Caregiver-reported impact of access to switch-adapted toys on play for children with complex medical conditions.

BACKGROUND: Play is essential for children's development of motor, social-emotional and cognitive skills. Traditional play activities are often difficult for children with complex medical conditions to access, which threatens their ability to maximize their developmental potential. Switch-adapted toys are a common strategy for expanding the play repertoire of children with disabilities by lowering the barrier to play with electronic toys. The aim of this study is to investigate the relationship between providing switch-adapted toys to children with disabilities and the children's total and self-initiated play time and access to a variety of cognition-appropriate toys, age-appropriate toys and independently accessible toys as reported by their caregivers. METHODS: Caregivers and their children with complex medical conditions were provided switch-adapted toys at a giveaway event. At the giveaway event and 6 months later, caregivers completed a survey that included questions about each child's current participation in play and their type of play, child's access to toys and questions specific to switches and switch-adapted toys. Data were analysed using Wilcoxon signed-rank tests with a Benjamini-Hochberg procedure to control for multiple comparisons. RESULTS: Nineteen caregivers completed both the pre- and post-surveys. The increases in the variety of toys and the number of independently accessibly and cognitively appropriate toys were statistically significant. The change in number of age-appropriate toys and the amount of total and active play time were not statistically significant. CONCLUSIONS: Providing switch-adapted toys may be an effective way to increase the number of independently accessible and cognitively appropriate toys for children with complex medical conditions. However, increasing the number of such toys may not be sufficient to increase active and total play time. Further research is needed to identify variables impacting play time and distal outcomes associated with switch-adapted toy access.

Tonsillitis and Tonsilloliths: Diagnosis and Management.

Tonsillitis, or inflammation of the tonsils, makes up approximately 0.4% of outpatient visits in the United States. Tonsillitis is caused by a viral infection in 70% to 95% of cases. However, bacterial infections caused by group A beta-hemolytic streptococcus (Streptococcus pyogenes) account for tonsillitis in 5% to 15% of adults and 15% to 30% of patients five to 15 years of age. It is important to differentiate group A beta-hemolytic streptococcus from other bacterial or viral causes of pharyngitis and tonsillitis because of the risk of progression to more systemic complications such as abscess, acute glomerulonephritis, rheumatic fever, and scarlet fever after infection with group A beta-hemolytic streptococcus. A variety of diagnostic tools are available, including symptom-based validated scoring systems (e.g., Centor score), and oropharyngeal and serum laboratory testing. Treatment is focused on supportive care, and if group A beta-hemolytic streptococcus is identified, penicillin should be used as the first-line antibiotic. In cases of recurrent tonsillitis, watchful waiting is strongly recommended if there have been less than seven episodes in the past year, less than five episodes per year for the past two years, or less than three episodes per year for the past three years. Tonsilloliths, or tonsil stones, are managed expectantly, and small tonsilloliths are common clinical findings. Rarely, surgical intervention is required if they become too large to pass on their own.

Systematic Review of Real-World Treatment Patterns of Oral Antipsychotics and Associated Economic Burden in Patients with Schizophrenia in the United States.

BACKGROUND: Schizophrenia is a chronic mental disorder associated with substantial morbidity and mortality affecting 0.25-1.6% of adults in the USA. Antipsychotic treatment is the standard of care for schizophrenia, but real-world treatment patterns and associated costs have not been systematically reviewed. OBJECTIVE: We conducted a systematic review to summarize treatment patterns and associated costs related to oral antipsychotic treatment of patients with schizophrenia in the USA. DATA SOURCES: We searched Medline (via PubMed) and Embase to identify relevant observational studies published from January 1, 2008, to June 1, 2018; costs were converted to 2018 US dollars. STUDY ELIGIBILITY: Observational, real-world studies reporting on patterns of treatment and/or associated costs for adult patients with schizophrenia treated with oral antipsychotics in the USA were included. RESULTS: Eighty-one studies were identified. Frequently prescribed oral second-generation antipsychotics were olanzapine (up to 50.9%), risperidone (up to 40.0%), and quetiapine (up to 30.7%). Suboptimal adherence was common across studies. Antipsychotic switching occurred in about half of patients, while antipsychotic combination therapy occurred in nearly 30%; all were associated with increased medication-related costs. Mean annual direct medical costs differed by treatment, with reported costs of $17,115 to $26,138 for patients treated with olanzapine, $18,395 for risperidone, and $17,656 to $28,101 for quetiapine. LIMITATIONS: This systematic review is limited by the variations in definitions of schizophrenia-related clinical terms used between studies and by the inclusion of studies focused on only the US health care system. CONCLUSIONS: In the treatment of schizophrenia, suboptimal adherence, antipsychotic switching, and antipsychotic augmentation were all associated with high costs of care in comparison to patients who were adherent and did not require antipsychotic switching or augmentation. These findings illustrate the need for the development of new treatments that address efficacy and adherence challenges of currently available therapies.

Schizophrenia is a debilitating mental disorder that affects up to 1.6% of adults in the USA. Antipsychotic medications reduce symptoms of the disease, but many patients with schizophrenia are not fully adherent or choose to discontinue treatment entirely, increasing their risk of hospitalization. In others, efforts to achieve better symptom control or to avoid intolerable side effects may result in switching antipsychotic medications or adding additional medications, leading to higher medical treatment costs. The magnitude of these cost increases is unclear. This study sought to assess medical costs associated with antipsychotic treatment adherence, switching, and adding additional antipsychotics. We reviewed 81 studies published from January 2008 through June 2018 examining treatment adherence in patients with schizophrenia. We calculated rates of adherence, switching, and adding antipsychotics, as well as associated medical costs. Overall adherence to antipsychotic treatment was less than 50%, with up to 50% of patients switching medications and up to 29% adding an additional antipsychotic medication to their current treatment. Patients who were not treatment adherent incurred annual medical costs of $10,316 compared with $5723 in patients who were adherent. The costs of immediate or delayed switching of antipsychotic medications ranged from $21,922 to $28,232, while costs of adding an additional antipsychotic ranged from $24,045 to $29,344. These data suggest that suboptimal medication adherence, along with high rates of patient discontinuation and medication switching, lead to higher treatment costs in the management of patients with schizophrenia.

