Enhanced efficacy of BCG vaccine formulated in adjuvant is dependent on IL-17A expression.

A new, more effective vaccine against tuberculosis (TB) is urgently needed to curtail the current TB problem. The only licensed vaccine, BCG, has been shown to have highly variable protective efficacy in several clinical trials ranging from zero to 80 % against TB disease. We have previously reported that BCG formulated in dimethyl dioctadecyl-ammonium bromide (DDA) with D-(+)-Trehalose 6,6'-Dibehenate (TDB) adjuvant (BCG + Adj) is significantly more protective than BCG alone following murine aerosol Mycobacterium tuberculosis infection. Here we investigate the immunological basis for this improved efficacy by examining expression of different immune markers and cytokines in the lungs of vaccinated mice after M. tuberculosis aerosol challenge. We found significantly greater numbers of pulmonary IL-17A-expressing CD4+ T cells in mice immunized with BCG+Adj as compared to nonvaccinated and BCG-immunized mice at one-month post-challenge and that the enhanced protection was abrogated in IL-17A-deficient mice. Furthermore, we found significantly higher levels of IL-17A, IL-12p40 and IL-33 expression in the lungs of BCG + Adj immunized animals relative to nonvaccinated mice after M. tuberculosis challenge. These results demonstrate that the DDA/TDB adjuvant increases expression of IL-17A in response to the BCG vaccine and that these augmented IL-17A levels enhance control of M. tuberculosis infection.

Pharmacogenomic Characterization of Childbearing-Aged Individuals With Mood Disorders in a Tertiary Care Perinatal Mental Health Clinic.

Objective: The effectiveness of antidepressant treatment for mood disorders is often limited by either a poor response or the emergence of adverse effects. These complications often necessitate multiple drug trials. This clinical challenge intensifies during pregnancy, when medications must be selected to improve the likelihood of response and optimize reproductive outcomes. We determined the distribution of common pharmacogenetic variants, metabolizer phenotypes, past medication responses, and side effects in childbearing-aged individuals seeking treatment in a tertiary care perinatal mental health clinic.Methods: Sixty treatment-seeking women (based on sex at birth) with DSM-5- defined bipolar disorder (n = 28) or major depressive disorder (n = 32) provided DNA samples and completed psychiatric diagnostic and severity assessments between April 2014 and December 2017. Samples were genotyped for single-nucleotide variants in drug metabolizing enzyme genes of commonly prescribed antidepressants (cytochrome P450 [CYP] 1A2, 2B6, 2C9, 2C19, 2D6, 3A4, and 3A5), and the frequency of normative metabolizer status was compared to reference populations data from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. The Antidepressant Treatment History Form was used to record historic medication trials and side effects.Results: A significantly greater proportion of extensive metabolizers for CYP2B6 was observed in the study population when compared to CPIC population frequency databases in Caucasians (0.64 vs 0.43 [95% CI: 0.49-0.76]; P value = .006) and African Americans (0.71 vs 0.33 [95% CI: 0.29-0.96]; P value = .045). No significant association was found between metabolizer phenotype and the likelihood of a medication side effect.Conclusion: Pharmacogenomic testing may have value for personalized prescribing in individuals capable of or considering pregnancy.

Use of regional anesthesia within a pediatric interventional radiology suite reduced periprocedural opioid use without delaying the overall workflow: a retrospective study.

