of an integrated healthcare delivery system in Pacific Northwest of the United States to estimate medical costs attributable to medically attended acute gastroenteritis (MAAGE) on the day care was sought and during 30-day follow-up. We used multivariable regression to compare costs of MAAGE and non-MAAGE cases matched on age, gender, and index time. Differences accounted for confounders, including race, ethnicity, and history of chronic underlying conditions. Analyses included 73,140 MAAGE episodes from adults and 18,617 from children who were Kaiser Permanente Northwest members during 2014-2016. Total costs were higher for MAAGE cases relative to non-MAAGE comparators as were costs on the day care was sought and costs during follow-up. Costs of MAAGE are substantial relative to the cost of usual-care medical services, and much of the burden accrues during short-term follow-up.

Health Care Utilization and Clinical Management of All-Cause and Norovirus-Associated Acute Gastroenteritis Within a US Integrated Health Care System.

Background: Norovirus-associated acute gastroenteritis (AGE) exacts a substantial disease burden, yet the health care utilization for and clinical management of norovirus-associated AGE are not well characterized. Methods: We describe the health care encounters and therapeutics used for patients with all-cause and norovirus-associated AGE in the Kaiser Permanente Northwest health system from 1 April 2014 through 30 September 2016. Medical encounters for patients with AGE were extracted from electronic health records, and encounters within 30 days of one another were grouped into single episodes. An age-stratified random sample of patients completed surveys and provided stool samples for norovirus testing. Results: In total, 40 348 individuals had 52 509 AGE episodes; 460 (14%) of 3310 participants in the substudy tested positive for norovirus. An overall 35% of all-cause AGE episodes and 29% of norovirus-associated AGE episodes had ≥2 encounters. While 80% of norovirus-associated AGE episodes had at least 1 encounter in the outpatient setting, all levels of the health care system were affected: 10%, 22%, 10%, and 2% of norovirus-associated AGE episodes had at least 1 encounter in virtual, urgent care, emergency department, and inpatient settings, respectively. Corresponding proportions of therapeutic use between norovirus-positive and norovirus-negative episodes were 13% and 10% for intravenous hydration (P = .07), 65% and 50% for oral rehydration (P < .001), 7% and 14% for empiric antibiotic therapy (P < .001), and 33% and 18% for antiemetics (P < .001). Conclusions: Increased health care utilization and therapeutics are likely needed for norovirus-associated AGE episodes during peak norovirus winter seasons, and these data illustrate that effective norovirus vaccines will likely result in less health care utilization.

Attitudes toward a future norovirus vaccine among members of an integrated healthcare delivery system in Portland, Oregon, 2016-2017.

With recent advances in U.S. clinical trials for norovirus vaccines, it is an opportune time to examine what is known about the public receptivity to this novel vaccine. From October 2016-September 2017, we surveyed Kaiser Permanente Northwest members in Portland, Oregon, to ask their level of agreement on a 5-point scale with statements about the need for and willingness to get a potential norovirus vaccine for themselves or their child and analyzed their responses according to age, occupational status, prior vaccine uptake, and history of prior norovirus diagnoses. The survey response rate was 13.5% (n = 3,894); 807 (21%) responded as legal guardians, on behalf of a child <18 y of age and 3,087 (79%) were adults aged 18+ y. The majority of respondents were in agreement about getting the norovirus vaccine, if available (60% of legal guardians, 52% of adults aged 18-64 y, and 55% of adults aged 65+ y). Prior vaccination for influenza and rotavirus (among children) was the only correlate significantly associated with more positive attitudes toward receiving norovirus vaccine. Pre-pandemic attitudes in our all-ages study population reveal generally positive attitudes toward willingness to get a norovirus vaccine, particularly among those who previously received influenza or rotavirus vaccines.

Burden of Medically Attended Diarrhea and Outpatient Clostridioides difficile Infection Among Persons in 2 Large Integrated Healthcare Settings, 2016-2021.

