Association of protective behaviors with SARS-CoV-2 infection: results from a longitudinal cohort study of adults in the San Francisco Bay Area.

PURPOSE: In an effort to decrease transmission during the first years of the COVID-19 pandemic, public health officials encouraged masking, social distancing, and working from home, and restricted travel. However, many studies of the effectiveness of these measures had significant methodologic limitations. In this analysis, we used data from the TrackCOVID study, a longitudinal cohort study of a population-based sample of 3846 adults in the San Francisco Bay Area, to evaluate the association between self-reported protective behaviors and incidence of SARS-CoV-2 infection. METHODS: Participants without SARS-CoV2 infection were enrolled from August to December 2020 and followed monthly with testing and surveys (median of four visits). RESULTS: A total of 118 incident infections occurred (3.0% of participants). At baseline, 80.0% reported always wearing a mask; 56.0% avoided contact with nonhousehold members some/most of the time; 9.6% traveled outside the state; and 16.0% worked 20 or more hours per week outside the home. Factors associated with incident infection included being Black or Latinx, having less than a college education, and having more household residents. The only behavioral factor associated with incident infection was working outside the home (adjusted hazard ratio 1.62, 95% confidence interval 1.02-2.59). CONCLUSIONS: Focusing on protecting people who cannot work from home could help prevent infections during future waves of COVID-19, or future pandemics from respiratory viruses. This focus must be balanced with the known importance of directing resources toward those at risk of severe infections.

Oral hymecromone decreases hyaluronan in human study participants.

BACKGROUNDHyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-MU]), an oral drug approved in Europe for biliary spasm treatment that also inhibits HA in vitro and in animal models, could be repurposed as an inhibitor of HA synthesis in humans.METHODSWe conducted an open-label, single-center, dose-response study of hymecromone in healthy adults. Subjects received hymecromone at 1200 (n = 8), 2400 (n = 9), or 3600 (n = 9) mg/d divided into 3 doses daily, administered orally for 4 days. We assessed safety and tolerability of hymecromone and analyzed HA, 4-MU, and 4-methylumbelliferyl glucuronide (4-MUG; the main metabolite of 4-MU) concentrations in sputum and serum.RESULTSHymecromone was well tolerated up to doses of 3600 mg/d. Both sputum and serum drug concentrations increased in a dose-dependent manner, indicating that higher doses lead to greater exposures. Across all dose arms combined, we observed a significant decrease in sputum HA from baseline after 4 days of treatment. We also observed a decrease in serum HA. Additionally, higher baseline sputum HA levels were associated with a greater decrease in sputum HA.CONCLUSIONAfter 4 days of exposure to oral hymecromone, healthy human subjects experienced a significant reduction in sputum HA levels, indicating this oral therapy may have potential in pulmonary diseases where HA is implicated in pathogenesis.TRIAL REGISTRATIONClinicalTrials.gov NCT02780752.FUNDINGStanford Medicine Catalyst, Stanford SPARK, Stanford Innovative Medicines Accelerator program, NIH training grants 5T32AI052073-14 and T32HL129970.

Figure Correction: The Effect of a Cellular-Enabled Glucose Meter on Glucose Control for Patients With Diabetes: Prospective Pre-Post Study.

[This corrects the article DOI: 10.2196/14799.].

The Effect of a Cellular-Enabled Glucose Meter on Glucose Control for Patients With Diabetes: Prospective Pre-Post Study.