BACKGROUND: Nerve block utility has been extensively described in the operating room, however, there is a paucity of evidence regarding blocks in the interventional radiology (IR) suite, with no studies examining its safety and efficacy in children. METHODS: A retrospective study was conducted at a single tertiary-care children's hospital to evaluate the analgesic utility of nerve blocks during IR-performed sclerotherapy for bone cysts, venous malformations, and lymphatic malformations. Lymphatic and venous malformations were combined for final analysis. Patients between January 2016 and September 2022 had their medical records reviewed for procedural data, postprocedural pain scores, and analgesic administration data. RESULTS: 309 patients were included in the final analysis. Opioids were required significantly less frequently intraprocedurally and postprocedurally across subgroups. The proportion of patients who received opioids during their hospital course was significant between block and non-block patients, respectively: bone cyst: 62.7% vs 100% (p<0.001); venous and lymphatic malformation: 65.7% vs 97.4% (p<0.001). Average maximum postanesthesia care unit (PACU) pain scores were significantly lower in bone cyst patients with no significant difference seen in pain scores among venous and lymphatic malformation patients. There were no reported nerve block-related complications. DISCUSSION: Nerve blocks demonstrated an opioid-sparing effect intraprocedurally and postprocedurally for all subgroups. Their use among bone cyst patients was associated with significant reductions in average maximum PACU pain scores. Nerve blocks may constitute an effective opioid-sparing component of multimodal analgesia in pediatric patients undergoing IR sclerosis procedures. Prospective data are needed to establish the optimal utility of nerve blocks in the IR setting.

Concentrations of Fluoxetine Enantiomers Decline During Pregnancy and Increase After Birth.

RATIONALE: Few studies of the effect of the dynamic physiologic changes during pregnancy on plasma concentrations of fluoxetine (FLX) have been published. OBJECTIVES: We determined the change in concentration to dose (C/D) ratios of R- and S-FLX and R- and S-norfluoxetine monthly during pregnancy and postpartum, assessed their relationships to cytochrome P450 (CYP) 2D6 and CYP2C9 metabolizer phenotypes, and evaluated the course of their depressive and anxiety symptoms. METHODS: In this observational study, 10 FLX-treated pregnant individuals provided blood samples at steady state every 4 weeks during pregnancy and once postpartum for measurement of plasma FLX and norfluoxetine enantiomer concentrations. Participants were genotyped for variants in CYP2C9 and CYP2D6 using commercial assays with Taqman probes. At each assessment, depressive and anxiety symptoms were quantified. RESULTS: The C/D ratios of all FLX and norfluoxetine enantiomers, and the active moiety, decreased steadily through pregnancy and rose after birth. In the final trimester, the mean C/D ratio of the active moiety was 24.9% lower compared with the mean nonpregnant, 12-week postpartum C/D ratio. One individual with CYP2D6 ultrarapid metabolizer status was prescribed the highest FLX dose among participants. In these treated individuals, the mean depressive and anxiety symptoms remained in the mild range across the perinatal period. CONCLUSIONS: These data do not support a recommendation for routine plasma concentration monitoring or CYP2D6 pharmacogenetic testing for pregnant people treated with FLX; however, monitoring for symptom relapse is recommended because of declining plasma drug concentrations.

Bright Light Therapy for Major Depressive Disorder in Adolescent Outpatients: A Preliminary Study.

BACKGROUND: Bright light therapy (BLT) has not been well-studied in adolescents with major depressive disorder, particularly in outpatient settings. METHODS: We conducted an 8-week clinical trial of BLT in adolescents recruited from a primary care practice with moderate to severe major depression. Acceptability and feasibility were defined by daily use of the light box and integration into daily routines. To assess treatment effects, we utilized the Short Mood and Feelings Questionnaire (SMFQ) and actigraphic sleep variables. RESULTS: Of the nine enrolled adolescents, the rate of daily use of the light therapy box was 100% at week 2, 78% at week 4 (n = 7), and 67% at weeks 6 and 8 (n = 6). Participants were better able to integrate midday BLT compared to morning BLT into their day-to-day routines. Mean depression scores improved during the 2-week placebo lead-in (dim red light-DRL) and continued to show significant improvement through 6 weeks of BLT. Sleep efficiency increased significantly (p = 0.046), and sleep onset latency showed a trend toward a significant decrease (p = 0.075) in the BLT phase compared to the DRL phase. CONCLUSION: Bright light treatment that was self-administered at home was feasible, acceptable, and effective for adolescent outpatients with depression. Findings support the development of larger, well-powered, controlled clinical trials of BLT in coordination with primary care.

Factors Associated with Depressive and Anxiety Symptom Trajectories Across Pregnancy and Postpartum in Selective Serotonin Reuptake Inhibitor-Treated Individuals.

