A unified metric of human immune health.

Immunological health has been challenging to characterize but could be defined as the absence of immune pathology. While shared features of some immune diseases and the concept of immunologic resilience based on age-independent adaptation to antigenic stimulation have been developed, general metrics of immune health and its utility for assessing clinically healthy individuals remain ill defined. Here we integrated transcriptomics, serum protein, peripheral immune cell frequency and clinical data from 228 patients with 22 monogenic conditions impacting key immunological pathways together with 42 age- and sex-matched healthy controls. Despite the high penetrance of monogenic lesions, differences between individuals in diverse immune parameters tended to dominate over those attributable to disease conditions or medication use. Unsupervised or supervised machine learning independently identified a score that distinguished healthy participants from patients with monogenic diseases, thus suggesting a quantitative immune health metric (IHM). In ten independent datasets, the IHM discriminated healthy from polygenic autoimmune and inflammatory disease states, marked aging in clinically healthy individuals, tracked disease activities and treatment responses in both immunological and nonimmunological diseases, and predicted age-dependent antibody responses to immunizations with different vaccines. This discriminatory power goes beyond that of the classical inflammatory biomarkers C-reactive protein and interleukin-6. Thus, deviations from health in diverse conditions, including aging, have shared systemic immune consequences, and we provide a web platform for calculating the IHM for other datasets, which could empower precision medicine.

The Effect of Shift Timing on Cesarean Delivery Outcomes and Operative Noise Levels.

OBJECTIVE: Intraoperative noise exposure has been associated with an increased risk of complications, communication errors, and stress among surgical team members. This study evaluates intraoperative noise levels in cesarean deliveries during different shift times, for example, night shifts, day shifts, and hand-off times between shifts. STUDY DESIGN: This is a secondary analysis of a prospective observational study which measured volume in decibels, percentage of time above safe levels (>60 dB), startle noise events (events with rapid increase of decibel level above baseline noise), and peak levels (>75 dB) for cesarean deliveries during a 3-month preintervention and postintervention study. This secondary analysis of noise data evaluated whether there were differences in noise for cases occurring during day shifts (6:31 a.m.-4:59 p.m.), night shifts (6:01 p.m.-5:29 a.m.), and hand-off times (5:30 a.m.-6:30 a.m. and 5:00 p.m.-6:00 p.m.). Correlates and postoperative complications during the respective shifts were additionally analyzed. RESULTS: Noise data were collected for a total of 312 cesarean deliveries; 203 occurred during the day shift, 94 during the night shift, and 15 during hand-off times. Median noise in decibels, median noise at various key intraoperative points, number of startle events, percentage of time above 60 dB, and above 75 dB had no significant differences throughout the various shift times. Significantly larger numbers of postpartum hemorrhages, unscheduled, urgent, and STAT cesarean deliveries occurred at hand-off times and on night shifts. CONCLUSION: Noise levels during cesarean deliveries did not significantly vary when comparing night shifts, day shifts, and hand-off times, despite significantly higher numbers of urgent and STAT cases occurring overnight and during hand-off times. However, more than 60% of case time had noise levels exceeding those considered safe. This suggests that ambient background noise may be contributing more to overall noise levels rather than the specific clinical scenario at hand. KEY POINTS: · Noise in cesarean delivery operating rooms frequently exceeded recommended levels.. · Noise in cesarean delivery operating rooms did not vary with shift type.. · Hand-off times had higher rates of urgent and STAT cesareans.. · Night shifts had higher rates of urgent and STAT cesareans..

Anti-Candida activity and in vitro toxicity screening of antifungals complexed with ß-cyclodextrin.