BACKGROUND: Diabetes is a global epidemic affecting approximately 30 million people in the United States. The World Health Organization recommends using technology and telecommunications to improve health care delivery and disease management. The Livongo for Diabetes Program offers a remote monitoring technology with Certified Diabetes Educator outreach. OBJECTIVE: The purpose of this study was to examine health outcomes measured by changes in HbA1c, in time in target blood glucose range, and in depression symptoms for patients enrolled in a remote digital diabetes management program in a Diabetes Center of Excellence setting. METHODS: The impact of the Livongo for Diabetes program on hemoglobin A1c (HbA1c), blood glucose ranges, and depression screening survey results (Patient Health Questionnaire-2 [PHQ-2]) were assessed over 12 months in a prospective cohort recruited from the University of South Florida Health Diabetes Home for Healthy Living. Any patient ≥18 years old with a diagnosis of diabetes was approached for voluntary inclusion into the program. The analysis was a pre-post design for those members enrolled in the study. Data was collected at outpatient clinic visits and remotely through the Livongo glucose meter. RESULTS: A total of 86 adults were enrolled into the Livongo for Diabetes program, with 49% (42/86) female, an average age of 50 (SD 15) years, 56% (48/86) with type 2 diabetes mellitus, and 69% (59/86) with insulin use. The mean HbA1c drop amongst the group was 0.66% (P=.17), with all participants showing a decline in HbA1c at 12 months. A 17% decrease of blood glucose checks <70 mg/dL occurred concurrently. Participants with type 2 diabetes not using insulin had blood glucose values within target range (70-180 mg/dL) 89% of the time. Participants with type 2 diabetes using insulin were in target range 68% of the time, and type 1 diabetes 58% of the time. Average PHQ-2 scores decreased by 0.56 points during the study period. CONCLUSIONS: Participants provided with a cellular-enabled blood glucose meter with real-time feedback and access to coaching from a certified diabetes educator in an outpatient clinical setting experienced improved mean glucose values and fewer episodes of hypoglycemia relative to the start of the program.

Reduced medical spending associated with increased use of a remote diabetes management program and lower mean blood glucose values.

Aims: Many new mobile technologies are available to assist people in managing chronic conditions, but data on the association between the use of these technologies and medical spending remains limited. As the available digital technology offerings to aid in diabetes management increase, it is important to understand their impact on medical spending. The aim of this study was to investigate the financial impact of a remote digital diabetes management program using medical claims and real-time blood glucose data. Materials and methods: A retrospective analysis of multivariate difference-in-difference and instrumental variables regression modeling was performed using data collected from a remote digital diabetes management program. All employees with diabetes were invited, in a phased introduction, to join the program. Data included blood glucose (BG) values captured remotely from members via connected BG meters and medical spending claims. Participants included members (those who accepted the invitation, n = 2,261) and non-members (n = 8,741) who received health insurance benefits from three self-insured employers. Medical spending was compared between people with well-controlled (BG ≤ 154 mg/dL) and poorly controlled (BG > 154 mg/dL) diabetes. Results: Program access was associated with a 21.9% (p < 0.01) decrease in medical spending, which translates into a $88 saving per member per month at 1 year. Compared to non-members, members experienced a 10.7% (p < 0.01) reduction in diabetes-related medical spending and a 24.6% (p < 0.01) reduction in spending on office-based services. Well-controlled BG values were associated with 21.4% (p = 0.03) lower medical spending. Limitations and conclusions: Remote digital diabetes management is associated with decreased medical spending at 1 year. Reductions in spending increased with active utilization. It will be beneficial for future studies to analyze the long-term effects of the remote diabetes management program and assess impacts on patient health and well-being.

Remote Lifestyle Coaching Plus a Connected Glucose Meter with Certified Diabetes Educator Support Improves Glucose and Weight Loss for People with Type 2 Diabetes.

BACKGROUND: Connected health devices with lifestyle coaching can provide real-time support for people with type 2 diabetes (T2D). However, the intensity of lifestyle coaching needed to achieve outcomes is unknown. METHODS: Livongo provides connected, two-way messaging glucose meters, unlimited blood glucose (BG) test strips, and access to certified diabetes educators. We evaluated the incremental effects of adding lifestyle coaching on BG, estimated HbA1c, and weight. We randomized 330 eligible adults (T2D, HbA1c > 7.5%, BMI ≥ 25) to receive no further intervention (n = 75), a connected scale (n = 115), scale plus lightweight coaching (n = 73), or scale plus intense coaching (n = 67) for 12 weeks. We evaluated the change in outcomes using ANOVA. RESULTS: Livongo participation alone resulted in improved BG control (mean HbA1c declined: 8.5% to 7.5%, p = 0.01). Mean weight loss and additional BG decreases were higher in the intensive compared with the lightweight coaching and scale-only groups (weight change (lb): -6.4, -4.1, and -1.1, resp., p = 0.01; BG change (mg/dL): -19.4, -11.3, and -2.9, resp., p = 0.02). The estimated 12-week program costs were 5.5 times more for intensive than lightweight coaching. CONCLUSION: Livongo participation significantly improves BG control in people with T2D. Additional lifestyle coaching may be a cost-effective intervention to achieve further glucose control and weight loss.

