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This study sought to characterize mechanical activation in pulmonary arterial hypertension (PAH) using 2-dimensional echocardiography with tissue Doppler imaging. Whether pathologic alterations of the right ventricle in PAH affect interventricular dyssynchrony due to changes in mechanical activation of the septum and the right ventricle is unclear. We studied 20 patients with PAH (14 women, mean age 55 +/- 16 years) and 20 healthy controls (15 women, mean age 41 +/- 11 years) that underwent tissue Doppler imaging between July 2006 and May 2007. PAH was associated with accelerated right ventricular (RV) (p <0.0001) and septal (p = 0.022) activation times, but no differences were found in lateral wall activation times between groups (p = 0.35). Measures of ventricular dyssynchrony indicated that patients with PAH had significantly lower RV-lateral wall delays (patients 3.2 +/- 66.2 ms vs controls 56.7 +/- 52.0 ms, p = 0.007), reflecting a faster activation of the right ventricle relative to the lateral wall than controls. In conclusion, PAH is associated with interventricular dyssynchrony manifested by accelerated RV free wall and septal activation times. Whether such dyssynchrony should serve as a therapeutic target remains to be determined. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the role of parental appearance-related commentary, body image, and psychological functioning in females and males. METHOD: Retrospective reports of teasing and appearance-based feedback were assessed, along with current levels of body image and overall psychological functioning. RESULTS: Women and men did not differ in their reports of comments received from mothers, however, women received significantly more appearance-related messages from fathers. Correlational analyses demonstrated significant relationships between feedback and body satisfaction for women, but not for men. Regression analyses indicated that fathers' and mothers' teasing about weight were predictive of daughters' body image. For both males and females, psychological functioning was significantly predicted from the combination of mothers' and fathers' feedback regarding appearance. DISCUSSION: The findings further support an emerging theoretical model of appearance-related commentary as a factor in body image disturbance and overall psychological functioning. [ABSTRACT FROM AUTHOR]

Uncontrolled bleeding remains the leading cause of preventable death in trauma. Hemostatic agents are effective in hemorrhage control but often fail following high-volume crystalloid resuscitation. Aggressive fluid resuscitation increases the blood pressure which may dislodge the newly formed clot causing rebleeding. The purpose of this study was to determine the systolic blood pressure (SBP) and the mean arterial pressure (MAP) at which rebleeding occurs when a clot is formed by one of these hemostatic agents (BleedArrest, TraumaDex, or Celox) compared to a control group. This was a prospective, experimental study using male 5 Yorkshire swine per group (BleedArrest, TraumaDex, Celox, or control). The femoral artery and vein were transected to simulate a traumatic injury. Subjects were allowed to bleed for 60 seconds then one of the agents was poured into the wound. The control group underwent the same procedures but without the hemostatic agent. After 30 minutes, dressings were removed and the SBP was increased incrementally using intravenous phenylephrine until rebleeding occurred or until the arterial blood pressure reached 210 mm/Hg. The SBP and MAP were significantly higher in the BleedArrest, TraumaDex, and Celox groups compared to a control group (p < 0.05). [ABSTRACT FROM AUTHOR]

Objective: Current literature supports a multidisciplinary approach to penicillin allergy delabeling. Our study aims to review the success rate of penicillin challenges performed at Walter Reed National Military Medical Center Allergy Clinic and assess the reaction rate associated with a direct oral challenge in low-risk patients., Materials and Methods: We conducted a retrospective review of the outcomes of pediatric penicillin challenges at the Walter Reed National Military Medical Center Allergy and Immunology clinic from June 2019 to May 2023. A total of 74 challenges were included in this study. Patients were initially screened to assess the date of reaction, nature of reaction, if the reaction was life-threatening, and if the patient was hospitalized or sought emergency medical care for the reported reaction. After completion of the screening questionnaire, a direct graded challenge was performed (without skin testing) if a patient's history was deemed low risk. Patients with a recent reaction or a history of multiple drug allergies were more likely to be directed to skin prick testing and intra-dermal testing with Pre-pen and Penicillin-G prior to challenge., Results: All patients passed all challenges. Thus, there was a 100% pass rate for both direct challenges and skin test with oral challenges., Conclusion: Given the low rate of adverse events in this study, expansion of penicillin delabeling in the primary care setting should be considered in patients deemed to be at low risk. It is important for allergists to empower and educate their peers and push forward a movement to create a multidisciplinary approach to penicillin delabeling., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

The complement system is an important component of innate and adaptive immunity that consists of three activation pathways. The classic complement pathway plays a role in humoral immunity, whereas the alternative and lectin pathways augment the innate response. Impairment, deficiency, or overactivation of any of the known 50 complement proteins may lead to increased susceptibility to infection with encapsulated organisms, autoimmunity, hereditary angioedema, or thrombosis, depending on the affected protein. Classic pathway defects result from deficiencies of complement proteins C1q, C1r, C1s, C2, and C4, and typically manifest with features of systemic lupus erythematosus and infections with encapsulated organisms. Alternative pathway defects due to deficiencies of factor B, factor D, and properdin may present with increased susceptibility to Neisseria infections. Lectin pathway defects, including Mannose-binding protein-associated serine protease 2 (MASP2) and ficolin 3, may be asymptomatic or lead to pyogenic infections and autoimmunity. Complement protein C3 is common to all pathways, deficiency of which predisposes patients to severe frequent infections and glomerulonephritis. Deficiencies in factor H and factor I, which regulate the alternative pathway, may lead to hemolytic uremic syndrome. Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9). Diagnosis of complement deficiencies involves screening with functional assays (i.e., total complement activity [CH50], alternative complement pathway activity [AH50], enzyme-linked immunosorbent assay [ELISA]) followed by measurement of individual complement factors by immunoassay. Management of complement deficiencies requires a comprehensive and individualized approach with special attention to vaccination against encapsulated bacteria, consideration of prophylactic antibiotics, treatment of comorbid autoimmunity, and close surveillance.