The emergence of resistant fungal species and the toxicity of currently available antifungal drugs are relevant issues that require special consideration. Cyclodextrins inclusion complexes could optimize the antimicrobial activity of such drugs and create a controlled release system with few side effects. This study aimed to assess the in vitro toxicity and antifungal effectiveness of nystatin (Nys) and chlorhexidine (Chx) complexed or not with ß-cyclodextrin (ßCD). First, a drug toxicity screening was performed through the Artemia salina bioassay. Then, the minimum inhibitory concentrations (MICs) against Candida albicans were determined with the broth microdilution test. After MICs determination, the cytotoxicity of the drugs was evaluated through the methyl-thiazolyl-tetrazolium (MTT) and neutral red (NR) assays and through cell morphology analysis. The PROBIT analysis was used to determine the median lethal concentration (LC50), and the cell viability values were submitted to one-way analysis of variance(ANOVA)/Tukey (α = 0.05). Overall, the ßCD-complexed antifungals were less toxic against A. salina than their raw forms, suggesting that inclusion complexes can reduce the toxicity of drugs. The MICs obtained were as follows: Nys 0.5 mg/L; Nys:ßCD 4 mg/L; Chx 4 mg/L; and Chx:ßCD 8 mg/L. Chx showed significant cytotoxicity (MTT: 12.9 ± 9.6%; NR: 10.6 ± 12.5%) and promoted important morphological changes. Cells exposed to the other drugs showed viability above 70% with no cellular damage. These results suggest that antifungals complexed with ßCD might be a biocompatible option for the treatment of Candida-related infections.

Characterization and antifungal activity of chlorhexidine:ß-cyclodextrin inclusion complexes.

Aim: This study aimed to develop, characterize and analyze the antifungal activity of chlorhexidine:ß-cyclodextrin inclusion complexes (Chx:ßCD). Materials & methods: Chx:ßCD were characterized by physicochemical techniques and the susceptibility of nine Candida strains was assessed. The inhibition of Candida albicans biofilm growth was evaluated in a denture material modified with the incorporation of Chx:ßCD. Results: Chx was better complexed in 1:2 molar ratio by freeze-drying. Chx:ßCD presented antifungal activity against all Candida strains. When incorporated into the denture material, Chx:ßCD showed better antifungal activity, as it required about 7.5% of Chx concentration compared with the raw Chx for 14 days. Conclusion: The improved characteristics of Chx:ßCD can result in new formulations to treat oral candidiasis and denture stomatitis.

Many people who wear dentures can get a fungal infection called denture stomatitis. Treating this infection is hard because it often comes back. There are many reasons why it can come back, like not following instructions, taking the wrong amount of medicine or having a bad reaction to the drugs. Using old and poorly fitting dentures and the difficulty to maintain the medicine in the right place can also make it harder to get better. One idea to make treatment easier is to add stronger drugs with fewer side effects to the material used to make dentures. That way, patients would only need to wear dentures with the right amount of medicine for a certain time to treat the infection.

Multiomics integration of 22 immune-mediated monogenic diseases reveals an emergent axis of human immune health.

Monogenic diseases are often studied in isolation due to their rarity. Here we utilize multiomics to assess 22 monogenic immune-mediated conditions with age- and sex-matched healthy controls. Despite clearly detectable disease-specific and "pan-disease" signatures, individuals possess stable personal immune states over time. Temporally stable differences among subjects tend to dominate over differences attributable to disease conditions or medication use. Unsupervised principal variation analysis of personal immune states and machine learning classification distinguishing between healthy controls and patients converge to a metric of immune health (IHM). The IHM discriminates healthy from multiple polygenic autoimmune and inflammatory disease states in independent cohorts, marks healthy aging, and is a pre-vaccination predictor of antibody responses to influenza vaccination in the elderly. We identified easy-to-measure circulating protein biomarker surrogates of the IHM that capture immune health variations beyond age. Our work provides a conceptual framework and biomarkers for defining and measuring human immune health.

Noise in cesarean deliveries: a comprehensive analysis of noise environments in the Labor and Delivery operating room and evaluation of a visual alarm noise abatement program.