Background: Identification of Clostridioides difficile infection (CDI) in the community setting is increasing. We describe testing for CDI among patients with medically attended diarrhea (MAD) in the outpatient setting, and the incidence of outpatient CDI. Methods: This was a retrospective cohort study among members ≥18 years of age from Kaiser Permanente Southern California and Kaiser Permanente Northwest from 1 January 2016 through 31 December 2021. MAD was identified by outpatient diarrheal International Classification of Diseases, Tenth Revision diagnosis codes, and CDI through positive laboratory results. Outpatient CDI was defined by no hospitalization ≤7 days after specimen collection. Incidence rates (IRs) of outpatient CDI were stratified by select demographic and clinical variables. Outpatient CDI burden 12 months following index date was measured by CDI-associated healthcare visits, and CDI testing and treatment. Results: We identified 777 533 MAD episodes; 12.1% (93 964/777 533) were tested for CDI. Of those tested, 10.8% (10 110/93 964) were positive. Outpatient CDI IR was 51.0 (95% confidence interval [CI], 49.8-52.2) per 100 000 person-years, decreasing from 58.2 (95% CI, 55.7-60.7) in 2016 to 45.7 (95% CI, 43.7-47.8) in 2021. Approximately 44% (n = 4200) received an antibiotic 30 days prior to index date and 84.1% (n = 8006) CDIs were "community-associated" (no hospitalizations 12 weeks prior to index date). Of outpatient CDIs, 6.7% (n = 526) had a CDI-associated hospitalization ≤12 months. Conclusions: There was a high incidence of outpatient CDI despite infrequent CDI testing among patients with MAD. The majority of those with outpatient CDI had no recent antibiotic use and no recent hospitalization. Further studies are needed to understand the source and management of medically attended outpatient CDI.

Household Transmission of Viral Acute Gastroenteritis Among Participants Within an Integrated Health Care Delivery System, 2014-2016.

Background: While enteric viruses are highly transmissible, household factors associated with transmission are less well documented. We identified individual- and household-level factors associated with viral acute gastroenteritis (AGE) transmission in a large health care network in the United States. Methods: Patients presenting with AGE were enrolled from April 2014 to September 2016. Patients and symptomatic household members were interviewed, and stool specimens were collected and tested for viral pathogens. Within a household, primary cases were those with the earliest symptom onset and a positive viral test result; secondary cases were household contacts (HHCs) with symptom onset 1-7 days from the primary case onset. Transmission households had at least 1 secondary case. Results: Our analysis included 570 primary cases with 1479 HHCs. The overall secondary attack rate was 23%. HHCs were likely to become secondary cases (n = 338) if they were <5 years old (adjusted odds ratio [aOR], 1.8; 95% CI, 1.2-2.6). Secondary transmission was likely to occur if the primary case was aged <5 years (aOR, 2.2; 95% CI, 1.4-3.6) or 5 to 17 years (aOR, 3.3; 95% CI, 1.9-5.7), was norovirus positive (aOR, 2.7; 95% CI, 1.9-3.7), had a diapered contact (aOR: 2.2, 95% CI: 1.6-3.2), or reported symptoms for >4 days (aOR, 1.5; 95% CI, 1.1-2.1). Households with ≥3 members (aOR, 2.1; 95% CI, 1.1-4.5) were more likely to experience transmission. Discussion: Risk of AGE transmission within households increased if the primary case was younger, was norovirus positive, had a longer symptom duration, or had a diapered contact. Targeted prevention messaging around appropriate cleaning, disinfection, and isolation of persons with AGE should be encouraged.

Rotavirus Vaccine Impact Within an Integrated Healthcare Delivery System in the United States.

We assessed rotavirus vaccine impact using data on acute gastroenteritis (AGE) encounters within an integrated healthcare delivery system during 2000-2018. Following rotavirus vaccine introduction, all-cause AGE rates among children <5 years declined by 36% (95% confidence interval [CI]: 32%-40%) for outpatient and 54% (95% CI: 46%-60%) for inpatient encounters.

Sexually Transmitted Infection Testing, Prevalence, and Treatment Among Individuals Receiving HIV Preexposure Prophylaxis Within an Integrated Healthcare Delivery System.