Background: PfSPZ vaccines comprising Plasmodium falciparum (Pf) sporozoites (SPZ) have demonstrated > 90% protection against variant Pf malaria infections for at least 12 weeks; they are the only vaccines with the level of efficacy necessary to protect travellers. PfSPZ are eukaryotic cells stabilized by cryopreservation and distributed using a cryogenic (below -150 °C) cold chain. The Ebola vaccine and mRNA vaccines against SARS-CoV-2 pioneered uptake of vaccines requiring non-standard ultra-low temperature cold chains. The cryogenic cold chain using liquid nitrogen (LN2) vapour phase (LNVP) cryoshippers, is simpler, more efficient than -80, -20 or 2-8 °C cold chains, and does not use electricity. This study was conducted to evaluate implementation and integration of a cryogenically distributed vaccine at travel and military immunization clinics., Methods: We conducted sequential 28-day studies evaluating vaccine shipping, storage, maintenance and accession at two US military and two civilian travel health/immunization clinics. In each clinic, personnel were trained in equipment use, procurement and handling of LN2, temperature monitoring and inventory record keeping by in-person or video instruction., Results: Sites required 2-4 h/person for two persons to assimilate and develop the expertise to manage vaccine storage and LNVP operations. LN2 for recharging cryoshippers was delivered every 1-2 weeks. Vaccine ordering, receipt, storage and inventory control was conducted effectively. Simulated single dose vaccine cryovial retrieval and thawing were performed successfully in different travel clinic settings. Continuous temperature monitoring at each site was maintained with only one short excursion above -150 °C (-145 °C) through shipping, use and reverse logistics. Staff, during and at study conclusion, provided feedback that has been incorporated into our models for cold chain logistics., Conclusions: These studies demonstrated that the training in delivery, storage, administration and integration of PfSPZ vaccines can be successfully managed in different immunization clinic settings for travellers and military personnel., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Asthma is a common allergic airway disease that has been associated with the development of the human microbiome early in life. Both the composition and function of the infant gut microbiota have been linked to asthma risk, but functional alterations in the gut microbiota of older patients with established asthma remain an important knowledge gap. Here, we performed whole metagenomic shotgun sequencing of 95 stool samples from a cross-sectional cohort of 59 healthy and 36 subjects with moderate-to-severe asthma to characterize the metagenomes of gut microbiota in adults and children 6 years and older. Mapping of functional orthologs revealed that asthma contributes to 2.9% of the variation in metagenomic content even when accounting for other important clinical demographics. Differential abundance analysis showed an enrichment of long-chain fatty acid (LCFA) metabolism pathways, which have been previously implicated in airway smooth muscle and immune responses in asthma. We also observed increased richness of antibiotic resistance genes (ARGs) in people with asthma. Several differentially abundant ARGs in the asthma cohort encode resistance to macrolide antibiotics, which are often prescribed to patients with asthma. Lastly, we found that ARG and virulence factor (VF) richness in the microbiome were correlated in both cohorts. ARG and VF pairs co-occurred in both cohorts suggesting that virulence and antibiotic resistance traits are coselected and maintained in the fecal microbiota of people with asthma. Overall, our results show functional alterations via LCFA biosynthetic genes and increases in antibiotic resistance genes in the gut microbiota of subjects with moderate-to-severe asthma and could have implications for asthma management and treatment., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

Importance: The travelers' gut microbiome is potentially assaulted by acute and chronic perturbations (e.g., diarrhea, antibiotic use, and different environments). Prior studies of the impact of travel and travelers' diarrhea (TD) on the microbiome have not directly compared antibiotic regimens, and studies of different antibiotic regimens have not considered travelers' microbiomes. This gap is important to be addressed as the use of antibiotics to treat or prevent TD-even in moderate to severe cases or in regions with high infectious disease burden-is controversial based on the concerns for unintended consequences to the gut microbiome and antimicrobial resistance (AMR) emergence. Our study addresses this by evaluating the impact of defined antibiotic regimens (single-dose treatment or daily prophylaxis) on the gut microbiome and resistomes of deployed servicemembers, using samples collected during clinical trials. Our findings indicate that the antibiotic treatment regimens that were studied generally do not lead to adverse effects on the gut microbiome and resistome and identify the relative risks associated with prophylaxis. These results can be used to inform therapeutic guidelines for the prevention and treatment of TD and make progress toward using microbiome information in personalized medical care., Competing Interests: The authors declare no conflict of interest.

Background: People who inject drugs (PWID) are at high risk of severe wounds, invasive infections, and overdoses. To date, there are few data on the bacterial and chemical contaminants PWID are exposed to when using illicitly manufactured fentanyls and stimulants., Methods: Previously used injection drug use equipment was recovered in St Louis, Missouri, by harm reduction organizations over a 12-month period. Syringe residue was analyzed for bacterial contaminants by routine culturing followed by whole genome sequencing of single bacterial isolates. Chemical adulterants in syringe residue were identified by liquid chromatography-mass spectrometry., Results: Bacteria were cultured from 58.75% of 160 syringes analyzed. Polymicrobial growth was common and was observed in 23.75% of samples. Bacillus cereus was the most common pathogen present and was observed in 20.6% of syringe residues, followed closely by Staphylococcus aureus at 18.8%. One hundred syringes underwent mass spectrometry, which demonstrated that chemical adulterants were common and included caffeine, diphenhydramine, lidocaine, quinine, and xylazine., Conclusions: Analysis of syringe residue from discarded drug use equipment demonstrates both chemical and biological contaminants, including medically important pathogens and adulterants., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Children with severe acute malnutrition are treated with antibiotics as outpatients. We aimed to determine the effect of 7 days of amoxicillin on acute and long-term changes to the gut microbiome and antibiotic resistome in children treated for severe acute malnutrition., Methods: We conducted a secondary analysis of a randomised, double-blinded, placebo-controlled trial (NCT01613547) of amoxicillin in children (aged 6-59 months) with severe acute malnutrition treated as outpatients in Madarounfa, Niger. We randomly selected 161 children from the overall cohort (n=2399) for initial 12-week follow-up from Sept 23, 2013 to Feb 3, 2014. We selected a convenience sample of those 161 children, on the basis of anthropometric measures, for follow-up 2 years later (Sept 28 to Oct 27, 2015). Children provided faecal samples at baseline, week 1, week 4, week 8, week 12, and, for those in the 2-year follow-up cohort, week 104. We conducted metagenomic sequencing followed by microbiome and resistome profiling of faecal samples. 38 children without severe acute malnutrition and six children with severe acute malnutrition matching the baseline ages of the original cohort were used as reference controls., Findings: In the 12-week follow-up group, amoxicillin led to an immediate decrease in gut microbiome richness from 37·6 species (95% CI 32·6-42·7) and Shannon diversity index (SDI) 2·18 (95% CI 1·97-2·39) at baseline to 27·7 species (95% CI 22·9-32·6) species and SDI 1·55 (95% CI 1·35-1·75) at week 1. Amoxicillin increased gut antibiotic resistance gene abundance to 6044 reads per kilobase million (95% CI 4704-7384) at week 1, up from 4800 (3391-6208) at baseline, which returned to baseline 3 weeks later. 35 children were included in the 2-year follow-up; the amoxicillin-treated children (n=22) had increased number of species in the gut microbiome compared with placebo-treated children (n=13; 60·7 [95% CI 54·7-66·6] vs 36·9 [29·4-44·3]). Amoxicillin-treated children had increased Prevotella spp and decreased Bifidobacterium spp relative to age-matched placebo-treated children, indicating a more mature, adult-like microbiome., Interpretation: Amoxicillin treatment led to acute but not sustained increases in antimicrobial resistance genes and improved gut microbiome maturation 2 years after severe acute malnutrition treatment., Funding: Bill & Melinda Gates Foundation; Médecins sans Frontières Operational Center Paris; National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Edward Mallinckrodt Jr Foundation; Doris Duke Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The standard method of Hymenoptera venom intradermal skin test is performed at a starting concentration of 0.001 to 0.01 μg/mL and increased by 10-fold concentrations until positive or a maximum concentration of 1 μg/mL. Accelerated methods that start at higher concentrations have been reported as safe; however, many institutions have not adopted this approach., Objective: To compare the outcome and safety of standard and accelerated venom skin test protocols., Methods: This was a retrospective chart review of patients with suspected venom allergy who underwent skin testing at 4 allergy clinics within a single health care system from 2012 to 2022. Demographic data, test protocol (standard vs accelerated), test results, and adverse reactions were reviewed., Results: Of 134 patients who underwent standard venom skin test, 2 (1.5%) experienced an adverse reaction, whereas none of the 77 patients who underwent accelerated venom skin test experienced an adverse reaction. One patient, with a history of chronic urticaria, experienced urticaria. The other experienced anaphylaxis requiring an epinephrine although had tested negative to all venom concentrations. Within the standard testing protocol, more than 75% of the positive results occurred at concentrations of 0.1 or 1 μg/mL. Within the accelerated testing protocol, more than 60% of the positive results occurred at 1 μg/mL., Conclusion: The study underscores the overall safety of venom intradermal skin test. Most of the positive results occurred at 0.1 or 1 μg/mL. Adopting an accelerated approach would reduce time and cost associated with testing., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Bacterial bloodstream infections (BSIs) resulting in late-onset sepsis affect up to half of extremely preterm infants and have substantial morbidity and mortality. Bacterial species associated with BSIs in neonatal intensive care units (NICUs) commonly colonize the preterm infant gut microbiome. Accordingly, we hypothesized that the gut microbiome is a reservoir of BSI-causing pathogenic strains that increase in abundance before BSI onset. We analyzed 550 previously published fecal metagenomes from 115 hospitalized neonates and found that recent ampicillin, gentamicin, or vancomycin exposure was associated with increased abundance of Enterobacteriaceae and Enterococcaceae in infant guts. We then performed shotgun metagenomic sequencing on 462 longitudinal fecal samples from 19 preterm infants (cases) with BSI and 37 non-BSI controls, along with whole-genome sequencing of the BSI isolates. Infants with BSI caused by Enterobacteriaceae were more likely than infants with BSI caused by other organisms to have had ampicillin, gentamicin, or vancomycin exposure in the 10 days before BSI. Relative to controls, gut microbiomes of cases had increased relative abundance of the BSI-causing species and clustered by Bray-Curtis dissimilarity according to BSI pathogen. We demonstrated that 11 of 19 (58%) of gut microbiomes before BSI, and 15 of 19 (79%) of gut microbiomes at any time, harbored the BSI isolate with fewer than 20 genomic substitutions. Last, BSI strains from the Enterobacteriaceae and Enterococcaceae families were detected in multiple infants, indicating BSI-strain transmission. Our findings support future studies to evaluate BSI risk prediction strategies based on gut microbiome abundance in hospitalized preterm infants.