BACKGROUND: Cesarean delivery is the most common major surgery worldwide. Noise in healthcare settings leads to impaired communication and concentration, and stress among healthcare providers. Limited information is available about noise at cesarean delivery. OBJECTIVE: This study aimed to achieve a comprehensive analysis of noise that occurs during cesarean deliveries. Sound level meters are used to determine baseline noise levels and to describe the frequency of acute noise generated during a cesarean delivery that will cause a human startle response. Secondarily, we aimed to evaluate the effectiveness of a visual alarm system in mitigating excessive noise. STUDY DESIGN: We completed a preintervention/postintervention observational study of noise levels during cesarean deliveries before and after introduction of a visual alarm system for noise mitigation between February 15, 2021 and August 26, 2021. There were 156 cases included from each study period. Sound pressure levels were analyzed by overall case median decibel levels and by time epoch for relevant phases of the operation. Rapid increases in noise events capable of causing a human startle response, "startle events," were detected by retrospective analysis, with quantification for baselines and analysis of frequency by case type. Median noise levels with interquartile ranges are presented. Data are compared between epochs and case characteristics with nonparametric 2-tailed testing. RESULTS: The median acoustic pressure for all cesarean deliveries was 61.8 (58.8-65.9) (median [interquartile range]) dBA (A-weighted decibels). The median dBA for the full case time period was significantly higher in cases with neonatal intensive care unit team presence (62.1 [60.5-63.9]), admission to the neonatal intensive care unit (62.0 [60.4-63.9]), 5-minute Apgar score <7 (62.2 [61.1-64.3]), multiple gestations (62.6 [62.0-64.2]), and intraoperative tubal sterilization (62.8 [61.5-65.1]). The use of visual alarms was associated with a statistically significant reduction of median noise level by 0.7 dBA, from 61.8 (60.6-63.5) to 61.1 (59.8-63.7) dBA (P<.001). CONCLUSION: The noise intensities recorded during cesarean deliveries were commonly at levels that affect communication and concentration, and above the safe levels recommended by the World Health Organization. Although noise was reduced by 0.7 dBA, the reduction was not clinically significant in reaching a discernible amount (a 3-dB change) or in reducing "startle events." Isolated use of visual alarms during cesarean deliveries is unlikely to be a satisfactory noise mitigation strategy.

Comparative Diagnostic Performance of Estimated Fetal Weight and Isolated Abdominal Circumference for the Detection of Fetal Growth Restriction.

OBJECTIVES: To describe the comparative incidence, detection of small-for-gestational age (SGA), and composite perinatal morbidity (CPM) associated with diagnostic criteria of fetal growth restriction (FGR) by estimated fetal weight (EFW) <10% with those with isolated abdominal circumference (AC) measurements <10%. METHODS: We performed a retrospective cohort study of 1587 patients receiving prenatal care and delivery at our institution. We included all patients with ultrasounds and delivery outcomes available, and excluded terminations, second trimester losses, and pregnancies without ultrasounds. EFW was calculated from Hadlock and use of the Duryea centiles, and AC from Hadlock's reference curves. We determined SGA at birth and defined CPM as birthweight less than 3% or birthweight less than 10% with neonatal morbidity. RESULTS: Of 1587 patients, 28 (1.8%) were classified as FGR by EFW <10%. Three of 12 patients with isolated AC <10% developed EFW <10% later in pregnancy (25%). The performance of each diagnostic criteria were comparable for the outcomes of SGA and CPM, with similar sensitivities, but with decreased specificity for SGA outcome, and an increased false positive rate for patients classified as FGR by isolated AC <10, with a tradeoff of decreased false negatives. CONCLUSIONS: Broadening the diagnosis of FGR to include patients with isolated AC <10 did not significantly increase the detection of pregnancies at risk for SGA or CPM. Our conclusions may be limited by a lack of statistical power given a low frequency of SGA and CPM.

Characterization, Antifungal Evaluation against Candida spp. Strains and Application of Nystatin: ß-cyclodextrin Inclusion Complexes.