BACKGROUND: Initial and follow-up sexually transmitted infection (STI) and human immunodeficiency virus (HIV) testing are recommended when taking HIV preexposure prophylaxis (PrEP). We assessed STI services before and after PrEP initiation among persons 18 years or older. METHODS: We conducted this retrospective cohort study at a US integrated healthcare delivery system. We measured HIV/STI testing rates, STI prevalence and treatment at 3 time points: (1) at PrEP initiation, (2) at 120 days, and (3) at 210 days. RESULTS: Of 685 PrEP initiators, 67.2% continued PrEP use at 120 days and 49.5% at 210 days. Of PrEP users, HIV and STI testing were greater than 85% and greater than 80%, respectively, at all 3 time points. Prevalence for any chlamydia, rectal chlamydia, and any gonorrhea, rectal gonorrhea, or pharyngeal gonorrhea was always high at the 120 days and 210 days (eg, 6.9%, 10.5%, 6.7%, 5.0%, and 5.2%, respectively, at the 120 days for continuous PrEP users). Over 90% of all individuals who tested positive for chlamydia and gonorrhea received antibiotic pharmacy fills within 7 days at 120 and 210 days. Monthly PrEP-related pharmacy cost was about $2259 to $2659. The proportion of the total medical cost that was PrEP-related pharmacy was about 82% for PrEP continuous users. CONCLUSIONS: Although HIV/STI testing rates were high, they can still be improved during HIV PrEP management. High STI prevalence after PrEP initiation in this study suggests that patients taking PrEP are at risk of acquiring an STI. Interventions to improve STI services during PrEP management are continuously needed.

Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes.

BACKGROUNDFasting and NAD+-boosting compounds, including NAD+ precursor nicotinamide riboside (NR), confer antiinflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined.METHODSWe explored the underlying biology in myeloid cells from healthy volunteers following in vivo placebo or NR administration and subsequently tested the findings in vitro in monocytes extracted from patients with systemic lupus erythematosus (SLE).RESULTSRNA-Seq of unstimulated and LPS-activated monocytes implicated NR in the regulation of autophagy and type I IFN signaling. In primary monocytes, NR blunted LPS-induced IFN-ß production, and genetic or pharmacological disruption of autophagy phenocopied this effect. Given that NAD+ is a coenzyme in oxidoreductive reactions, metabolomics was performed and identified that NR increased the inosine level. Inosine supplementation similarly blunted autophagy and IFN-ß release. Finally, because SLE exhibits type I IFN dysregulation, we assessed the NR effect on monocytes from patients with SLE and found that NR reduced autophagy and IFN-ß release.CONCLUSIONWe conclude that NR, in an NAD+-dependent manner and in part via inosine signaling, mediated suppression of autophagy and attenuated type I IFN in myeloid cells, and we identified NR as a potential adjunct for SLE management.TRIAL REGISTRATIONClinicalTrials.gov registration numbers NCT02812238, NCT00001846, and NCT00001372.FUNDINGThis work was supported by the NHLBI and NIAMS Intramural Research divisions.

Dynamic Risk Prediction of Response to Ursodeoxycholic Acid Among Patients with Primary Biliary Cholangitis in the USA.

BACKGROUND: Ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC); however, inadequate treatment response (ITR) is common. The UK-PBC Consortium developed the modified UDCA Response Score (m-URS) to predict ITR (using alkaline phosphatase [ALP] > 1.67 times the upper limit of normal [*ULN]) at 12 months post-UDCA initiation). Using data from the US-based Fibrotic Liver Disease Consortium, we assessed the m-URS in our multi-racial cohort. We then used a dynamic modeling approach to improve prediction accuracy. METHODS: Using data collected at the time of UDCA initiation, we assessed the m-URS using the original formula; then, by calibrating coefficients to our data, we also assessed whether it remained accurate when using Paris II criteria for ITR. Next, we developed and validated a dynamic risk prediction model that included post-UDCA initiation laboratory data. RESULTS: Among 1578 patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander; 25% Hispanic), the rate of ITR was 27% using ALP > 1.67*ULN and 45% using Paris II criteria. M-URS accuracy was "very good" (AUROC = 0.87, sensitivity = 0.62, and specificity = 0.82) for ALP > 1.67*ULN and "moderate" (AUROC = 0.74, sensitivity = 0.57, and specificity = 0.70) for Paris II. Our dynamic model significantly improved accuracy for both definitions of ITR (ALP > 1.67*ULN: AUROC = 0.91; Paris II: AUROC = 0.81); specificity approached 100%. Roughly 9% of patients in our cohort were at the highest risk of ITR. CONCLUSIONS: Early identification of patients who will not respond to UDCA treatment using a dynamic prediction model based on longitudinal, repeated risk factor measurements may facilitate earlier introduction of adjuvant treatment.

Norovirus and Other Viral Causes of Medically Attended Acute Gastroenteritis Across the Age Spectrum: Results from the Medically Attended Acute Gastroenteritis Study in the United States.

