Rapid Generation of Somatic Mouse Mosaics with Locus-Specific, Stably Integrated Transgenic Elements.

In situ transgenesis methods such as viruses and electroporation can rapidly create somatic transgenic mice but lack control over copy number, zygosity, and locus specificity. Here we establish mosaic analysis by dual recombinase-mediated cassette exchange (MADR), which permits stable labeling of mutant cells expressing transgenic elements from precisely defined chromosomal loci. We provide a toolkit of MADR elements for combination labeling, inducible and reversible transgene manipulation, VCre recombinase expression, and transgenesis of human cells. Further, we demonstrate the versatility of MADR by creating glioma models with mixed reporter-identified zygosity or with "personalized" driver mutations from pediatric glioma. MADR is extensible to thousands of existing mouse lines, providing a flexible platform to democratize the generation of somatic mosaic mice. VIDEO ABSTRACT.

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.

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.

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.

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.

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.

Nonredundant functions of Mycobacterium tuberculosis chaperones promote survival under stress.

Bacterial chaperones ClpB and DnaK, homologs of the respective eukaryotic heat shock proteins Hsp104 and Hsp70, are essential in the reactivation of toxic protein aggregates that occur during translation or periods of stress. In the pathogen Mycobacterium tuberculosis (Mtb), the protective effect of chaperones extends to survival in the presence of host stresses, such as protein-damaging oxidants. However, we lack a full understanding of the interplay of Hsps and other stress response genes in mycobacteria. Here, we employ genome-wide transposon mutagenesis to identify the genes that support clpB function in Mtb. In addition to validating the role of ClpB in Mtb's response to oxidants, we show that HtpG, a homolog of Hsp90, plays a distinct role from ClpB in the proteotoxic stress response. While loss of neither clpB nor htpG is lethal to the cell, loss of both through genetic depletion or small molecule inhibition impairs recovery after exposure to host-like stresses, especially reactive nitrogen species. Moreover, defects in cells lacking clpB can be complemented by overexpression of other chaperones, demonstrating that Mtb's stress response network depends upon finely tuned chaperone expression levels. These results suggest that inhibition of multiple chaperones could work in concert with host immunity to disable Mtb.

The landscape of chimeric RNAs in non-diseased tissues and cells.

Chimeric RNAs and their encoded proteins have been traditionally viewed as unique features of neoplasia, and have been used as biomarkers and therapeutic targets for multiple cancers. Recent studies have demonstrated that chimeric RNAs also exist in non-cancerous cells and tissues, although large-scale, genome-wide studies of chimeric RNAs in non-diseased tissues have been scarce. Here, we explored the landscape of chimeric RNAs in 9495 non-diseased human tissue samples of 53 different tissues from the GTEx project. Further, we established means for classifying chimeric RNAs, and observed enrichment for particular classifications as more stringent filters are applied. We experimentally validated a subset of chimeric RNAs from each classification and demonstrated functional relevance of two chimeric RNAs in non-cancerous cells. Importantly, our list of chimeric RNAs in non-diseased tissues overlaps with some entries in several cancer fusion databases, raising concerns for some annotations. The data from this study provides a large repository of chimeric RNAs present in non-diseased tissues, which can be used as a control dataset to facilitate the identification of true cancer-specific chimeras.

Clinical factors associated with acute exacerbations of chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is complicated by frequent acute exacerbations leading to significant health care burden and impaired quality of life. OBJECTIVE: The objective of this study was to identify clinical factors associated with frequent acute exacerbation of CRS (AECRS). METHODS: This is a retrospective cohort study of patients with CRS from January 1, 2014, to May 31, 2016. Frequent AECRS was defined as at least 4 episodes over a 12-month period in which an antibiotic was prescribed for worsening sinus symptoms, and infrequent AECRS was defined as 0 to 3 episodes. Clinical factors, including asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, and autoimmune disease, were evaluated for associations between the 2 groups. RESULTS: Of the 3109 patients with CRS who were identified, 600 (19.3%) were classified as having frequent exacerbation. Asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, and autoimmune disease were associated with frequent AECRS with statistically significant adjusted odds ratios (aORs) after controlling for age, race, and sex in multivariate analysis (asthma aOR = 2.61 [95% CI = 2.14-3.18]; allergic rhinitis aOR = 1.96 [95% CI = 1.58-2.42]; eosinophil count of at least 150 cells per microliter aOR = 1.54 [95% CI = 1.21-1.97]; and autoimmune disease aOR = 1.68 [95% CI = 1.36-2.07]). Antibody deficiency, antibiotic allergy, lower FEV1, radiographic sinus disease severity, nasal polyposis, and systemic corticosteroid use were also associated with frequent AECRS. CONCLUSION: Patients with frequent episodes of AECRS were characterized by a higher prevalence of asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, autoimmune disease, and other allergic and immunologic diseases. These findings identify a high-risk phenotype of patients with CRS for preventive interventions to reduce exacerbation frequency.