Purpose: The purpose of this study was to describe an unusual case of unilateral, endogenous endophthalmitis in an otherwise healthy, term neonate., Methods: A 3-week-old otherwise healthy, term male infant was referred to St. Louis Children's Hospital for a second opinion of presumed panuveitis of the right eye., Results: Diffusion-weighted magnetic resonance imaging demonstrating purulent intraocular contents facilitated the diagnosis of endophthalmitis. Examination of surgical vitreous samples by staining and cytology demonstrated gram-positive bacterial cocci in short chains, thereby confirming endophthalmitis. Polymerase chain reaction testing of vitreous fluid identified Streptococcus agalactiae , despite an unremarkable systemic workup and a negative prepartum maternal Group B streptococcal screen., Conclusion: Endogenous endophthalmitis is a rare but devastating cause of vision loss in otherwise healthy, term neonates. Prompt diagnosis may be facilitated by magnetic resonance imaging and diagnostic vitreous biopsy.

Study Objectives: To explore the relationship between polysomnography-derived respiratory indices and chronic pain status among individuals following traumatic brain injury (TBI)., Methods: Participants (n = 66) with moderate to severe TBI underwent polysomnography during inpatient acute rehabilitation and their chronic pain status was assessed at 1- to 2-year follow-up as part of the TBI Model Systems Pain Collaborative Study. Pairwise comparisons across pain cohorts (ie, chronic pain, no history of pain) were made to explore differences on polysomnography indices., Results: Among our total sample, approximately three-quarters (74.2%) received sleep apnea diagnoses utilizing American Academy of Sleep Medicine criteria, with 61.9% of those endorsing a history of chronic pain. Of those endorsing chronic pain, the average pain score was 4.8 (standard deviation = 2.1), with a mean interference score of 5.3 (2.7). Pairwise comparisons revealed that those endorsing a chronic pain experience at follow-up experienced categorically worse indicators of sleep-related breathing disorders during acute rehabilitation relative to those who did not endorse chronic pain. Important differences were observed with elevations on central (chronic pain: 2.6; no pain: 0.8 per hour) and obstructive apnea (chronic pain: 15.7; no pain: 11.1 per hour) events, as well as oxygen desaturation indices (chronic pain: 19.6; no pain: 7.9 per hour)., Conclusions: Sleep-disordered breathing appears worse among those who endorse chronic pain following moderate-to-severe TBI, but additional research is needed to understand its relation to postinjury pain. Prospective investigation is necessary to determine how clinical decisions (eg, opioid therapy) and intervention (eg, positive airway pressure) may mutually influence outcomes., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Comparison of Sleep Apnea Assessment Strategies to Maximize TBI Rehabilitation Participation and Outcome (C-SAS); URL: https://clinicaltrials.gov/ct2/show/NCT03033901; Identifier: NCT03033901., Citation: Martin AM, Pinto SM, Tang X, et al. Associations between early sleep-disordered breathing following moderate-to-severe traumatic brain injury and long-term chronic pain status: a Traumatic Brain Injury Model Systems study. J Clin Sleep Med . 2023;19(1):135-143., (© 2023 American Academy of Sleep Medicine.)

International travel contributes to the global spread of antimicrobial resistance. Travelers' diarrhea exacerbates the risk of acquiring multidrug-resistant organisms and can lead to persistent gastrointestinal disturbance post-travel. However, little is known about the impact of diarrhea on travelers' gut microbiomes, and the dynamics of these changes throughout travel. Here, we assembled a cohort of 159 international students visiting the Andean city of Cusco, Peru and applied next-generation sequencing techniques to 718 longitudinally-collected stool samples. We find that gut microbiome composition changed significantly throughout travel, but taxonomic diversity remained stable. However, diarrhea disrupted this stability and resulted in an increased abundance of antimicrobial resistance genes that can remain high for weeks. We also identified taxa differentially abundant between diarrheal and non-diarrheal samples, which were used to develop a classification model that distinguishes between these disease states. Additionally, we sequenced the genomes of 212 diarrheagenic Escherichia coli isolates and found those from travelers who experienced diarrhea encoded more antimicrobial resistance genes than those who did not. In this work, we find the gut microbiomes of international travelers' are resilient to dysbiosis; however, they are also susceptible to colonization by multidrug-resistant bacteria, a risk that is more pronounced in travelers with diarrhea., (© 2022. The Author(s).)

Intestinal host-microbiota interactions during the first year of life are critical for infant development. Early-life antibiotic exposures disrupt stereotypical gut microbiota maturation and adversely affect childhood health. Furthermore, antibiotics increase the abundance of resistant bacteria and enrich the resistome-the compendium of antibiotic resistance genes-within the gut microbiota. Here, we discuss acute and persistent impacts of antibiotic exposure during infancy on pediatric health, the gut microbiome, and, particularly, the resistome. Reviewing our current understanding of antibiotic resistance acquisition and dissemination within and between microbiomes, we highlight open questions, which are imperative to resolve in the face of rising bacterial resistance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Imported fire ant (IFA) venom immunotherapy (VIT) is the only disease-modifying treatment reported to be effective at decreasing the risk of systemic reactions (SRs) to IFA stings., Objective: Our aims were to determine the baseline rates of IFA sensitization in subjects, describe IFA VIT prescribing patterns across the military health system (MHS), and retrospectively evaluate the safety and efficacy of IFA VIT., Methods: We prospectively compared IFA sensitization in participants with and without an SR to flying Hymenoptera venom. Separately, IFA VIT prescription records were extracted from a centralized repository, and rates were described across the MHS. Additionally, we retrospectively reviewed the clinical course of patients being treated with IFA VIT at 11 military treatment facilities., Results: The in vitro IFA sensitization rates in our prospective cohort ranged from 19.1% to 24.1%. Sensitization rates did not differ statistically between the subjects with or without an SR to flying Hymenoptera venom. We found that 60.9% of all MHS IFA VIT prescriptions (491 of 806) were from the 11 facilities in this study. We retrospectively identified 137 subjects actively undergoing IFA VIT. Among the subjects actively undergoing IFA VIT, 28 reported an SR to IFA venom and repeat stings by IFAs after reaching VIT maintenance, and 85.7% (24 of 28) of the subjects noted symptoms no worse than a large swelling reaction after a repeat IFA sting. Notably, only 2.9% of the subjects (4 of 137) had an SR due to VIT., Conclusion: This study's results align with those of prior IFA sensitization reports. A substantial proportion of patients undergoing IFA VIT experienced protection against anaphylaxis with reexposure, with relatively few adverse events.