Objective: The primary purpose of this article is to identify factors that are associated with worsening mood and anxiety trajectories across the perinatal period among pregnant individuals receiving treatment with a selective-serotonin reupdate inhibitor. Methods: This secondary analysis of primary data from the original article, Trajectories of Depressive and Anxiety Symptoms Across Pregnancy and Postpartum in Selective Serotonin Reuptake Inhibitor-Treated Women, explores if number of lifetime episodes of depression as characterized in the Mini-International Neuropsychiatric Interview, elevated maternal adverse childhood experiences (ACE) score, or specific obstetric or neonatal factors from the Peripartum Events Scale (PES) were associated with membership in trajectory groups with the highest symptom burden. Results: No difference in ACE scores or obstetric or neonatal factors were associated with membership in the trajectory groups using Wilcoxon rank sum tests and bi-variable logistic regression. The trajectory group with the highest anxiety symptom burden experienced more lifetime episodes of depression compared to other groups (odds ratio = 1.17, 95% confidence intervals, 1.02-1.34, p = 0.03). Conclusions: Congruent with other studies, we found a high prevalence of co-occurring mood and anxiety symptoms and that past episodes of depression remain an important historical risk factor for perinatal symptom burden. This reinforces that past experiences of depression increase not only the risk of future symptoms but also higher symptom burden during antidepressant treatment.

Symptoms, viral loads, and rebound among COVID-19 outpatients treated with nirmatrelvir/ritonavir compared to propensity score matched untreated individuals.

BACKGROUND: Nirmatrelvir/ritonavir (N/R) reduces severe outcomes among patients with COVID-19; however, rebound after treatment has been reported. We compared symptom and viral dynamics in community-based individuals with COVID-19 who completed N/R and similar untreated individuals. METHODS: We identified symptomatic participants who tested SARS-CoV-2 positive and were N/R eligible from a COVID-19 household transmission study: index cases from ambulatory settings and their households were enrolled, collecting daily symptoms, medication use, and respiratory specimens for quantitative PCR for 10 days, March 2022-May 2023. Participants who completed N/R (treated) were propensity score matched to untreated participants. We compared symptom rebound, viral load (VL) rebound, average daily symptoms, and average daily VL by treatment status measured after N/R completion or, if untreated, seven days after symptom onset. RESULTS: Treated (n=130) and untreated participants (n=241) had similar baseline characteristics. After treatment completion, treated participants had greater occurrence of symptom rebound (32% vs 20%; p=0.009) and VL rebound (27% vs 7%; p<0.001). Average daily symptoms were lower among treated participants compared to untreated participants without symptom rebound (1.0 vs 1.6; p<0.01), but not statistically lower with symptom rebound (3.0 vs 3.4; p=0.5). Treated participants had lower average daily VLs without VL rebound (0.9 vs 2.6; p<0.01), but not statistically lower with VL rebound (4.8 vs 5.1; p=0.7). CONCLUSIONS: Individuals who completed N/R experienced fewer symptoms and lower VL but were more likely to have rebound compared to untreated individuals. Providers should still prescribe N/R, when indicated, and communicate possible increased rebound risk to patients.

Valve-sparing aortic root replacement: Long-term variables significantly associated with mortality and morbidity.