BACKGROUND: Nystatin (Nys) is a fungicidal drug commonly prescribed for candidiasis disease in several administration routes. However, Nys is a class IV drug, according to the Biopharmaceutical Classification System, that possesses limited bioavailability and is used for local activity. OBJECTIVE: This study developed and characterized nystatin:ß-cyclodextrin (Nys:ßCD) inclusion complexes and evaluated their activity against Candida spp. METHODS: Complexes were characterized by physicochemical techniques and drug dissolution profiles. The susceptibility of C. albicans, C. krusei, C. parapsilosis, C. glabrata, C. guilliermondii, C. tropicalis, and C. auris was assessed using the broth microdilution method. The applicability of Nys:ßCD inclusion complex was evaluated by incorporating it into a temporary soft material for denture stomatitis treatment. RESULTS: Nys was better complexed in a 1:1 molar ratio by freeze-drying and spray-drying methods. The inclusion complexes show bi-exponential release, an initial burst release followed by a sustained manner, presenting higher dissolution efficiency than raw Nys. The 1:1 freeze-drying Nys:ßCD complex presents antifungal activity against all evaluated Candida strains, showing the maintenance of the drug effectiveness. The inclusion complex incorporated into a tissue conditioner material for denture stomatitis treatment effectively inhibited more than 90% of C. albicans biofilm growth during 7 and 14 days, in a half dose compared to raw Nys. CONCLUSION: This work represents a significant contribution to treating a wide variety of diseases caused by the Candida species, optimizing the drug bioavailability and compliance to the treatment due to improved drug solubility, dissolution, and sustained delivery.

Efficacy of Cochleated Amphotericin B in Mouse and Human Mucocutaneous Candidiasis.

Candida albicans causes debilitating, often azole-resistant, infections in patients with chronic mucocutaneous candidiasis (CMC). Amphotericin B (AMB) resistance is rare, but AMB use is limited by parenteral administration and nephrotoxicity. In this study, we evaluated cochleated AMB (CAMB), a new oral AMB formulation, in mouse models of oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC) and in patients with azole-resistant CMC. OPC and VVC were modeled in Act1-/- mice, and mucosal tissue fungal burden was assessed after once-daily treatment with CAMB, vehicle, or AMB-deoxycholate (AMB-d). Four patients with azole-resistant CMC enrolled in a phase 2 CAMB dose-escalation study. The primary endpoint was clinical improvement at 2 weeks followed by optional extension for long-term CMC suppression to assess safety and efficacy. CAMB-treated mice had significantly reduced tongue and vaginal fungal burdens compared to vehicle-treated mice and exhibited comparable fungal burden reduction relative to AMB-d-treated mice. All CAMB-treated patients reached clinical efficacy by 2 weeks, three at 400 mg twice daily and one at 200 mg twice-daily dosing. All patients continued to the extension phase, with three having sustained clinical improvement of OPC and esophageal candidiasis (EC) for up to 60 months. One patient had a relapse of esophageal symptoms at week 24 and was withdrawn from further study. Clinical responses were not seen for onychomycosis or VVC. CAMB was safe and well-tolerated, without any evidence of nephrotoxicity. In summary, oral CAMB reduced tongue and vaginal fungal burdens during murine candidiasis. A proof-of-concept clinical trial in human CMC showed efficacy with good tolerability and safety. This study has been registered at ClinicalTrials.gov under identifier NCT02629419.

Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity.