De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.

PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

Introduction of an interprofessional gynaecology surgical skills workshop for undergraduate medical and nursing students.

BACKGROUND: Medical and nursing students may feel under-prepared to perform basic surgical and gynaecology procedural skills. There also remains scope within undergraduate programs to integrate interprofessional education, and better prepare students for interprofessional collaboration to improve patient care. AIMS: A simulation-based gynaecology surgical skills workshop program was introduced for undergraduate medical and nursing students. The aim of this study was to explore students' perceptions of a simulation-based interprofessional gynaecological skills program, using students' pre- and post-workshop confidence in taught skills reported in a post-workshop questionnaire as an outcome measure. MATERIALS AND METHODS: One hundred and sixty undergraduate medical (n = 133) and nursing (n = 27) students attended the workshop program at a tertiary university in Melbourne, Australia. A survey was completed by all students immediately after the workshop, addressing students' perceptions of surgical education, the four skill-stations (gowning/gloving, suturing, intrauterine device insertion, and urethral catheterisation), and interprofessional education. A Wilcoxon signed-rank test was performed to compare students' pre- and post-workshop confidence scores. RESULTS: Most medical and nursing students (86%) agreed their course should provide more structured surgical education. There was a statistically significant increase in post-workshop self-reported confidence scores for medical and nursing students in all four taught skills. Confidence in interprofessional behaviours also improved in both cohorts, but the improvement in nursing students did not reach statistical significance. CONCLUSIONS: Simulation-based, interprofessional, gynaecological surgery skills workshops are practical and valuable additions to undergraduate medical and nursing curricula. Further research should explore long-term retention of procedural skills and changes in interprofessional attitudes in clinical practice.

Parainfluenza Virus in Hospitalized Adults: A 7-Year Retrospective Study.

Background: Parainfluenza virus (PIV) is a cause of respiratory tract infection in children and the immunocompromised population, but its clinical manifestations, impact, and outcomes in hospitalized adults are not well studied. Methods: This retrospective study included adults (≥18 years old) admitted to Northwestern Memorial Hospital or Prentice Women's Hospital (both in Chicago, Illinois) between 1 August 2009 and 31 July 2016 with a positive molecular test result for PIV. Epidemiologic, clinical, and outcomes data were collected from the enterprise data warehouse and patient electronic health records after institutional review board approval. Descriptive statistics were used to summarize the data. Results: A total of 550 adults with a positive molecular test for PIV were identified. Differences in seasonality, clinical presentation, and prevalence between the different PIV serotypes (PIV-1, PIV-2, and PIV-3) were identified. The most common signs/symptoms were cough (88%), productive sputum (55%), fever (63%), and dyspnea (49%). Of the patients administered antibiotics, 349 (79.6%) had no confirmed bacterial infection throughout their hospitalization. The average length of hospitalization was 7.7 days. Presence of bacterial coinfection (P = .01), fungal coinfection (P < .01), decreased body mass index (P = .03), and increased respiratory rate (P < .01) were associated with significant differences in mortality rates. Conclusions: PIV infection is associated with substantial morbidity in hospitalized adults. Such data will be useful in understanding the impact on epidemiology and outcomes if a PIV-specific vaccine becomes available. Furthermore, this highlights the need for novel preventive and therapeutic approaches to PIV infection.

The New York pilot newborn screening program for lysosomal storage diseases: Report of the First 65,000 Infants.