OBJECTIVES: In aortic root surgery, valve-sparing aortic root replacement is an attractive alternative by mitigating the risks inherent to prosthetic valves; however, little is known about the variables that impact its durability. We review our mid- to long-term outcomes after valve-sparing aortic root replacement and describe factors that impact survival and valve reintervention and insufficiency. METHODS: A retrospective review of 284 consecutive patients undergoing valve-sparing aortic root replacement between November 1999 and January 2022 at Austin Health, Melbourne, Australia, was undertaken, with a median follow-up of 6.43 ± 4.83 years, but up to 22.0 years. Freedom from mortality, aortic reintervention, and insufficiency was analyzed using Kaplan-Meier methods, Cox proportional hazard models, and Fine-Gray analysis. RESULTS: The median age of patients at intervention was 60.0 years (interquartile range, 48.0-67.0), of whom 68 (23.9%) had bicuspid aortic valve disease, 27 (9.5%) had Marfan syndrome, 119 (41.9%) had severe aortic root dilation (>50 mm), and 155 had (54.6%) severe aortic insufficiency at the time of intervention. The 30-day mortality was 1.8%, with freedom from mortality of 96.0% (95% CI, 92.6-97.8) at 5 years and 88.2% (95% CI, 81.4-92.6) at 10 years. Freedom from aortic reintervention was 92.2% (95% CI, 87.7-95.2) at 5 years and 79.8% (95% CI, 71.8-85.8) at 10 years. Factors associated with reintervention were concomitant leaflet repair (hazard ratio, 8.13, 95% CI, 1.07-61.7) and bicuspid valvulopathy (hazard ratio, 2.23, 95% CI, 1.07-4.68), with reintervention in the bicuspid aortic valve being more likely due to aortic stenosis and in the tricuspid aortic valve due to aortic insufficiency (chi-square P = .05). The freedom from aortic insufficiency was 89.1% (95% CI, 83.5-92.9), 84.9% (95% CI, 77.8-89.9) at 5 and 10 years, respectively, and 80.7% (95% CI, 71.0-87.4). CONCLUSIONS: Valve-sparing aortic root replacement has excellent long-term outcomes, with low mortality and reintervention rates. Concomitant leaflet repair and bicuspid valve disease are the only long-term factors associated with reintervention.

Intracranial Atherosclerosis Increases the Risk of Postoperative Stroke After Cardiac Surgery: A Review and Meta-Analysis.

BACKGROUND: Postoperative stroke is a devastating complication of cardiac surgery with high morbidity, mortality, and health care cost. Extracranial carotid atherosclerosis (ECAS) is a known risk factor for stroke; however, the impact of intracranial atherosclerosis (ICAS) remains unclear. To our knowledge, this is the first literature review of ICAS in cardiac surgery. We aimed to assess the prevalence, association with postoperative stroke, and perioperative management of ICAS in cardiac surgery. METHOD: A search was performed to identify studies reporting rates of ICAS and stroke after cardiac surgery. Data extraction and primary outcomes for meta-analysis included the prevalence of preoperative ICAS and the association between ICAS and stroke. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled by random-effects modelling. RESULTS: Seventeen studies were reviewed and seven were included in the meta-analysis, comprising 4,936 patients. Prevalence of intracranial atherosclerosis (ICAS) among cardiac surgery patients was 21% (95% CI 13%-32%). Patients with ICAS were more likely to develop postoperative stroke (RR 3.61; 95% CI 2.30-5.67; p<0.001). ICAS was more closely associated with stroke than ECAS. Preoperative brain perfusion single-photon emission computed tomography with acetazolamide challenge, staged intracerebral revascularisation, or conversion to off-pump coronary artery bypass grafting are described management options for ICAS. CONCLUSION: Patients with ICAS are 3.61 times more likely to develop stroke after cardiac surgery. Known predictors for ICAS can be used to develop risk stratification screening tools. Further research with diverse cohorts is required to develop evidence-based guidelines for screening and management of ICAS in cardiac surgery.

Left brachiocephalic venous thrombus initially presenting as acute aortic syndrome.

Upper extremity deep venous thrombosis (UEDVT) is rare but carries significant morbidity. Primary UEDVT presents non-specifically and there are no clear diagnostic or management guidelines, which are essential for early treatment to prevent potentially devastating complications such as pulmonary embolus or post-thrombotic pain syndrome. A patient with left brachiocephalic vein UEDVT initially diagnosed radiographically as an acute aortic syndrome and referred to a cardiothoracic unit is presented. Computed tomography venogram confirmed the diagnosis of UEDVT and therapeutic anticoagulation was started. This case highlights the need for validated diagnostic and management algorithms for UEDVT. Furthermore, this relatively rare condition should be considered for patients with acute chest pain and abnormal imaging referred to surgical units.

Use of the dTAG system in vivo to degrade CDK2 and CDK5 in adult mice and explore potential safety liabilities.