Objectives: To describe patient and clinical characteristics associated with receipt of opioid medications and identify differences in sleep quality, architecture, and sleep-related respiration between those receiving and not receiving opioid medications., Setting: Acute inpatient rehabilitation care for moderate to severe traumatic brain injury (TBI)., Participants: A total of 248 consecutive admissions for inpatient rehabilitation care following moderate to severe TBI (average age of 43.6 years), who underwent level 1 polysomnography (PSG) (average time since injury: 120 days) across 6 sites., Design: Cross-sectional, secondary analyses., Main Measures: The PSG sleep parameters included total sleep time (TST), sleep efficiency (SE), wake after sleep onset, rapid eye movement (REM) latency, sleep staging, and arousal and awakening indices. Respiratory measures included oxygen saturation, central apnea events per hour, obstructive apnea and hypopnea events per hour, and total apnea-hypopnea index., Results: After adjustment for number of prescribed medication classes, those receiving opioid medications on the day of PSG experienced increased TST relative to those not receiving opioid medications (estimated mean difference [EMD] = 31.58; 95% confidence interval [CI], 1.9-61.3). Other indices of sleep did not differ significantly between groups. Among respiratory measures those receiving opioids on the day of PSG experienced increased frequency of central sleep apnea events during total (EMD = 2.92; 95% CI, 0.8-5.0) and non-REM sleep (EMD = 3.37; 95% CI, 1.0-5.7) and higher frequency of obstructive sleep apnea events during REM sleep (EMD = 6.97; 95% CI, 0.1-13.8). Compared with those who did not, receiving opioids was associated with lower oxygen saturation nadir during total sleep (EMD = -3.03; 95% CI, -5.6 to -0.4) and a greater number of oxygen desaturations across REM (EMD = 8.15; 95% CI, 0.2-16.1), non-REM (EMD = 7.30; 95% CI, 0.3-14.4), and total sleep (EMD = 8.01; 95% CI, 0.8-15.2) Greater total apnea-hypopnea index was observed during REM (EMD = 8.13; 95% CI, 0.8-15.5) and total sleep (EMD = 7.26; 95% CI, 0.08-14.4) for those receiving opioids., Conclusion: Opioid use following moderate to severe TBI is associated with an increase in indicators of sleep-related breathing disorders, a modifiable condition that is prevalent following TBI. As sleep-wake disorders are associated with poorer rehabilitation outcomes and opioid medications may frequently be administered following traumatic injury, additional longitudinal investigations are warranted in determining whether a causal relation between opioids and sleep-disordered breathing in those following moderate to severe TBI exists. Given current study limitations, future studies can improve upon methodology through the inclusion of indication for and dosage of opioid medications in this population when examining these associations., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Lipodystrophic mice are protected from cartilage damage following joint injury. This protection can be reversed by the implantation of a small adipose tissue graft. The purpose of this study was to evaluate the relationship between the gut microbiota and knee cartilage damage while controlling for adiposity, high fat diet, and joint injury using lipodystrophic (LD) mice. LD and littermate control (WT) mice were fed a high fat diet, chow diet, or were rescued with fat implantation, then challenged with destabilization of the medial meniscus surgery to induce osteoarthritis (OA). 16S rRNA sequencing was conducted on feces. MaAslin2 was used to determine associations between taxonomic relative abundance and OA severity. While serum LPS levels between groups were similar, synovial fluid LPS levels were increased in both limbs of HFD WT mice compared to all groups, except for fat transplanted animals. The Bacteroidetes:Firmicutes ratio of the gut microbiota was significantly reduced in HFD and OA-rescued animals when compared to chow. Nine novel significant associations were found between gut microbiota taxa and OA severity. These findings suggest the presence of causal relationships the gut microbiome and cartilage health, independent of diet or adiposity, providing potential therapeutic targets through manipulation of the microbiome., (© 2021. The Author(s).)

Background: Once antibiotic-resistant bacteria become established within the gut microbiota, they can cause infections in the host and be transmitted to other people and the environment. Currently, there are no effective modalities for decreasing or preventing colonization by antibiotic-resistant bacteria. Intestinal microbiota restoration can prevent Clostridioides difficile infection (CDI) recurrences. Another potential application of microbiota restoration is suppression of non-C. difficile multidrug-resistant bacteria and overall decrease in the abundance of antibiotic resistance genes (the resistome) within the gut microbiota. This study characterizes the effects of RBX2660, a microbiota-based investigational therapeutic, on the composition and abundance of the gut microbiota and resistome, as well as multidrug-resistant organism carriage, after delivery to patients suffering from recurrent CDI., Methods: An open-label, multi-center clinical trial in 11 centers in the USA for the safety and efficacy of RBX2660 on recurrent CDI was conducted. Fecal specimens from 29 of these subjects with recurrent CDI who received either one (N = 16) or two doses of RBX2660 (N = 13) were analyzed secondarily. Stool samples were collected prior to and at intervals up to 6 months post-therapy and analyzed in three ways: (1) 16S rRNA gene sequencing for microbiota taxonomic composition, (2) whole metagenome shotgun sequencing for functional pathways and antibiotic resistome content, and (3) selective and differential bacterial culturing followed by isolate genome sequencing to longitudinally track multidrug-resistant organisms., Results: Successful prevention of CDI recurrence with RBX2660 correlated with taxonomic convergence of patient microbiota to the donor microbiota as measured by weighted UniFrac distance. RBX2660 dramatically reduced the abundance of antibiotic-resistant Enterobacteriaceae in the 2 months after administration. Fecal antibiotic resistance gene carriage decreased in direct relationship to the degree to which donor microbiota engrafted., Conclusions: Microbiota-based therapeutics reduce resistance gene abundance and resistant organisms in the recipient gut microbiome. This approach could potentially reduce the risk of infections caused by resistant organisms within the patient and the transfer of resistance genes or pathogens to others., Trial Registration: ClinicalTrials.gov, NCT01925417 ; registered on August 19, 2013.