BACKGROUND: Acute gastroenteritis (AGE) causes a substantial burden in the United States, but its etiology frequently remains undetermined. Active surveillance within an integrated healthcare delivery system was used to estimate the prevalence and incidence of medically attended norovirus, rotavirus, sapovirus, and astrovirus. METHODS: Active surveillance was conducted among all enrolled members of Kaiser Permanente Northwest during July 2014-June 2016. An age-stratified, representative sample of AGE-associated medical encounters were recruited to provide a stool specimen to be tested for norovirus, rotavirus, sapovirus, and astrovirus. Medically attended AGE (MAAGE) encounters for a patient occurring within 30 days were grouped into 1 episode, and all-cause MAAGE incidence was calculated. Pathogen- and healthcare setting-specific incidence estimates were calculated using age-stratified bootstrapping. RESULTS: The overall incidence of MAAGE was 40.6 episodes per 1000 person-years (PY), with most episodes requiring no more than outpatient care. Norovirus was the most frequently detected pathogen, with an incidence of 5.5 medically attended episodes per 1000 PY. Incidence of norovirus MAAGE was highest among children aged < 5 years (20.4 episodes per 1000 PY), followed by adults aged ≥ 65 years (4.5 episodes per 1000 PY). Other study pathogens showed similar patterns by age, but lower overall incidence (sapovirus: 2.4 per 1000 PY; astrovirus: 1.3 per 1000 PY; rotavirus: 0.5 per 1000 PY). CONCLUSIONS: Viral enteropathogens, particularly norovirus, are important contributors to MAAGE, especially among children < 5 years of age. The present findings underline the importance of judicious antibiotics use for pediatric AGE and suggest that an effective norovirus vaccine could substantially reduce MAAGE.

Low Uptake of Direct-acting Antiviral Therapy Among Hepatitis C Patients With Advanced Liver Disease and Access to Care, 2014-2017.

GOALS: To determine the proportion and characteristics of adults with hepatitis C at health care organizations in 4 US states who initiated direct-acting antivirals (DAAs). BACKGROUND: There are almost no data to assess the penetrance of treatment of the hepatitis C population in general US health care settings. STUDY: We conducted a prospective observational study using electronic clinical, pharmacy, and mortality data to determine the fraction of patients who initiated DAAs between January 2014 and December 2017, by start date and regimen. We used stepwise multivariate logistic regression analysis to identify sociodemographic and clinical characteristics associated with receipt of DAAs. RESULTS: Of 8823 patients, 2887 (32.7%) received DAAs. Quarterly (Q) uptake ranged from 1.1% in Q3 2014 to a high of 5.6% in Q2 2015. Characteristics associated with receipt of DAAs included age 51 to 70 years, higher income, pre-2014 treatment failure, and higher noninvasive fibrosis score (FIB4); however, over one half of patients with FIB4 scores >3.25, consistent with severe liver disease, were not treated. A lower likelihood of initiation was associated with Medicaid coverage. Of 5936 patients who did not initiate treatment, 911 (15.3%) had died and 2774 (46.7%) had not had a clinical encounter in ≥12 months by the end of the study. Fewer than 1% of DAA prescriptions originated from nonspecialty providers. CONCLUSIONS: During 4 calendar years of follow-up, one third of patients initiated DAAs. Large fractions of untreated patients had advanced liver disease, died, or were lost to follow-up. Even among patients in integrated health care systems, receipt of DAAs was limited.

Incidence, clinical outcomes, and transmission dynamics of severe coronavirus disease 2019 in California and Washington: prospective cohort study.

