IgA deficiency destabilizes homeostasis toward intestinal microbes and increases systemic immune dysregulation.

The ability of most patients with selective immunoglobulin A (IgA) deficiency (SIgAD) to remain apparently healthy has been a persistent clinical conundrum. Compensatory mechanisms, including IgM, have been proposed, yet it remains unclear how secretory IgA and IgM work together in the mucosal system and, on a larger scale, whether the systemic and mucosal anti-commensal responses are redundant or have unique features. To address this gap in knowledge, we developed an integrated host-commensal approach combining microbial flow cytometry and metagenomic sequencing (mFLOW-Seq) to comprehensively define which microbes induce mucosal and systemic antibodies. We coupled this approach with high-dimensional immune profiling to study a cohort of pediatric patients with SIgAD and household control siblings. We found that mucosal and systemic antibody networks cooperate to maintain homeostasis by targeting a common subset of commensal microbes. In IgA-deficiency, we find increased translocation of specific bacterial taxa associated with elevated levels of systemic IgG targeting fecal microbiota. Associated features of immune system dysregulation in IgA-deficient mice and humans included elevated levels of inflammatory cytokines, enhanced follicular CD4 T helper cell frequency and activation, and an altered CD8 T cell activation state. Although SIgAD is clinically defined by the absence of serum IgA, the symptomatology and immune dysregulation were concentrated in the SIgAD participants who were also fecal IgA deficient. These findings reveal that mucosal IgA deficiency leads to aberrant systemic exposures and immune responses to commensal microbes, which increase the likelihood of humoral and cellular immune dysregulation and symptomatic disease in patients with IgA deficiency.

Acute Kidney Injury During Treatment with Intravenous Acyclovir for Suspected or Confirmed Neonatal Herpes Simplex Virus Infection.

OBJECTIVE: To describe the epidemiology of and risk factors associated with acute kidney injury (AKI) during acyclovir treatment in neonates and infants. STUDY DESIGN: We conducted a multicenter (n = 4), retrospective cohort study of all hospitalized infants age <60 days treated with intravenous acyclovir (≥1 dose) for suspected or confirmed neonatal herpes simplex virus disease from January 2011 to December 2015. Infants with serum creatinine measured both before acyclovir (baseline) and during treatment were included. We classified AKI based on changes in creatinine according to published neonatal AKI criteria and performed Cox regression analysis to evaluate risk factors for AKI during acyclovir treatment. RESULTS: We included 1017 infants. The majority received short courses of acyclovir (median, 5 doses). Fifty-seven infants (5.6%) developed AKI during acyclovir treatment, with an incidence rate of AKI at 11.6 per 1000 acyclovir days. Cox regression analysis identified having confirmed herpes simplex virus disease (OR, 4.35; P = .002), receipt of ≥2 concomitant nephrotoxic medications (OR, 3.07; P = .004), receipt of mechanical ventilation (OR, 5.97; P = .001), and admission to an intensive care unit (OR, 6.02; P = .006) as risk factors for AKI during acyclovir treatment. CONCLUSIONS: Among our cohort of infants exposed to acyclovir, the rate of AKI was low. Sicker infants and those exposed to additional nephrotoxic medications seem to be at greater risk for acyclovir-induced toxicity and warrant closer monitoring.

Patient's experience with comorbidity management in primary care: a qualitative study of comorbid pain and obesity.

AIM: The aim of this research is to examine perceptions of those with comorbid chronic pain and obesity regarding their experience of comorbidity management in primary care settings. BACKGROUND: Chronic pain and obesity are common comorbidities frequently managed in primary care settings. Evidence suggests individuals with this comorbidity may be at risk for suboptimal clinical interactions; however, treatment experiences and preferences of those with comorbid chronic pain and obesity have received little attention. METHODS: Semi-structured interviews conducted with 30 primary care patients with mean body mass index=36.8 and comorbid persistent pain. The constant comparative method was used to analyze data. FINDINGS: Participants discussed frustration with a perceived lack of information tailored to their needs and a desire for a personalized treatment experience. Participants found available medical approaches unsatisfying and sought a more holistic approach to management. Discussions also focused around the need for providers to initiate efforts at education and motivation enhancement and to show concern for and understanding of the unique difficulties associated with comorbidity. Findings suggest providers should engage in integrated communication regarding weight and pain, targeting this multimorbidity using methods aligned with priorities discussed by patients.

A randomized clinical trial of an integrated behavioral self-management intervention Simultaneously Targeting Obesity and Pain: the STOP trial.

BACKGROUND: Obesity often occurs co-morbid with chronic, non-cancer pain. While behavioral treatments have proved effective for pain management and weight loss independently, integrated interventions are lacking. The study Simultaneously Targeting Obesity and Pain (STOP) is a prospective, pragmatic, randomized controlled trial that aims to determine whether overweight/obese individuals with chronic pain who are randomized to receive an integrated treatment Simultaneously Targeting Obesity and Pain (STOP) will show more weight loss and greater reduction in pain intensity over a 6-month period and greater maintenance at 12 months than those who receive standard care behavioral weight loss or standard care behavioral pain management. We hypothesize that individuals randomized to receive the STOP treatment will demonstrate improved weight loss, pain reduction, and maintenance compared to standard care treatment approaches. METHODS/DESIGN: Adults aged ≥ 18 with a body mass index ≥ 25 and who report persistent pain (≥4 out of 0-10 for > 6 months) will be recruited for treatment at the Health Behavior Research Lab at the University of the Sciences. After baseline assessments and goal setting, participants will be randomized to receive one of three treatments. Participants will receive eleven treatment sessions delivered during 1 hour, weekly individual meetings with a clinic therapist. Follow-up will occur at 3, 6 and 12-month time points; assessments will include measures of weight and pain intensity (primary outcomes). A mixed-method approach to evaluating study outcomes will include individual interviews with participants about their treatment experience. These interviews will be led by a research staffer who was not involved in study intervention or assessment using a semi-structured discussion guide. DISCUSSION: This study fills an important gap in intervention research, evaluating best-practices for behavioral management of a highly prevalent co-morbidity that has sub-optimal outcomes with currently-implemented approaches. STOP's pragmatic focus builds upon treatments already in use in clinical practice. Should STOP be found efficacious in achieving the dual outcomes of pain management and weight loss, such an approach could be integrated into practice with minimal additional cost or training. TRIAL REGISTRATION: Clinical Trials.gov NCT02100995 Date of Registration: March 2014.