Gut microbiome composition correlates with responsiveness to immune checkpoint inhibitor therapy. In a recent study in Science, Baruch et al. manipulated gut microbiome composition in patients with refractory metastatic melanoma using fecal microbiota transplants. Fecal microbiota transplant was safe and partially effective in inducing remission in refractory patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The first large-scale evaluation of prescribing patterns for imported fire ant (IFA) in a large US health care system was published by Haymore et al in 2009. In this first evaluation of prescriptions from 1990 to 2007, the most often prescribed maintenance IFA prescription was 0.5 mL of 1:200 wt/vol., Objective: To provide an updated description of IFA prescribing patterns over the ensuing 11 years from same large health care system., Methods: We reviewed 1349 new IFA prescriptions written from 2007 to 2018, from a large nationwide health care system, with primary end points being maintenance prescription strength and prescribing patterns., Results: In comparison to the data published by Haymore et al in 2009, which reported that 17% of the prescriptions were written for 0.5 mL of 1:100 wt/vol maintenance, we found that 69% (95% CI: 66.4%-71.4%) of IFA prescriptions written in the past 11 years were for the maintenance concentration of 0.5 mL of 1:100 wt/vol. We further studied the linear trend over time of percentage of prescriptions written for individual concentrations and observed that the percentage of 1:100 wt/vol prescriptions increased 3.5% yearly (R 2  = 0.68, P < .001) from 2007 (40.0%, 95% CI: 24.6%-57.7%) to 2018 (84.4%, 95% CI: 77.4%-89.5%)., Conclusion: Our study shows significant improvement in the accuracy and precision of IFA immunotherapy dosing for patients with IFA hypersensitivity, with ascendancy of 0.5 mL 1:100 wt/vol as the predominant treatment dose. A total of 87% of patients within our study were treated within the parameter recommendations, a stark improvement from findings in the 2009 Haymore study., (Published by Elsevier Inc.)

Background: OSA is prevalent during a time of critical neural repair after traumatic brain injury (TBI). The diagnostic utility of existing sleep studies is needed to inform clinical management during acute recovery from TBI., Research Question: This study aimed to evaluate the non-inferiority and diagnostic accuracy of a portable level 3 sleep study relative to level 1 polysomnography in hospitalized neurorehabilitation patients with TBI., Study Design and Methods: This is a prospective clinical trial conducted at six TBI Model System study sites between May 2017 and February 2019. Of 896 admissions, 449 were screened and eligible for the trial, with 345 consented. Additional screening left 263 eligible for and completing simultaneous administration of both level 1 and level 3 sleep studies, with final analyses completed on 214 (median age = 42 years; ED Glasgow Coma Scale = 6; time to polysomnography [PSG] = 52 days)., Results: Agreement was moderate to strong (weighted kappa = 0.78, 95% CI, 0.72-0.83) with the misclassification commonly occurring with mild sleep apnea due to underestimation of apnea hypopnea index (AHI). Most of those with moderate to severe sleep apnea were correctly classified (n = 54/72). Non-inferiority was not demonstrated: the minimum tolerable specificity of 0.5 was achieved across all AHI cutoff scores (lower confidence limits [LCL] range, 0.807-0.943), but the minimum tolerable sensitivity of 0.8 was not (LCL range, 0.665-0.764)., Interpretation: Although the non-inferiority of level 3 portable diagnostic testing relative to level 1 was not established, strong agreement was seen across sleep apnea indexes. Most of those with moderate to severe sleep apnea were correctly identified; however, there was risk of misclassification with level 3 sleep studies underestimating disease severity for those with moderate to severe AHI and disease presence for those with mild AHI during early TBI neurorehabilitation., (Published by Elsevier Inc.)

The human gut microbiome is a dynamic collection of bacteria, archaea, fungi, and viruses that performs essential functions for immune development, pathogen colonization resistance, and food metabolism. Perturbation of the gut microbiome's ecological balance, commonly by antibiotics, can cause and exacerbate diseases. To predict and successfully rescue such perturbations, first, we must understand the underlying taxonomic and functional dynamics of the microbiome as it changes throughout infancy, childhood, and adulthood. We offer an overview of the healthy gut bacterial architecture over these life stages and comment on vulnerability to short and long courses of antibiotics. Second, the resilience of the microbiome after antibiotic perturbation depends on key characteristics, such as the nature, timing, duration, and spectrum of a course of antibiotics, as well as microbiome modulatory factors such as age, travel, underlying illness, antibiotic resistance pattern, and diet. In this review, we discuss acute and chronic antibiotic perturbations to the microbiome and resistome in the context of microbiome stability and dynamics. We specifically discuss key taxonomic and resistance gene changes that accompany antibiotic treatment of neonates, children, and adults. Restoration of a healthy gut microbial ecosystem after routine antibiotics will require rationally managed exposure to specific antibiotics and microbes. To that end, we review the use of fecal microbiota transplantation and probiotics to direct recolonization of the gut ecosystem. We conclude with our perspectives on how best to assess, predict, and aid recovery of the microbiome after antibiotic perturbation.

Objective: To describe the cost benefit of 4 different approaches to screening for sleep apnea in a cohort of participants with moderate to severe traumatic brain injury (TBI) receiving inpatient rehabilitation from the payor's perspective., Design: A cost-benefit analysis of phased approaches to sleep apnea diagnosis., Setting: Six TBI Model System Inpatient Rehabilitation Centers., Participants: Trial data from participants (N=214) were used in analyses (mean age 44±18y, 82% male, 75% white, with primarily motor vehicle-related injury [44%] and falls [33%] with a sample mean emergency department Glasgow Coma Scale of 8±5)., Intervention: Not applicable., Main Outcome: Cost benefit., Results: At apnea-hypopnea index (AHI) ≥15 (34%), phased modeling approaches using screening measures (Snoring, Tired, Observed, Blood Pressure, Body Mass Index, Age, Neck Circumference, and Gender [STOPBANG] [-$5291], Multivariable Apnea Prediction Index MAPI [-$5262]) resulted in greater cost savings and benefit relative to the portable diagnostic approach (-$5210) and initial use of laboratory-quality polysomnography (-$5,011). Analyses at AHI≥5 (70%) revealed the initial use of portable testing (-$6323) relative to the screening models (MAPI [-$6250], STOPBANG [-$6237) and initial assessment with polysomnography (-$5977) resulted in greater savings and cost-effectiveness., Conclusions: The high rates of sleep apnea after TBI highlight the importance of accurate diagnosis and treatment of this comorbid disorder. However, financial and practical barriers exist to obtaining an earlier diagnosis during inpatient rehabilitation hospitalization. Diagnostic cost savings are demonstrated across all phased approaches and OSA severity levels with the most cost-beneficial approach varying by incidence of OSA., (Published by Elsevier Inc.)

Study Objectives: The objective of this study was to compare obstructive sleep apnea (OSA), demographic, and traumatic brain injury (TBI) characteristics across the American Academy of Sleep Medicine (AASM) and Centers for Medicare and Medicare (CMS) scoring rules in moderate to severe TBI undergoing inpatient neurorehabilitation., Methods: This is a secondary analysis from a prospective clinical trial of sleep apnea at 6 TBI Model System study sites (n = 248). Scoring was completed by a centralized center using both the AASM and CMS criteria for OSA. Hospitalization and injury characteristics were abstracted from the medical record, and demographics were obtained by interview by trained research assistants using TBI Model System standard procedures., Results: OSA was prevalent using the AASM (66%) and CMS (41.5%) criteria with moderate to strong agreement (weighted κ = 0.64; 95% confidence interval = 0.58-0.70). Significant differences were observed for participants meeting AASM and CMS criteria (concordant group) compared with those meeting criteria for AASM but not CMS (discordant group). At an apnea-hypopnea index ≥ 5 events/h, the discordant group (n = 61) had lower Emergency Department Glasgow Coma Scale Scores consistent with greater injury severity (median, 5 vs 13; P = .0050), younger age (median, 38 vs 58; P < .0001), and lower body mass index (median, 22.1 vs 24.8; P = .0007) compared with the concordant group (n = 103). At an apnea-hypopnea index ≥ 15 events/h, female sex but no other differences were noted, possibly because of the smaller sample size., Conclusions: The underestimation of sleep apnea using CMS criteria is consistent with prior literature; however, this is the first study to report the impact of the criteria in persons with moderate to severe TBI during a critical stage of neural recovery. Management of comorbidities in TBI has become an increasing focus for optimizing TBI outcomes. Given the chronic morbidity after moderate to severe TBI, the impact of CMS policy for OSA diagnosis for persons with chronic disability and young age are considerable., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Comparison of Sleep Apnea Assessment Strategies to Maximize TBI Rehabilitation Participation and Outcome; Identifier: NCT03033901., (© 2020 American Academy of Sleep Medicine.)