OBJECTIVE: To understand the epidemiology and burden of severe coronavirus disease 2019 (covid-19) during the first epidemic wave on the west coast of the United States. DESIGN: Prospective cohort study. SETTING: Kaiser Permanente integrated healthcare delivery systems serving populations in northern California, southern California, and Washington state. PARTICIPANTS: 1840 people with a first acute hospital admission for confirmed covid-19 by 22 April 2020, among 9 596 321 healthcare plan enrollees. Analyses of hospital length of stay and clinical outcomes included 1328 people admitted by 9 April 2020 (534 in northern California, 711 in southern California, and 83 in Washington). MAIN OUTCOME MEASURES: Cumulative incidence of first acute hospital admission for confirmed covid-19, and subsequent probabilities of admission to an intensive care unit (ICU) and mortality, as well as duration of hospital stay and ICU stay. The effective reproduction number (RE ) describing transmission dynamics was estimated for each region. RESULTS: As of 22 April 2020, cumulative incidences of a first acute hospital admission for covid-19 were 15.6 per 100 000 cohort members in northern California, 23.3 per 100 000 in southern California, and 14.7 per 100 000 in Washington. Accounting for censoring of incomplete hospital stays among those admitted by 9 April 2020, the estimated median duration of stay among survivors was 9.3 days (with 95% staying 0.8 to 32.9 days) and among non-survivors was 12.7 days (1.6 to 37.7 days). The censoring adjusted probability of ICU admission for male patients was 48.5% (95% confidence interval 41.8% to 56.3%) and for female patients was 32.0% (26.6% to 38.4%). For patients requiring critical care, the median duration of ICU stay was 10.6 days (with 95% staying 1.3 to 30.8 days). The censoring adjusted case fatality ratio was 23.5% (95% confidence interval 19.6% to 28.2%) among male inpatients and 14.9% (11.8% to 18.6%) among female inpatients; mortality risk increased with age for both male and female patients. Reductions in RE were identified over the study period within each region. CONCLUSIONS: Among residents of California and Washington state enrolled in Kaiser Permanente healthcare plans who were admitted to hospital with covid-19, the probabilities of ICU admission, of long hospital stay, and of mortality were identified to be high. Incidence rates of new hospital admissions have stabilized or declined in conjunction with implementation of social distancing interventions.

Modulation of the cardiac sodium channel NaV1.5 peak and late currents by NAD+ precursors.

RATIONALE: The cardiac sodium channel NaV1.5, encoded by SCN5A, produces the rapidly inactivating depolarizing current INa that is responsible for the initiation and propagation of the cardiac action potential. Acquired and inherited dysfunction of NaV1.5 results in either decreased peak INa or increased residual late INa (INa,L), leading to tachy/bradyarrhythmias and sudden cardiac death. Previous studies have shown that increased cellular NAD+ and NAD+/NADH ratio increase INa through suppression of mitochondrial reactive oxygen species and PKC-mediated NaV1.5 phosphorylation. In addition, NAD+-dependent deacetylation of NaV1.5 at K1479 by Sirtuin 1 increases NaV1.5 membrane trafficking and INa. The role of NAD+ precursors in modulating INa remains unknown. OBJECTIVE: To determine whether and by which mechanisms the NAD+ precursors nicotinamide riboside (NR) and nicotinamide (NAM) affect peak INa and INa,Lin vitro and cardiac electrophysiology in vivo. METHODS AND RESULTS: The effects of NAD+ precursors on the NAD+ metabolome and electrophysiology were studied using HEK293 cells expressing wild-type and mutant NaV1.5, rat neonatal cardiomyocytes (RNCMs), and mice. NR increased INa in HEK293 cells expressing NaV1.5 (500 µM: 51 ± 18%, p = .02, 5 mM: 59 ± 22%, p = .03) and RNCMs (500 µM: 60 ± 26%, p = .02, 5 mM: 74 ± 39%, p = .03) while reducing INa,L at the higher concentration (RNCMs, 5 mM: -45 ± 11%, p = .04). NR (5 mM) decreased NaV1.5 K1479 acetylation but increased INa in HEK293 cells expressing a mutant form of NaV1.5 with disruption of the acetylation site (NaV1.5-K1479A). Disruption of the PKC phosphorylation site abolished the effect of NR on INa. Furthermore, NAM (5 mM) had no effect on INa in RNCMs or in HEK293 cells expressing wild-type NaV1.5, but increased INa in HEK293 cells expressing NaV1.5-K1479A. Dietary supplementation with NR for 10-12 weeks decreased QTc in C57BL/6 J mice (0.35% NR: -4.9 ± 2.0%, p = .14; 1.0% NR: -9.5 ± 2.8%, p = .01). CONCLUSIONS: NAD+ precursors differentially regulate NaV1.5 via multiple mechanisms. NR increases INa, decreases INa,L, and warrants further investigation as a potential therapy for arrhythmic disorders caused by NaV1.5 deficiency and/or dysfunction.

Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures.

Nicotinamide adenine dinucleotide (NAD+) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR.

Maternal Nicotinamide Riboside Enhances Postpartum Weight Loss, Juvenile Offspring Development, and Neurogenesis of Adult Offspring.