The degradation tag (dTAG) system for target protein degradation can remove proteins from biological systems without the drawbacks of some genetic methods, such as slow kinetics, lack of reversibility, low specificity, and the inability to titrate dosage. These drawbacks can make it difficult to compare toxicity resulting from genetic and pharmacological interventions, especially in vivo. Because the dTAG system has not been studied extensively in vivo, we explored the use of this system to study the physiological sequalae resulting from CDK2 or CDK5 degradation in adult mice. Mice with homozygous knock-in of the dTAG sequence onto CDK2 and CDK5 were born at Mendelian ratios despite decreased CDK2 or CDK5 protein levels in comparison with wild-type mice. In bone marrow cells and duodenum organoids derived from these mice, treatment with the dTAG degrader dTAG-13 resulted in rapid and robust protein degradation but caused no appreciable change in viability or the transcriptome. Repeated delivery of dTAG-13 in vivo for toxicity studies proved challenging; we explored multiple formulations in an effort to maximize degradation while minimizing formulation-related toxicity. Degradation of CDK2 or CDK5 in all organs except the brain, where dTAG-13 likely did not cross the blood brain barrier, only caused microscopic changes in the testis of CDK2dTAG mice. These findings were corroborated with conditional CDK2 knockout in adult mice. Our results suggest that the dTAG system can provide robust protein degradation in vivo and that loss of CDK2 or CDK5 in adult mice causes no previously unknown phenotypes.

Perioperative Outcomes of Patients with Bleeding Disorders Undergoing Major Surgery at an Academic Hemophilia Treatment Center.

Persons with bleeding disorders (PwBD) are at high risk for bleeding with invasive procedures. However, the risk of bleeding in PwBD undergoing major surgery and outcomes of patients managed perioperatively at a hemophilia treatment center (HTC) are not well described. We performed a retrospective review of surgical outcomes among PwBD undergoing major surgery between January 1st, 2017 and December 31st, 2019 at the Cardeza Foundation Hemophilia and Thrombosis Center in Philadelphia, PA. The primary outcome was postoperative bleeding, assessed according to the ISTH-SSC's 2010 definition. Secondary outcomes included use of unplanned postoperative hemostatic therapy, LOS, and 30-day readmission rate. Results were compared to non-PwBD population from a surgical database, matched for surgery, age, and sex. During the study period, 50 PwBD underwent 63 major surgeries. The most common diagnoses were VWD (64%) and hemophilia A (20.0%). The most common surgical procedure category was orthopedic (33.3%), predominantly arthroplasties. Postoperatively,4.8% of procedures were complicated by major bleeding and 1.6% by non-major bleeding. The mean LOS was 1.65 days, and 30-day readmission rate was 1.6%. In comparison to matched, non-PwBD patients in a national surgical database undergoing the same procedures, study patients had a similar rate of bleeding complications per procedure (5.0% vs 1.04% P = .071, Fisher's exact test). PwBD undergoing major surgeries have low rates of major bleeding when receiving comprehensive care at an HTC. Bleeding and hospital readmission rates were similar to non-PwBD baseline in a large database.

Temporal changes in the systemic concentrations of retinoids in pregnant and postpartum women.

Retinoids and vitamin A are essential for multiple biological functions, including vision and immune responses, as well as the development of an embryo during pregnancy. Despite its importance, alterations in retinoid homeostasis during normal human pregnancy are incompletely understood. We aimed to characterize the temporal changes in the systemic retinoid concentrations across pregnancy and postpartum period. Monthly blood samples were collected from twenty healthy pregnant women, and plasma concentrations of retinol, all-trans-retinoic acid (atRA), 13-cis-retinoic acid (13cisRA), and 4-oxo-retinoic acids were measured using liquid chromatography-tandem mass spectrometry. Significant decreases in 13cisRA concentrations over the pregnancy were observed, with rebound increases in retinol and 13cisRA levels after delivery. Of note, atRA concentrations exhibited a unique temporal pattern with levels peaking at mid-pregnancy. While the 4-oxo-atRA concentration was below the limit of quantification, 4-oxo-13cisRA was readily detectable, and its temporal change mimicked that of 13cisRA. The time profiles of atRA and 13cisRA remained similar after correction by albumin levels for plasma volume expansion adjustment. Together, the comprehensive profiling of systemic retinoid concentrations over the course of pregnancy provides insights into pregnancy-mediated changes in retinoid disposition to maintain its homeostasis.