PURPOSE: We conducted a consented pilot newborn screening (NBS) for Pompe, Gaucher, Niemann-Pick A/B, Fabry, and MPS 1 to assess the suitability of these lysosomal storage disorders (LSDs) for public health mandated screening. METHODS: At five participating high-birth rate, ethnically diverse New York City hospitals, recruiters discussed the study with postpartum parents and documented verbal consent. Screening on consented samples was performed using multiplexed tandem mass spectrometry. Screen-positive infants underwent confirmatory enzymology, DNA testing, and biomarker quantitation when available. Affected infants are being followed for clinical management and long-term outcome. RESULTS: Over 4 years, 65,605 infants participated, representing an overall consent rate of 73%. Sixty-nine infants were screen-positive. Twenty-three were confirmed true positives, all of whom were predicted to have late-onset phenotypes. Six of the 69 currently have undetermined disease status. CONCLUSION: Our results suggest that NBS for LSDs is much more likely to detect individuals at risk for late-onset disease, similar to results from other NBS programs. This work has demonstrated the feasibility of using a novel consented pilot NBS study design that can be modified to include other disorders under consideration for public health implementation as a means to gather critical evidence for evidence-based NBS practices.

Atrial fibrillation is highly prevalent yet undertreated in patients with biopsy-proven nonalcoholic steatohepatitis.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular disease. Atrial fibrillation is a prominent risk marker for underlying cardiovascular disease with a prevalence of 2% in patients <65 years old. Atrial fibrillation prevalence in NASH is unknown. We sought to assess the prevalence and impact of atrial fibrillation on healthcare utilization in NASH. METHODS: Patients were identified from a tertiary care centre Electronic Database from 2002 to 2015. International Classification of Diseases 9 (ICD9) codes identified comorbidities and atrial fibrillation. Descriptive statistics were used to compare characteristics between patients with NASH with and without atrial fibrillation. RESULTS: Of 9108 patients with ICD9 diagnosis of NASH, 215 (2.3%, mean age 57 years, 32% male) had biopsy-proven NASH. Atrial fibrillation prevalence was 4.6%. Patients with NASH and atrial fibrillation had a higher prevalence of heart failure (54.5% vs 8.8%, P < 0.001) and cerebrovascular (27.3% vs 2.0%, P < 0.001) or vascular disease (54.5% vs 13.2%, P = 0.002), compared to NASH without atrial fibrillation. All patients with NASH and atrial fibrillation had a CHA2DS2VASc score ≥2 indicating high stroke risk and need for anticoagulation. Eight of 10 patients were eligible for anticoagulation and 5 of 8 (62.5%) received appropriate therapy. CONCLUSION: Atrial fibrillation prevalence is two-fold higher in patients with NASH compared to the general population. Patients with NASH have a high risk of stroke; however, many do not receive appropriate guideline-directed therapy. Future studies are needed to identify whether guideline-based management of atrial fibrillation in NASH reduces cardiovascular morbidity and mortality.

Plasma and cerebrospinal fluid inflammatory cytokines in perinatal depression.

BACKGROUND: While perinatal depression is one of the most common complications of pregnancy, there is an insufficient understanding of the mechanistic underpinnings of disease. While an association between peripheral inflammatory cytokines and major depressive disorder has been demonstrated, cytokines cannot freely cross the blood-brain barrier, and thus, they give little insight into alternations in brain function. Because the brain is in direct communication with the cerebrospinal fluid, assessment of inflammation in the cerebrospinal fluid may be more directly related to the biologic markers of affective change. OBJECTIVE: Our objectives were to examine the association between perinatal depression and inflammatory cytokines in plasma, the association between perinatal depression and inflammatory cytokines in cerebrospinal fluid, and the correlations between plasma and cerebrospinal fluid inflammatory cytokines. STUDY DESIGN: This was a prospective, observational study of women with a singleton gestation at term undergoing a scheduled cesarean delivery. Women were screened for depression and those with depressive symptomatology preferentially enrolled. The Mini-International Neuropsychiatric Interview was administered to confirm the clinical diagnosis of depression. Maternal plasma and cerebrospinal fluid were collected preoperatively and cytokines measured via flow cytometry. Bivariable and multivariable analyses were used to determine the association between each cytokine and perinatal depression. Correlations were measured between the cytokines in plasma and cerebrospinal fluid. RESULTS: Of the 117 women who met inclusion criteria, 76 (65%) screened positive for depression, 15 (20%) of whom met the clinical diagnostic criteria for depression. There were no significant associations between any of the plasma cytokines and perinatal depression in our sample. Conversely, in multivariable analyses, higher cerebrospinal fluid interleukin-1ß (adjusted odds ratio, 232.7, 95% confidence interval, 5.9-9148.5), interleukin-23 (adjusted odds ratio, 22.1, 95% confidence interval, 1.7-294.5), and interleukin-33 (adjusted odds ratio, 1.7, 95% confidence interval, 1.1-2.6) concentrations were significantly associated with increased odds of perinatal depression. The plasma and cerebrospinal fluid cytokine concentrations were not strongly correlated. CONCLUSION: Higher concentrations of cerebrospinal fluid cytokines were associated with perinatal depression. These cerebrospinal fluid cytokines were not strongly correlated with plasma cytokines, and accordingly, plasma cytokines were not significantly associated with perinatal depression. Central neuroinflammation, as opposed to peripheral inflammation, may represent a mechanistic pathway that contributes to perinatal depression.