Objective: The purpose of this study was to describe incidence and assess predictors of adherence to Positive Airway Pressure (PAP) therapy for Obstructive Sleep Apnea (OSA) in persons with acquired brain injury (ABI)., Methods: A 2012-2015 retrospective analysis of consecutive ABI patients admitted for neurorehabilitation, referred for polysomnography (PSG), and prescribed PAP for OSA. Univariable linear regressions were conducted to examine predictors of average hours of nightly PAP use. Univariable logistic regressions were conducted to examine predictors of PAP adherence using the conventional clinical definition of ≥4 h per night ≥70% of the time. Persons with traumatic etiology were separately analyzed., Results: ABI etiology was 51% traumatic, 36% stroke, and 13% other nontraumatic causes. Nearly two-thirds were nonadherent to PAP. For the overall sample, higher average nightly PAP usage was significantly predicted by positive hypertension diagnosis (β = 0.271, p = 0.019). Likewise, greater adherence based on the conventional cutoff was predicted by poorer motor functioning at hospital admission (OR = 0.98, p = 0.001) and lower oxygen saturation nadir (OR = 0.99, p = 0.003). For those with traumatic injuries, greater adherence was predicted by poorer functional status at hospital admission (OR = 0.98, p = 0.010) and positive hypertension diagnosis (OR = 0.16, p = 0.023)., Conclusions: In this study of hospitalized neurorehabilitation patients with ABI and comorbid OSA, predictors of adherence included lower oxygen saturation, poorer functional status and hypertension diagnosis, perhaps signifying the role of greater severity of illness on treatment adherence. High rates of refusal and nonadherence to frontline PAP therapy for sleep apnea is a concern for persons in recovery form ABI who are at a time of critical neural repair., (Published by Elsevier B.V.)

Objective: To determine the diagnostic sensitivity and specificity and comparative effectiveness of traditional sleep apnea screening tools in traumatic brain injury (TBI) neurorehabilitation admissions., Design: Prospective diagnostic comparative effectiveness trial of sleep apnea screening tools relative to the criterion standard, attended level 1 polysomnography including encephalography., Setting: Six TBI Model System Inpatient Rehabilitation Centers., Participants: Between May 2017 and February 2019, 449 of 896 screened were eligible for the trial with 345 consented (77% consented). Additional screening left 263 eligible for and completing polysomnography with final analyses completed on 248., Intervention: Not applicable., Main Outcome Measures: Area under the curve (AUC) of screening tools relative to total apnea hypopnea index≥15 (AHI, moderate to severe apnea) measured at a median of 47 days post-TBI (interquartile range, 29-47)., Results: The Berlin high-risk score (receiving operating curve [ROC] AUC=0.634) was inferior to the Multivariable Apnea Prediction Index (MAPI) (ROC AUC=0.780) (P=.0211; CI, 0.018-0.223) and Snoring, Tired, Observed, Blood Pressure, Body Mass Index, Age, Neck Circumference, and Gender (STOPBANG) score (ROC AUC=0.785) (P=.001; CI, 0.063-0.230), both of which had comparable AUC (P=.7245; CI, -0.047 to 0.068). Findings were similar for AHI≥30 (severe apnea); however, no differences across scales was observed at AHI≥5. The pattern was similar across TBI severity subgroups except for posttraumatic amnesia (PTA) status wherein the MAPI outperformed the Berlin. Youden's index to determine risk yielded lower sensitivities but higher specificities relative to non-TBI samples., Conclusion: This study is the first to provide clinicians with data to support a choice for which sleep apnea screening tools are more effective during inpatient rehabilitation for TBI (STOPBANG, MAPI vs Berlin) to help reduce comorbidity and possibly improve neurologic outcome., (Copyright © 2019 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Immuno-oncology has rapidly grown in the last thirty years, and immunotherapeutic agents are now approved to treat many disparate cancers. Immune checkpoint inhibitors (ICIs) are employed to augment cytotoxic anti-cancer activity by inhibiting negative regulatory elements of the immune system. Modulating the immune system to target neoplasms has improved survivability of numerous cancers in many individuals, but forecasting outcomes post therapy is difficult due to insufficient predictive biomarkers. Recently, the tumor and gastrointestinal microbiome and immune milieu have been investigated as predictors and influencers of cancer immune therapy. In this review, we discuss: (1) ways to measure the microbiome including relevant bioinformatic analyses, (2) recent developments in animal studies and human clinical trials utilizing gut microbial composition and function as biomarkers of cancer immune therapy response and toxicity, and (3) using prebiotics, probiotics, postbiotics, antibiotics, and fecal microbiota transplant (FMT) to modulate immune therapy. We discuss the respective benefits of 16S ribosomal RNA (rRNA) gene and shotgun metagenomic sequencing including important considerations in obtaining samples and in designing and interpreting human and animal microbiome studies. We then focus on studies discussing the differences in response to ICIs in relation to the microbiome and inflammatory mediators. ICIs cause colitis in up to 25% of individuals, and colitis is often refractory to common immunosuppressive medications. Researchers have measured microbiota composition prior to ICI therapy and correlated baseline microbiota composition with efficacy and colitis. Certain bacterial taxa that appear to enhance therapeutic benefit are also implicated in increased susceptibility to colitis, alluding to a delicate balance between pro-inflammatory tumor killing and anti-inflammatory protection from colitis. Pre-clinical and clinical models have trialed probiotic administration, e.g. Bifidobacterium spp. or FMT, to treat colitis when immune suppressive agents fail. We are excited about the future of modulating the microbiome to predict and influence cancer outcomes. Furthermore, novel therapies employed for other illnesses including bacteriophage and genetically-engineered microbes can be adapted in the future to promote increased advancements in cancer treatment and side effect management.

Survivors of brain injury who have disorders of consciousness often have chronic functional deficits and disability. Obstructive sleep apnoea, a sleep-related breathing disorder, is a medical comorbid condition common among persons with brain injury and is injurious to health. Research on obstructive sleep apnoea treatment among brain-injured patients-particularly persons with disorders of consciousness-is sparse. This case study describes a patient with severe brain injury admitted for neurorehabilitation in a minimally conscious state. Obstructive sleep apnoea was identified and treated. Treatment compliance was variable, and functional motor and cognitive improvement were observed during periods of better compliance. Study design does not permit casual attribution for functional improvement, but identification and treatment of obstructive sleep apnoea are suggested as a possible way to promote recovery after brain injury.