BACKGROUND: SARS-CoV-2 vaccination is recommended in patients with inborn errors of immunity (IEIs); however, little is known about immunogenicity and safety in these patients. OBJECTIVE: We sought to evaluate the impact of genetic diagnosis, age, and treatment on antibody response to COVID-19 vaccine and related adverse events in a cohort of patients with IEIs. METHODS: Plasma was collected from 22 health care worker controls, 81 patients with IEIs, and 2 patients with thymoma; the plasma was collected before immunization, 1 to 6 days before the second dose of mRNA vaccine, and at a median of 30 days after completion of the immunization schedule with either mRNA vaccine or a single dose of Johnson & Johnson's Janssen vaccine. Anti-spike (anti-S) and anti-nucleocapsid antibody titers were measured by using a luciferase immunoprecipitation systems method. Information on T- and B-cell counts and use of immunosuppressive drugs was extracted from medical records, and information on vaccine-associated adverse events was collected after each dose. RESULTS: Anti-S antibodies were detected in 27 of 46 patients (58.7%) after 1 dose of mRNA vaccine and in 63 of 74 fully immunized patients (85.1%). A lower rate of seroconversion (7 of 11 [63.6%]) was observed in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Previous use of rituximab and baseline counts of less than 1000 CD3+ T cells/mL and less than 100 CD19+ B cells/mL were associated with lower anti-S IgG levels. No significant adverse events were reported. CONCLUSION: Vaccinating patients with IEIs is safe, but immunogenicity is affected by certain therapies and gene defects. These data may guide the counseling of patients with IEIs regarding prevention of SARS-CoV-2 infection and the need for subsequent boosts.

An Unusual Pattern of Premature Cervical Spine Degeneration in STAT3-LOF.

Loss of function mutations in STAT3 (STAT3-LOF; autosomal dominant hyper-IgE (Job's) syndrome) are associated with a variety of musculoskeletal manifestations, including scoliosis, osteoporosis, and minimal trauma fractures. This retrospective magnetic resonance (MR) imaging study sought to characterize an unusual pattern of cervical spine degeneration among a cohort of STAT3-LOF patients. Cervical spine MR images of the STAT3-LOF cohort (n = 38) were assessed for a variety of degenerative changes and compared to age-matched groups of controls (n = 42) without known immune or musculoskeletal abnormalities. A unique pattern of premature cervical spine degeneration was identified among the STAT3-LOF cohort which included straightening and eventual reversal of the normal cervical lordosis, mainly due to multi-level spondylolisthesis, as well as early development of spinal canal narrowing, cord compression, and myelomalacia. Cervical spine degeneration in the STAT3-LOF cohort was significantly worse than controls in both the 30-45 and 45 + age groups. Moderate to severe degenerative changes were present after age 30, and markedly worsened over time in several cases. Bone mineral density (BMD) had a moderate negative correlation with cervical degeneration severity and a strong negative correlation with age among STAT3-LOF participants. Cervical degeneration in STAT3-LOF appears to be progressive and could result in cord compromise if left unaddressed. Focused history and physical examination for signs of neurologic compromise as well as periodic MR imaging are thus recommended for the evaluation of premature cervical spine degeneration in STAT3-LOF patients after age 30 so that timely surgical interventions may be considered to prevent spinal cord damage and permanent neurological deficits.

Cognition and Other Predictors of Functional Disability Among Veterans With Mild Traumatic Brain Injury and Posttraumatic Stress Disorder.

BACKGROUND: Limitations in everyday functioning are frequently reported by veterans with a history of mild traumatic brain injury (mTBI) and/or posttraumatic stress disorder (PTSD). Multiple factors are associated with functional disability among veterans, including depression, poor social support, cognition, and substance use. However, the degree to which these factors, particularly cognitive capacities, contribute to functional limitations remains unclear. METHODS: We evaluated performance on tests of processing speed, executive functioning, attention, and memory as predictors of functioning on the World Health Organization Disability Assessment Scale (WHODAS) 2.0 in 288 veterans. Participants were placed in one of the following groups: PTSD-only, mTBI-only, mTBI + PTSD, and neither PTSD nor mTBI (deployed control group). Cognitive test performances were evaluated as predictors of WHODAS 2.0 functional ratings in regression models that included demographic variables and a range of mood, behavioral health, and postconcussive symptom ratings. RESULTS: Multiple cognitive test performances predicted WHODAS 2.0 scores in the deployed control group, but they generally did not predict functioning in the clinical groups when accounting for demographics, mood, behavioral health, and postconcussive symptoms. CONCLUSIONS: In veterans with mTBI and/or PTSD, cognitive test performances are less associated with everyday functioning than mood and postconcussive symptoms.