Elimination diet and the development of multiple tree-nut allergies.

BackgroundDespite its high prevalence, relatively little is known about the characteristics of patients with multiple tree-nut allergies.MethodsPatients (n=60, aged 4-15 years), recruited for a multiple food (tree nuts, peanut, milk, egg, soy, sesame, and wheat) oral immunotherapy (OIT) study, filled a questionnaire on their initial allergy evaluation. Medical records were reviewed. At OIT enrollment (median interval, 7.5 years), patients underwent oral food challenges (OFCs) to foods still eliminated.ResultsThere was significantly less evidence for eliminating tree nuts compared with other foods, as reflected by a lower rate of acute reaction to the offending food, either as the trigger for initial allergy evaluation (5.9% for tree-nuts vs. 20-40% for other foods, respectively P<0.001) or later in life (14.5% vs. 38-75%, respectively P=0.001), and a higher rate of negative skin prick test (SPT)/specific IgE (sIgE) at initial diagnosis (25% vs. <10%, P<0.001). SPT/sIgE increased significantly from past initial levels to present for tree nuts (P<0.001) and peanut (P=0.001) but not for other foods, and most OFCs performed at present were positive.ConclusionsTree nuts are often eliminated from the diet of multiple-food-allergic patients, despite their low probability for allergy. Sensitization and allergy to most tree nuts exist years later, suggesting that it developed during the period of elimination.

Association of Clinical Reactivity with Sensitization to Allergen Components in Multifood-Allergic Children.

BACKGROUND: Thirty percent of children with food allergies have multiple simultaneous allergies; however, the features of these multiple allergies are not well characterized serologically or clinically. OBJECTIVE: We comprehensively evaluated 60 multifood-allergic patients by measuring serum IgE to key allergen components, evaluating clinical histories and medication use, performing skin tests, and conducting double-blind, placebo-controlled food challenges (DBPCFCs). METHODS: Sixty participants with multiple food allergies were characterized by clinical history, DBPCFCs, total IgE, specific IgE, and component-resolved diagnostics (IgE and IgG4) data. The food allergens tested were almond, egg, milk, sesame, peanut, pecan, walnut, hazelnut, cashew, pistachio, soy, and wheat. RESULTS: Our data demonstrate that of the reactions observed during a graded DBPCFC, gastrointestinal reactions occurred more often in boys than in girls, as well as in individuals with high levels of IgE to 2S albumins from cashew, walnut, and hazelnut. Certain food allergies often occurred concomitantly in individuals (ie, cashew/pistachio and walnut/pecan/hazelnut). IgE testing to components further corroborated serological relationships between and among these clustered food allergies. CONCLUSIONS: Associations of certain food allergies were shown by DBPCFC outcomes as well as by correlations in IgE reactivity to structurally related food allergen components. Each of these criteria independently demonstrated a significant association between allergies to cashew and pistachio, as well as among allergies to walnut, pecan, and hazelnut.

4-methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy in inflammation, autoimmunity, and cancer.

Hyaluronan (HA) is a prominent component of the extracellular matrix at many sites of chronic inflammation, including type 1 diabetes (T1D), multiple sclerosis, and numerous malignancies. Recent publications have demonstrated that when HA synthesis is inhibited using 4-methylumbelliferone (4-MU), beneficial effects are observed in several animal models of these diseases. Notably, 4-MU is an already approved drug in Europe and Asia called "hymecromone" where it is used to treat biliary spasm. However, there is uncertainty regarding how 4-MU treatment provides benefit in these animal models and the potential long-term consequences of HA inhibition. Here, we review what is known about how HA contributes to immune dysregulation and tumor progression. Then, we review what is known about 4-MU and hymecromone in terms of mechanism of action, pharmacokinetics, and safety. Finally, we review recent studies detailing the use of 4-MU to treat animal models of cancer and autoimmunity.