Household Transmission of Influenza A Viruses in 2021-2022.

Importance: Influenza virus infections declined globally during the COVID-19 pandemic. Loss of natural immunity from lower rates of influenza infection and documented antigenic changes in circulating viruses may have resulted in increased susceptibility to influenza virus infection during the 2021-2022 influenza season. Objective: To compare the risk of influenza virus infection among household contacts of patients with influenza during the 2021-2022 influenza season with risk of influenza virus infection among household contacts during influenza seasons before the COVID-19 pandemic in the US. Design, Setting, and Participants: This prospective study of influenza transmission enrolled households in 2 states before the COVID-19 pandemic (2017-2020) and in 4 US states during the 2021-2022 influenza season. Primary cases were individuals with the earliest laboratory-confirmed influenza A(H3N2) virus infection in a household. Household contacts were people living with the primary cases who self-collected nasal swabs daily for influenza molecular testing and completed symptom diaries daily for 5 to 10 days after enrollment. Exposures: Household contacts living with a primary case. Main Outcomes and Measures: Relative risk of laboratory-confirmed influenza A(H3N2) virus infection in household contacts during the 2021-2022 season compared with prepandemic seasons. Risk estimates were adjusted for age, vaccination status, frequency of interaction with the primary case, and household density. Subgroup analyses by age, vaccination status, and frequency of interaction with the primary case were also conducted. Results: During the prepandemic seasons, 152 primary cases (median age, 13 years; 3.9% Black; 52.0% female) and 353 household contacts (median age, 33 years; 2.8% Black; 54.1% female) were included and during the 2021-2022 influenza season, 84 primary cases (median age, 10 years; 13.1% Black; 52.4% female) and 186 household contacts (median age, 28.5 years; 14.0% Black; 63.4% female) were included in the analysis. During the prepandemic influenza seasons, 20.1% (71/353) of household contacts were infected with influenza A(H3N2) viruses compared with 50.0% (93/186) of household contacts in 2021-2022. The adjusted relative risk of A(H3N2) virus infection in 2021-2022 was 2.31 (95% CI, 1.86-2.86) compared with prepandemic seasons. Conclusions and Relevance: Among cohorts in 5 US states, there was a significantly increased risk of household transmission of influenza A(H3N2) in 2021-2022 compared with prepandemic seasons. Additional research is needed to understand reasons for this association.

Clearing away barriers to oral drug delivery.

Ingestible devices have the potential to clear away barriers to oral delivery of biologics to improve drug bioavailability.

The biological dimensions of transcendent states: A randomized controlled trial.

This study evaluated the biological dimension of meditation and self-transcendent states. A convenience sample of 513 participants was drawn from attendees at a 4-day guided meditation workshop. Half were randomly assigned to an active placebo control intervention. All were assessed on a variety of measures, both psychological [anxiety, pain, posttraumatic stress disorder (PTSD), positive emotions, and transcendent states], and physiological (physical functioning). Additional biological assessments including salivary immunoglobulin-A (SIgA), cortisol, and Quantitative Electroencephalography (qEEG) were obtained from subset of the Experimental group (N = 117). No significant difference in psychological symptoms or positive emotions was observed between Experimental and placebo groups at baseline. At post-test, significant improvements were noted in the Experimental group, including a 49.5% median increase in SIgA (p = 0.01), though cortisol remained unchanged. qEEG z-score analysis identified sustained stress reduction, including delta frequency band amplitude increases, high beta decreases, and faster acquisition of sustained alpha states (all p < 0.001). Psychological symptoms also improved on all measures. At 6-month follow-up (N = 140), PTSD and somatic symptoms significantly improved from baseline, and post-test versus 6-month follow-up results indicated significant increases in happiness and spiritual and physical oneness, along with decreases in depressive symptoms. These findings suggest that autonomic self-regulation and transcendent states may be measured in both biological and psychological dimensions and are associated with pervasive health benefits.