Conditions of metabolic stress dysregulate the NAD metabolome. By restoring NAD, nicotinamide riboside (NR) provides resistance to such conditions. We tested the hypotheses that postpartum might dysregulate maternal NAD and that increasing systemic NAD with NR might benefit mothers and offspring. In postpartum mothers, the liver NAD metabolome is depressed while blood increases circulation of NAD metabolites to enable a >20-fold increase in mammary NAD+ and NADP+. Lactation and NR synergize in stimulating prolactin synthesis and mammary biosynthetic programs. NR supplementation of new mothers increases lactation and nursing behaviors and stimulates maternal transmission of macronutrients, micronutrients, and BDNF into milk. Pups of NR-supplemented mothers are advantaged in glycemic control, size at weaning, and synaptic pruning. Adult offspring of mothers supplemented during nursing retain advantages in physical performance, anti-anxiety, spatial memory, delayed onset of behavioral immobility, and promotion of adult hippocampal neurogenesis. Thus, postgestational maternal micronutrition confers lasting advantages to offspring.

A model for rapid, active surveillance for medically-attended acute gastroenteritis within an integrated health care delivery system.

BACKGROUND: This study presents a novel methodology for estimating all-age, population-based incidence rates of norovirus and other pathogens that contribute to acute gastroenteritis in the United States using an integrated healthcare delivery system as a surveillance platform. METHODS: All cases of medically attended acute gastroenteritis within the delivery system were identified from April 1, 2014 through September 30, 2016. A sample of these eligible patients were selected to participate in two phone-based surveys and to self-collect a stool sample for laboratory testing. To ascertain household transmission patterns, information on household members with acute gastroenteritis was gathered from participants, and symptomatic household members were contacted to participate in a survey and provide stool sample as well. RESULTS: 54% of individuals who met enrollment criteria agreed to participate, and 76% of those individuals returned a stool sample. Among household members, 85% of eligible individuals agreed to participate, and 68% of those returned a stool sample. Participant demographics were similar to those of the eligible population, although minority racial/ethnic groups were somewhat underrepresented in the final sample. CONCLUSIONS: This study demonstrates the feasibility of conducting acute infectious disease research within an integrated health care delivery system. The surveillance, sampling, recruitment, and data collection methods described here are broadly applicable to conduct baseline and epidemiological assessments, as well as for other research requiring representative samples of stool specimens.

A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects.

Background: Animal studies suggest a positive role for nicotinamide riboside (NR) on insulin sensitivity and hepatic steatosis in models of obesity and type 2 diabetes. NR, an NAD+ precursor, is a member of the vitamin B-3 family now available as an over-the-counter supplement. Although data from preclinical trials appear consistent, potential effects and safety need to be evaluated in human clinical trials. Objective: The aim of this study was to test the safety of dietary NR supplementation over a 12-wk period and potential to improve insulin sensitivity and other metabolic parameters in obese, insulin-resistant men. Design: In an investigator-initiated randomized, placebo-controlled, double-blinded, and parallel-group designed clinical trial, forty healthy, sedentary men with a body mass index (BMI) > 30 kg/m2, age-range 40-70 y were randomly assigned to 12 wk of NR (1000 mg twice daily) or placebo. We determined the effects of NR supplementation on insulin sensitivity by a hyperinsulinemic euglycemic clamp and substrate metabolism by indirect calorimetry and labeled substrates of tritiated glucose and palmitate. Body composition and fat mass distribution were determined by whole-body dual-energy X-ray absorptiometry (DXA) and MRI scans, and measurements of intrahepatic lipid content were obtained by MR spectroscopy. Results: Insulin sensitivity, endogenous glucose production, and glucose disposal and oxidation were not improved by NR supplementation. Similarly, NR supplementation had no effect on resting energy expenditure, lipolysis, oxidation of lipids, or body composition. No serious adverse events due to NR supplementation were observed and safety blood tests were normal. Conclusion: 12 wk of NR supplementation in doses of 2000 mg/d appears safe, but does not improve insulin sensitivity and whole-body glucose metabolism in obese, insulin-resistant men. This trial was registered at clinicaltrials.gov as NCT02303483.

Assessment of Tdap Vaccination Effectiveness in Adolescents in Integrated Health-Care Systems.