The rise of antimicrobial resistance in uropathogens has complicated the management of urinary tract infections (UTIs), particularly in patients who are afflicted by recurrent episodes of UTIs. Antimicrobial-resistant (AR) uropathogens persistently colonizing individuals at asymptomatic time points have been implicated in the pathophysiology of UTIs. The dynamics of uropathogen persistence following the resolution of symptomatic disease are, however, mostly unclear. To further our understanding, we determined longitudinal AR uropathogen carriage and clonal persistence of uropathogenic Escherichia coli , Proteus mirabilis , and Klebsiella pneumoniae isolates in the intestinal and urinary tracts of patients affected by recurrent and nonrecurrent UTIs. Clonal tracking of isolates in consecutively collected urine and fecal specimens indicated repeated transmission of uropathogens between the urinary tract and their intestinal reservoir. Our results further implicate three independent routes of recurrence of UTIs: (i) following an intestinal bloom of uropathogenic bacteria and subsequent bladder colonization, (ii) reinfection of the urinary tract from an external source, and (iii) bacterial persistence within the urinary tract. Taken together, our observation of clonal persistence following UTIs and uropathogen transmission between the intestinal and urinary tracts warrants further investigations into the connection between the intestinal microbiome and recurrent UTIs. IMPORTANCE The increasing antimicrobial resistance of uropathogens is challenging the continued efficacy of empiric antibiotic therapy for UTIs, which are among the most frequent bacterial infections worldwide. It has been suggested that drug-resistant uropathogens could persist in the intestine after the resolution of UTI and cause recurrences following periurethral contamination. A better understanding of the transmission dynamics between the intestinal and urinary tracts, combined with phenotypic characterization of the uropathogen populations in both habitats, could inform prudent therapies designed to overcome the rising resistance of uropathogens. Here, we integrate genomic surveillance with clinical microbiology to show that drug-resistant clones persist within and are readily transmitted between the intestinal and urinary tracts of patients affected by recurrent and nonrecurrent UTIs. Thus, our results advocate for understanding persistent intestinal uropathogen colonization as part of the pathophysiology of UTIs, particularly in patients affected by recurrent episodes of symptomatic disease., (Copyright © 2019 Thänert et al.)

Background: Cannabis is the most widely used illicit drug, but knowledge of the neurological consequences of cannabis use is deficient. Two primary components of cannabis are Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). We established a THC+CBD model of self-administration and reinstated drug seeking to determine if, similar to other addictive drugs, cannabis produces enduring synaptic changes in nucleus accumbens core (NAcore) thought to contribute vulnerability to drug reinstatement., Methods: Sprague Dawley rats were trained to self-administer THC+CBD (n = 165) or were used as vehicle self-administering control animals (n = 24). Reinstatement was initiated by context, cues, drug priming, and stress (yohimbine injection). Enduring neuroadaptations produced by THC+CBD self-administration were assayed using four measures: dendritic spine morphology, long-term depression, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate ratios, and behavioral pharmacology., Results: We described a novel rodent model of cannabis relapse involving intravenous THC+CBD self-administration and drug seeking induced by conditioned context, cues, and stress. Cued reinstatement of THC+CBD seeking depended on a sequence of events implicated in relapse to other addictive drugs, as reinstatement was prevented by daily treatment with N-acetylcysteine or acute intra-NAcore pretreatment with a neuronal nitric oxide synthase or matrix metalloprotease-9 inhibitor, all of which normalize impaired glutamate homeostasis. The capacity to induce N-methyl-D-aspartate long-term depression in NAcore medium spiny neurons was abolished and dendritic spine density was reduced, but alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate ratio was unaltered in THC+CBD-trained animals, akin to opioids, but not to psychostimulants., Conclusions: We report enduring consequences of THC+CBD use on critical relapse circuitry and synaptic physiology in NAcore following rat self-administration and provide the first report of cue- and stress-induced reinstatement with this model., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Importance: Allergic diseases are prevalent in childhood. Early exposure to medications that can alter the microbiome, including acid-suppressive medications and antibiotics, may influence the likelihood of allergy., Objective: To determine whether there is an association between the use of acid-suppressive medications or antibiotics in the first 6 months of infancy and development of allergic diseases in early childhood., Design, Setting, and Participants: A retrospective cohort study was conducted in 792 130 children who were Department of Defense TRICARE beneficiaries with a birth medical record in the Military Health System database between October 1, 2001, and September 30, 2013, with continued enrollment from within 35 days of birth until at least age 1 year. Children who had an initial birth stay of greater than 7 days or were diagnosed with any of the outcome allergic conditions within the first 6 months of life were excluded from the study. Data analysis was performed from April 15, 2015, to January 4, 2018., Exposures: Exposures were defined as having any dispensed prescription for a histamine-2 receptor antagonist (H2RA), proton pump inhibitor (PPI), or antibiotic., Main Outcomes and Measures: The main outcome was allergic disease, defined as the presence of food allergy, anaphylaxis, asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, urticaria, contact dermatitis, medication allergy, or other allergy., Results: Of 792 130 children (395 215 [49.9%] girls) included for analysis, 60 209 (7.6%) were prescribed an H2RA, 13 687 (1.7%) were prescribed a PPI, and 131 708 (16.6%) were prescribed an antibiotic during the first 6 months of life. Data for each child were available for a median of 4.6 years. Adjusted hazard ratios (aHRs) in children prescribed H2RAs and PPIs, respectively, were 2.18 (95% CI, 2.04-2.33) and 2.59 (95% CI, 2.25-3.00) for food allergy, 1.70 (95% CI, 1.60-1.80) and 1.84 (95% CI, 1.56-2.17) for medication allergy, 1.51 (95% CI, 1.38-1.66) and 1.45 (95% CI, 1.22-1.73) for anaphylaxis, 1.50 (95% CI, 1.46-1.54) and 1.44 (95% CI, 1.36-1.52) for allergic rhinitis, and 1.25 (95% CI, 1.21-1.29) and 1.41 (95% CI, 1.31-1.52) for asthma. The aHRs after antibiotic prescription in the first 6 months of life were 2.09 (95% CI, 2.05-2.13) for asthma, 1.75 (95% CI, 1.72-1.78) for allergic rhinitis, 1.51 (95% CI, 1.38-1.66) for anaphylaxis, and 1.42 (95% CI, 1.34-1.50) for allergic conjunctivitis., Conclusions and Relevance: This study found associations between the use of acid-suppressive medications and antibiotics during the first 6 months of infancy and subsequent development of allergic disease. Acid-suppressive medications and antibiotics should be used during infancy only in situations of clear clinical benefit.

Background: There is increasing evidence that the pathological overeating underlying some forms of obesity is compulsive in nature and therefore contains elements of an addictive disorder. However, direct physiological evidence linking obesity to synaptic plasticity akin to that occurring in addiction is lacking. We sought to establish whether the propensity to diet-induced obesity (DIO) is associated with addictive-like behavior, as well as synaptic impairments in the nucleus accumbens core considered hallmarks of addiction., Methods: Sprague Dawley rats were allowed free access to a palatable diet for 8 weeks then separated by weight gain into DIO-prone and DIO-resistant subgroups. Access to palatable food was then restricted to daily operant self-administration sessions using fixed ratio 1, 3, and 5 and progressive ratio schedules. Subsequently, nucleus accumbens brain slices were prepared, and we tested for changes in the ratio between α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate currents and the ability to exhibit long-term depression., Results: We found that propensity to develop DIO is linked to deficits in the ability to induce long-term depression in the nucleus accumbens, as well as increased potentiation at these synapses as measured by AMPA/N-methyl-D-aspartate currents. Consistent with these impairments, we observed addictive-like behavior in DIO-prone rats, including 1) heightened motivation for palatable food; 2) excessive intake; and 3) increased food seeking when food was unavailable., Conclusions: Our results show overlap between the propensity for DIO and the synaptic changes associated with facets of addictive behavior, supporting partial coincident neurological underpinnings for compulsive overeating and drug addiction., (Copyright © 2016 Society of Biological Psychiatry. All rights reserved.)