Newborn screening for Fabry disease in Oregon: Approaching the iceberg of A143T and variants of uncertain significance.

Fabry disease newborn screening (NBS) has been ongoing in Oregon for over 41 months by first-tier enzyme quantitation and second-tier DNA testing. During that period the majority of abnormal referrals received (34/60) were for the presence of the controversial c.427G > A (p.Ala143Thr) aka A143T and the majority of non-A143T referrals were for other variants of uncertain significance (17/60) resulting in at least 32 infants with an inconclusive case outcome even after clinical evaluation and/or diagnostic testing. To date there has been no significant family history or onset of symptoms in individuals with an inconclusive outcome. Based on our experience, we have developed a framework for approaching A143T and other variants of uncertain clinical significance in an attempt to balance sensitivity with the unnecessary medicalization of healthy infants.

Computational modeling of corneal and scleral collagen photocrosslinking.

Scleral photocrosslinking is increasingly investigated for treatment of myopia and glaucoma. In this study a computational model was developed to predict crosslinking efficiency of visible/near infrared photosensitizers in the sclera. Photocrosslinking was validated against riboflavin corneal crosslinking experimental studies and subsequently modeled for the sensitizer, methylene blue, administered by retrobulbar injection to the posterior sclera and irradiated with a transpupillary light beam. Optimal ranges were determined for treatment parameters including light intensity, methylene blue concentration, injection volume, and inspired oxygen concentration. Additionally, sensitivity of crosslinking to various parameters was quantified. The most sensitive parameters were oxygen concentration in the injection solution, scleral thickness, and injection reservoir thickness (i.e., injection volume).

A comparison of symptoms of bipolar and unipolar depression in postpartum women.

BACKGROUND: Distinguishing postpartum women with bipolar from unipolar depression remains challenging, particularly in obstetrical and primary care settings. The post-birth period carries the highest lifetime risk for the onset or recurrence of Bipolar Disorder (BD). Characterization of differences between unipolar and bipolar depression symptom presentation and severity is critical to differentiate the two disorders. METHODS: We performed a secondary analysis of a study of 10,000 women screened by phone with the Edinburgh Postnatal Depression Scale at 4-6 weeks post-birth. Screen-positive mothers completed the Structured Clinical Interview for DSM-4 and those diagnosed with BD and unipolar Major Depressive Disorder (UD) were included. Depressive symptoms were assessed with the 29-item Structured Interview Guide for the Hamilton Rating Scale for Depression (SIGH-ADS). RESULTS: The sample consisted of 728 women with UD and 272 women with BD. Women with BD had significantly elevated levels of depression severity due to the higher scores on 8 of the 29 SIGH-ADS symptoms. Compared to UD, women with BD had significantly higher rates of comorbid anxiety disorders and were twice as likely to report sexual and/or physical abuse. LIMITATIONS: Only women who screened positive for depression were included in this analysis. Postpartum women with unstable living situations, who were hospitalized or did not respond to contact attempts did not contribute data. CONCLUSIONS: Severity of specific symptom constellations may be a useful guide for interviewing postpartum depressed women along with the presence of anxiety disorder comorbidity and physical and/or sexual abuse.

An allosteric inhibitor of bacterial Hsp70 chaperone potentiates antibiotics and mitigates resistance.

DnaK is the bacterial homolog of Hsp70, an ATP-dependent chaperone that helps cofactor proteins to catalyze nascent protein folding and salvage misfolded proteins. In the pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), DnaK and its cofactors are proposed antimycobacterial targets, yet few small-molecule inhibitors or probes exist for these families of proteins. Here, we describe the repurposing of a drug called telaprevir that is able to allosterically inhibit the ATPase activity of DnaK and to prevent chaperone function by mimicking peptide substrates. In mycobacterial cells, telaprevir disrupts DnaK- and cofactor-mediated cellular proteostasis, resulting in enhanced efficacy of aminoglycoside antibiotics and reduced resistance to the frontline TB drug rifampin. Hence, this work contributes to a small but growing collection of protein chaperone inhibitors, and it demonstrates that these molecules disrupt bacterial mechanisms of survival in the presence of different antibiotic classes.