Heterogeneity in recent-onset type 1 diabetes - a clinical trial perspective.

BACKGROUND: Type 1 diabetes (T1D) TrialNet is a National Institutes of Health-sponsored clinical trial network aimed at altering the disease course of T1D. The purpose of this study is to evaluate age-dependent heterogeneity in clinical, metabolic and immunologic characteristics of individuals with recent-onset T1D, to identify cohorts of interest and to aid in planning of future studies. METHODS: Eight hundred eighty-three individuals with recent-onset T1D involved in five TrialNet studies were categorized by age as follows: ≥18 years, 12-17 years, 8-12 years and <8 years. Data were compared with healthy age-matched subjects in the National Health and Nutrition Examination Survey. RESULTS: Only 2.0% of the individuals overall were excluded from trial participation because of insufficient C-peptide values (<0.2 pmol/mL). A disproportionate number of these subjects were <8 years old. Leukopenia was present in 21.2% of individuals and lymphopenia in 11.6%; these frequencies were markedly higher than age-matched healthy National Health and Nutrition Examination Survey population. Of the cohort, 24.5% were overweight or obese. Neither high-risk human leukocyte antigen type DR3 nor DR4 was present in 31% of adults and 21% of children. CONCLUSIONS: The ability of recent-onset T1D patients to meet key entry criteria for TrialNet studies, including C-peptide >0.2 pmol/mL, varies by age. Lower C-peptide level requirements for younger participants and other aspects of heterogeneity of recent-onset T1D patients, such as white blood cell count abnormalities and body mass index should be considered in the design of future clinical studies.

The role of hyaluronan and the extracellular matrix in islet inflammation and immune regulation.

Type 1 diabetes (T1D) is a disease that in most individuals results from autoimmune attack of a single tissue type, the pancreatic islet. A fundamental, unanswered question in T1D pathogenesis is how the islet tissue environment influences immune regulation. This crosstalk is likely to be communicated through the extracellular matrix (ECM). Here, we review what is known about the ECM in insulitis and examine how the tissue environment is synchronized with immune regulation. In particular, we focus on the role of hyaluronan (HA) and its interactions with Foxp3+ regulatory T-cells (Treg). We propose that HA is a "keystone molecule" in the inflammatory milieu and that HA, together with its associated binding proteins and receptors, is an appropriate point of entry for investigations into how ECM influences immune regulation in the islet.

Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs ß-cell function.

Rapamycin/interleukin-2 (IL-2) combination treatment of NOD mice effectively treats autoimmune diabetes. We performed a phase 1 clinical trial to test the safety and immunologic effects of rapamycin/IL-2 combination therapy in type 1 diabetic (T1D) patients. Nine T1D subjects were treated with 2-4 mg/day rapamycin orally for 3 months and 4.5 × 10(6) IU IL-2 s.c. three times per week for 1 month. ß-Cell function was monitored by measuring C-peptide. Immunologic changes were monitored using flow cytometry and serum analyses. Regulatory T cells (Tregs) increased within the first month of therapy, yet clinical and metabolic data demonstrated a transient worsening in all subjects. The increase in Tregs was transient, paralleling IL-2 treatment, whereas the response of Tregs to IL-2, as measured by STAT5 phosphorylation, increased and persisted after treatment. No differences were observed in effector T-cell subset frequencies, but an increase in natural killer cells and eosinophils occurred with IL-2 therapy. Rapamycin/IL-2 therapy, as given in this phase 1 study, resulted in transient ß-cell dysfunction despite an increase in Tregs. Such results highlight the difficulties in translating therapies to the clinic and emphasize the importance of broadly interrogating the immune system to evaluate the effects of therapy.