Ideal vs. real: a systematic review on handling covariates in randomized controlled trials.

BACKGROUND: In theory, efficient design of randomized controlled trials (RCTs) involves randomization algorithms that control baseline variable imbalance efficiently, and corresponding analysis involves pre-specified adjustment for baseline covariates. This review sought to explore techniques for handling potentially influential baseline variables in both the design and analysis phase of RCTs. METHODS: We searched PubMed for articles indexed "randomized controlled trial", published in the NEJM, JAMA, BMJ, or Lancet for two time periods: 2009 and 2014 (before and after updated CONSORT guidelines). Upon screening (343), 298 articles underwent full review and data abstraction. RESULTS: Typical articles reported on superiority (86%), multicenter (92%), two-armed (79%) trials; 81% of trials involved covariates in the allocation and 84% presented adjusted analysis results. The majority reported a stratified block method (69%) of allocation, and of the trials reporting adjusted analyses, 91% were pre-specified. Trials published in 2014 were more likely to report adjusted analyses (87% vs. 79%, p = 0.0100) and more likely to pre-specify adjustment in analyses (95% vs. 85%, p = 0.0045). Studies initiated in later years (2010 or later) were less likely to use an adaptive method of randomization (p = 0.0066; 7% of those beginning in 2010 or later vs. 31% of those starting before 2000) but more likely to report a pre-specified adjusted analysis (p = 0.0029; 97% for those initiated in 2010 or later vs. 69% of those started before 2000). CONCLUSION: While optimal reporting procedures and pre-specification of adjusted analyses for RCTs tend to be progressively more prevalent over time, we see the opposite effect on reported use of covariate-adaptive randomization methods.

Four maternal characteristics determine the 12-month course of chronic severe postpartum depressive symptoms.

BACKGROUND: Postpartum depression is a heterogeneous disorder in phenotype and etiology. Characterizing the longitudinal course of depressive symptoms over the first year after birth and identifying variables that predict distinct symptom trajectories will expedite efficient mental health treatment planning. The purpose was to determine 12-month trajectories of postpartum depressive symptoms, identify characteristics that predict the trajectories, and provide a computational algorithm that predicts trajectory membership. METHODS: A prospective cohort of women delivering at an academic medical center (2006-2011) was recruited from an urban women's hospital in Pittsburgh, PA. Women with a postpartum depressive disorder (n = 507) participated and completed symptom severity assessments at 4-8 weeks (intake), 3 months, 6 months, and 12 months. Women were predominantly Caucasian (71.8%), married (53.3%), and college educated (38.7%). Clinician interviews of depressive symptom severity, medical and psychiatric history, assessment of function, obstetric experience, and infant status were conducted. RESULTS: Analyses resulted in identification of three distinct trajectories of depressive symptoms: (1) gradual remission (50.4%), (2) partial improvement (41.8%), and (3) chronic severe (7.8%). Key predictive characteristics of the chronic severe versus gradual remission and partial improvement trajectories included parity, education, and baseline global functioning and depression severity. We were able to predict trajectory membership with 72.8% accuracy from these characteristics. CONCLUSIONS: Four maternal characteristics predicted membership in the chronic severe versus gradual remission and partial improvement trajectories with 72.8% accuracy. The trajectory groups comprise clinically relevant subgroups with the potential for tailored treatments to reduce the disease burden of postpartum depression.

Obstetric patients' perspectives on functional magnetic neuroimaging research in pregnant women.