PURPOSE: Despite high national vaccination coverage with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines among U.S. adolescents, rates of adolescent pertussis disease are increasing. We estimated the duration of protection after Tdap vaccination and the possible effects of the change from whole-cell to acellular childhood pertussis vaccines in the United States during the 1990s. METHODS: We conducted a retrospective cohort analysis among 11- to 18-year-olds enrolled in two integrated health-care delivery systems during 2005-2012. Cases met the Council of State and Territorial Epidemiologists' confirmed or probable definition or a polymerase chain reaction-positive suspect definition. We estimated vaccine effectiveness (VE) overall and by time since Tdap receipt. We stratified VE estimates by primary series pertussis vaccine received (based on birth year): mixed-vaccine cohort (1987-1997) and acellular vaccine cohort (1998-2001). RESULTS: The overall Tdap VE was 57% (95% confidence interval [CI]: 42%-68%); the VE in the mixed-vaccine and acellular cohorts was 65% (95% CI: 44%-78%) and 52% (95% CI: 30%-68%), respectively. Tdap VE within <2 years post vaccination (69%, 95% CI: 54%-79%) was significantly different from VE ≥2 years post vaccination (34%, 95% CI: 1%-55%, p value < .01). VE was significantly higher <2 years post vaccination compared with ≥2 years post vaccination in both mixed-vaccine (87%, 95% CI: 58%-96%, and 52%, 95% CI: 13%-73%; p value = .04) and acellular cohorts (62%, 95% CI: 41%-76%, and 21%, 95% CI: -30% to 52%; p value = .01). CONCLUSIONS: Although Tdap vaccination remains the best pertussis prevention method for adolescents, protection wanes within 2 years regardless of the type of childhood primary vaccine. Vaccines with longer duration of protection could decrease pertussis burden.

Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice.

The role in longevity and healthspan of nicotinamide (NAM), the physiological precursor of NAD+, is elusive. Here, we report that chronic NAM supplementation improves healthspan measures in mice without extending lifespan. Untargeted metabolite profiling of the liver and metabolic flux analysis of liver-derived cells revealed NAM-mediated improvement in glucose homeostasis in mice on a high-fat diet (HFD) that was associated with reduced hepatic steatosis and inflammation concomitant with increased glycogen deposition and flux through the pentose phosphate and glycolytic pathways. Targeted NAD metabolome analysis in liver revealed depressed expression of NAM salvage in NAM-treated mice, an effect counteracted by higher expression of de novo NAD biosynthetic enzymes. Although neither hepatic NAD+ nor NADP+ was boosted by NAM, acetylation of some SIRT1 targets was enhanced by NAM supplementation in a diet- and NAM dose-dependent manner. Collectively, our results show health improvement in NAM-supplemented HFD-fed mice in the absence of survival effects.

Nicotinamide riboside, a form of vitamin B3 and NAD+ precursor, relieves the nociceptive and aversive dimensions of paclitaxel-induced peripheral neuropathy in female rats.

Injury to sensory afferents may contribute to the peripheral neuropathies that develop after administration of chemotherapeutic agents. Manipulations that increase levels of nicotinamide adenine dinucleotide (NAD) can protect against neuronal injury. This study examined whether nicotinamide riboside (NR), a third form of vitamin B3 and precursor of NAD, diminishes tactile hypersensitivity and place escape-avoidance behaviors in a rodent model of paclitaxel-induced peripheral neuropathy. Female Sprague-Dawley rats received 3 intravenous injections of 6.6 mg/kg paclitaxel over 5 days. Daily oral administration of 200 mg/kg NR beginning 7 days before paclitaxel treatment and continuing for another 24 days prevented the development of tactile hypersensitivity and blunted place escape-avoidance behaviors. These effects were sustained after a 2-week washout period. This dose of NR increased blood levels of NAD by 50%, did not interfere with the myelosuppressive effects of paclitaxel, and did not produce adverse locomotor effects. Treatment with 200 mg/kg NR for 3 weeks after paclitaxel reversed the well-established tactile hypersensitivity in a subset of rats and blunted escape-avoidance behaviors. Pretreatment with 100 mg/kg oral acetyl-L-carnitine (ALCAR) did not prevent paclitaxel-induced tactile hypersensitivity or blunt escape-avoidance behaviors. ALCAR by itself produced tactile hypersensitivity. These findings suggest that agents that increase NAD, a critical cofactor for mitochondrial oxidative phosphorylation systems and cellular redox systems involved with fuel utilization and energy metabolism, represent a novel therapeutic approach for relief of chemotherapy-induced peripheral neuropathies. Because NR is a vitamin B3 precursor of NAD and a nutritional supplement, clinical tests of this hypothesis may be accelerated.