Background: Sleep problems and disorders are prevalent in patients with traumatic brain injury (TBI) and are associated with negative outcomes. Incidence varies because of challenges including differences in assessment methods, particularly in the acute stages of recovery when patients are cognitively impaired and unable to complete traditional self-report methods. Actigraphy (ACG) recently has been validated in the acute TBI rehabilitation setting and may serve as a superior method of assessing sleep-wake patterns at this stage of recovery. Although a few studies with small sample sizes have described the use of ACG, none have described feasibility and implementation protocols., Objective: To describe the feasibility and implementation protocol of ACG to evaluate sleep-wake patterns and white-light exposure data in patients with acute TBI during inpatient rehabilitation. Sleep-wake patterns and light exposure data are presented to characterize the sample using these methods to inform future research., Design: Retrospective study., Setting: Acute inpatient rehabilitation unit at a Veterans' Affairs Polytrauma Rehabilitation Center., Participants: Veterans (age ≥18 years) admitted to inpatient rehabilitation and enrolled in the Traumatic Brain Injury Model Systems study who were admitted and discharged in the calendar year 2013., Methods: Veterans underwent actigraph watch placement as soon as possible after admission. Records from the calendar year 2013 were reviewed to determine the number of admissions that met study criteria and what percentage of those patients had 3 days of continuous ACG data collected. The barriers to successful watch placement in this population were reviewed. Average sleep, light, and wake data from available records were collected for the study sample., Main Outcome Measurements: Percentage of patients who met study criteria and who had 72 hours of continuous ACG data collected. The barriers to successful watch placement in this population were reviewed. Average sleep, light, and wake data from available records were collected., Results: Of 22 eligible Traumatic Brain Injury Model Systems admissions, 3 consecutive nights of ACG data were successfully obtained for 86% (n = 19) of the sample. Barriers to data collection included patient access due to abbreviated lengths of stay, staff availability for ACG placement, and data collection protocols to prevent loss of data in Veterans' Affairs computing systems., Conclusions: ACG is feasible for collecting data about sleep, wake, and light exposure in patients who are in acute TBI inpatient rehabilitation settings., Level of Evidence: III., (Copyright © 2016 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

Recurrent bacterial infections are a significant burden worldwide, and prior history of infection is often a significant risk factor for developing new infections. For urinary tract infection (UTI), a history of two or more episodes is an independent risk factor for acute infection. However, mechanistic knowledge of UTI pathogenesis has come almost exclusively from studies in naive mice. Here we show that, in mice, an initial Escherichia coli UTI, whether chronic or self-limiting, leaves a long-lasting molecular imprint on the bladder tissue that alters the pathophysiology of subsequent infections, affecting host susceptibility and disease outcome. In bladders of previously infected versus non-infected, antibiotic-treated mice, we found (1) an altered transcriptome and defects in cell maturation, (2) a remodelled epithelium that confers resistance to intracellular bacterial colonization, and (3) changes to cyclooxygenase-2-dependent inflammation. Furthermore, in mice with a history of chronic UTI, cyclooxygenase-2-dependent inflammation allowed a variety of clinical E. coli isolates to circumvent intracellular colonization resistance and cause severe recurrent UTI, which could be prevented by cyclooxygenase-2 inhibition or vaccination. This work provides mechanistic insight into how a history of infection can impact the risk for developing recurrent infection and has implications for the development of therapeutics for recurrent UTI.

Purpose: Radiotherapy-related dermatological toxicities over time have not been well quantified. We examined during and immediately following radiation therapy skin toxicities over time in a randomized study of mometasone furoate vs placebo during breast radiotherapy., Material and Methods: Patients with breast cancer undergoing radiotherapy to the breast or chest wall were randomized. Symptoms related to skin toxicity were addressed weekly using provider-reported Common Terminology Criteria for Adverse Events (CTCAE v3.0) and 4 patient-reported outcomes (PRO) surveys. We applied repeated measures and risk analysis methodologies., Results: One hundred seventy-six patients were enrolled. By CTCAE, significant differences favoring mometasone were detected over time in all toxicities except skin striae, atrophy, and infection. Statistically significant differences between arms at baseline but not over time occurred for all Linear Analog Self-Assessment. Statistically significant differences occurred for all symptoms in the temporal profile of symptoms as measured by PRO surveys (all P < .001)., Conclusions: The use of longitudinal methods enhanced the ability of PRO tools to detect differences between study arms. Our results strengthened the conclusions of the original report that mometasone reduced acute skin toxicities. PRO surveys can accurately assess patients' experiences of symptom type and intensity over time and should be included in future clinical trials. For radiotherapy-related dermatological toxicity, we hypothesized that clinically significant differences over time, if any, can be found by repeated measures. We examined the acute skin toxicities in a randomized study of mometasone vs placebo during breast radiotherapy. For secondary end points, we showed that longitudinal methods enhanced the detection of differences between study arms and strengthened the conclusions from the original report. Frequent patient-reported outcome surveys over time should be included in future clinical trials.

Objective: To examine concordance of accelerometer-based actigraphy (ACG) with polysomnography (PSG) in the determination of sleep states in inpatients with traumatic brain injury (TBI), and examine the impact of injury severity and comorbid conditions (spasticity, apnea) on concordance., Participants: This was a convenience sample of 50 participants with primarily severe TBI., Design: This was a retrospective chart review of concurrent administration of PSG with ACG in nonconsecutive rehabilitation admissions with TBI., Main Measures: Total sleep time and sleep efficiency were measured by PSG and ACG., Results: Moderate to strong correlations between ACG and PSG were observed for total sleep time (r = 0.78, P < .01) and sleep efficiency (r = 0.66, P < .01). PSG and ACG estimates of total sleep time (316 minutes vs 325 minutes, respectively) and sleep efficiency (78% vs 77%, respectively) were statistically indistinguishable., Conclusions: Actigraphy is a valid proxy for monitoring of sleep in this population across injury severity and common comorbidity groups. However, further research with larger sample sizes to examine concordance in patients with TBI with disorder of consciousness and spasticity is recommended.

Objective: To prospectively examine the incidence and risk factors for sleep apnea in consecutive brain injury rehabilitation admissions., Setting: Inpatient neurorehabilitation hospital., Participants: Participants (n = 86) were consecutive neurorehabilitation admissions., Design: Retrospective analysis of prospectively collected data., Main Measures: Polysomnography., Results: Half (49%) of the sample was diagnosed with sleep apnea. For the full sample, univariate logistic regression revealed age (odds ratio: 1.08; 95% confidence interval: 1.04-1.11) and hypertension (odds ratio: 7.77; 95% confidence interval: 2.81-21.47) as significant predictors of sleep apnea diagnosis. Results of logistic regression conducted within the traumatic brain injury group revealed age (odds ratio: 1.07; 95% confidence interval: 1.02-1.13) as the only significant predictor of apnea diagnosis after adjustment for other variables. Hierarchical generalized linear regression models for the prediction of apnea severity (ie, apnea-hypopnea index found that Functional Independence Measure Cognition Score (P = .01) and age (P < .01) were significant predictors. Following adjustment for all other terms, only age (P < .01) remained significant., Conclusion: Sleep apnea is prevalent in acute neurorehabilitation admissions and traditional risk profiles for sleep apnea may not effectively screen for the disorder. Given the progressive nature of obstructive sleep apnea and morbidity associated with even mild obstructive sleep apnea, early identification and intervention may address comorbidities influencing acute and long-term outcome.

It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their information directly to the output nuclei of the basal ganglia, whereas D2-expressing neurons do so indirectly via pallidal neurons. Combining optogenetics and electrophysiology, we found that this architecture does not apply to mouse nucleus accumbens projections to the ventral pallidum. Thus, current thinking attributing D1 and D2 selectivity to accumbens projections akin to dorsal striatal pathways needs to be reconsidered.