Magnetic resonance neuroimaging (MRI) studies of healthy pregnant women could identify key mechanisms of spontaneous health behavior changes observed in expectant mothers as novel intervention targets, but are currently unprecedented. As balancing potential benefits of research with unknown risks, including participant perceptions of risk, is foundational to ethical conduct, we surveyed a convenience obstetric sample to understand pregnant women's perspectives on this issue. Respondents were 76 pregnant women (modal age of 30-39 years; 64% multiparous) presenting for obstetric care from April to June 2016 at privately and publicly funded clinics at an urban academic medical center in the Midwestern USA. Following a written description about functional magnetic resonance neuroimaging (fMRI) and its known and unknown risks, women were queried on their willingness to participate in a hypothetical study involving fMRI during pregnancy, and specific concerns about doing so, if hesitant or unwilling. Willingness to participate was "yes" (28.4%, n = 21), "maybe" (28.4%, n = 21), and "no" (43.2%, n = 32). Among those responding "maybe" or "no" (n = 53, 73.6%), 11 women (20.7%) articulated concern about the fetus. Other concerns expressed were time commitment (n = 11, 20.7%) and discomfort being in an MRI machine (n = 4; 7.5%). Pregnant women may be open to participating in research involving MRI provided concerns about fetal health, time, and personal comfort are addressed.

Immune-mediated graft dysfunction in liver transplant recipients with hepatitis C virus treated with direct-acting antiviral therapy.

Interferon treatment of hepatitis C virus (HCV) infection after liver transplantation (LT) can result in immune-mediated graft dysfunction (IGD). The occurrence of, risk factors for, and outcomes of IGD with direct-acting antiviral (DAA) therapy have not been reported. We conducted a multicenter study of HCV+LT recipients who did or did not develop DAA-IGD (1 case: 2 controls-33 vs 66). Among all treated between 2014 and 2016, DAA-IGD occurred in 3.4% (33/978). IGD occurred only after treatment completion (76.0 [IQR, 47.0;176]). Among those treated, 48% had plasma cell hepatitis, 36% acute cellular rejection, 6% chronic rejection, and 9% combined findings. Median time to liver enzyme resolution was 77.5 days (IQR, 31.5;126). After diagnosis, hospitalizations, steroid-induced hyperglycemia, and infection occurred in a higher percentage of cases vs controls (33% vs 7.5%, 21% vs 1.5%, 9% vs 0%; all P < .05). Only one IGD patient died and none required retransplant. A multivariate regression analysis found that liver enzyme elevations during and soon after DAA therapy completion correlated with subsequent IGD. In conclusion, while DAA-IGD is uncommon, liver enzyme elevations during or after DAA therapy may be a sign of impending IGD. These indicators should guide clinicians to diagnose and treat IGD early before the more deleterious later clinical presentation.

Impact of electronic health record-based, pharmacist-driven valganciclovir dose optimization in solid organ transplant recipients.

BACKGROUND: Prophylaxis with valganciclovir reduces the incidence of cytomegalovirus (CMV) infection following solid organ transplant (SOT). Under-dosing of valganciclovir is associated with an increased risk of CMV infection and development of ganciclovir-resistant CMV. METHODS: An automated electronic health record (EHR)-based, pharmacist-driven program was developed to optimize dosing of valganciclovir in solid organ transplant recipients at a large transplant center. Two cohorts of kidney, pancreas-kidney, and liver transplant recipients from our center pre-implementation (April 2011-March 2012, n = 303) and post-implementation of the optimization program (September 2012-August 2013, n=263) had demographic and key outcomes data collected for 1 year post-transplant. RESULTS: The 1-year incidence of CMV infection dropped from 56 (18.5%) to 32 (12.2%, P = .05) and the incidence of breakthrough infections on prophylaxis was cut in half (61% vs 34%, P = .03) after implementation of the dose optimization program. The hazard ratio of developing CMV was 1.64 (95% CI 1.06-2.60, P = .027) for the pre-implementation group after adjusting for potential confounders. The program also resulted in a numerical reduction in the number of ganciclovir-resistant CMV cases (2 [0.7%] pre-implementation vs 0 post-implementation). CONCLUSIONS: An EHR-based, pharmacist-driven valganciclovir dose optimization program was associated with reduction in CMV infections.