Diffuse lymphadenopathy and fever without a rash: an atypical presentation of secondary syphilis.

A woman in her 30s presented to the emergency department with 4 days of fever, headache and back pain. The patient was admitted for pain control, inability to tolerate oral intake and intravenous antibiotics for presumed diagnosis of pyelonephritis. Following admission, CT of the abdomen/pelvis showed multiple prominent pelvic and inguinal lymph nodes, and the patient was noted to have anterior and posterior cervical and submandibular lymphadenopathy on examination. The differential diagnosis was broadened to infectious, haematological, malignant and autoimmune aetiologies of diffuse lymphadenopathy. Workup included serum studies, imaging, lumbar puncture and lymph node biopsy. Rapid plasma reagin (RPR) returned positive with titre 1:16 and confirmatory reactive Treponema pallidum particle agglutination. With an otherwise unrevealing workup, the diagnosis of secondary syphilis was confirmed. This case highlights the differential and diagnostic approach for diffuse lymphadenopathy and an unusual presentation of secondary syphilis. Additionally, it indicates that secondary syphilis can be present even with a relatively low RPR titre.

National Policy Response to the United Nations Sustainable Development Goals: A Physical Activity Case Study of Wales.

BACKGROUND: Population level changes in physical activity (PA) may benefit from policy intervention. In response to the United Nations Sustainable Development Goals, Wales introduced legislation to holistically improve health and well-being, including Public Service Boards, to improve the translation of national policy into practice. METHOD: An audit of policies published by national and subnational public bodies since 2015 was conducted. Content of the policies were extracted and synthesized to determine: (1) how many policies included a PA action, (2) what the drivers of those policies were, (3) the content of the PA actions, and (4) how the PA actions aligned with the Well-being of Future Generations (Wales) Act 2015. RESULTS: Sixteen national-level documents with a PA action were published by 4 of 13 public bodies. The policies vary in terms of the clarity and specificity of the actions, the assignment of clear roles/responsibilities, and the setting of targets. Of the 19 subnational Public Service Boards well-being policies, 15 included PA actions. CONCLUSION: This audit provides a valuable example of how connections between national and subnational policy can be achieved. The appointment of Public Service Boards has supported the translation of policies into practice in Wales, and similar approaches could be utilized in other countries.

Epidemiological and clinical burden associated with plexiform neurofibromas in pediatric neurofibromatosis type-1 (NF-1): a systematic literature review.

PURPOSE: Patients with neurofibromatosis type-1 (NF-1) and associated plexiform neurofibromas (PNs) often have a high burden of illness owing to debilitating symptoms of these tumors and limited management options. To investigate this complex disease, a systematic literature review (SLR) was conducted on the epidemiology of pediatric NF-1 and associated PNs, the burden of illness, and outcomes of surgical resection of these tumors. METHODS: Searches of MEDLINE and Embase (from database inception to October 2019) and conference proceedings (2017-2019) were performed to identify relevant studies. The review methodology was informed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Twenty studies were identified. Evidence confirmed NF-1 is rare but that occurrence may differ geographically. Only limited data on the birth incidence of NF-1 were identified. Prevalence estimates for pediatric NF-1 varied from one per 960 individuals (aged 17 years) to one per 5681 children (aged < 16 years) across five large registry/surveillance studies (each involving > 19,000 individuals). The prevalence of associated PNs was 0-29.6%. PNs carried increased mortality risk in pediatric NF-1 in both studies that explored this potential association. Patients with PNs reported high use of analgesics. The complication rate post-surgery for PNs was around 17-19%. The recurrence rate (18-68%) was dependent on the extent of excision achieved during surgery. CONCLUSIONS: Data suggest NF-1 is a rare disease with increased morbidity and mortality in children with associated PNs. Surgical outcomes for PNs are often poor. These findings suggest significant unmet needs in patients with NF-1-associated PNs.

DREAMM-2: Indirect Comparisons of Belantamab Mafodotin vs. Selinexor + Dexamethasone and Standard of Care Treatments in Relapsed/Refractory Multiple Myeloma.

INTRODUCTION: Single-agent belantamab mafodotin (belamaf; BLENREP) demonstrated deep and durable responses in patients with relapsed/refractory multiple myeloma and ≥ 3 prior lines of therapy, including an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody (DREAMM-2; NCT03525678). METHODS: At the time of this study, STORM Part 2, NCT02336815 (selinexor plus low-dose dexamethasone; sel + dex) was systematically identified as the only feasible comparator to the DREAMM-2 cohort. Matching-adjusted indirect comparisons (MAIC) evaluated efficacy and safety of belamaf (2.5 mg/kg; n = 97) versus sel + dex (80 mg + 20 mg, respectively; n = 123). Populations were weighted for clinically validated effect modifiers and prognostic factors. Outcomes included overall survival (OS), progression-free survival (PFS), duration of response (DoR), overall response rate (ORR), time to response (TTR), and safety. The relative efficacy of belamaf versus standard of care (SoC) on OS was estimated by a Bucher indirect treatment comparison using the MAIC-adjusted hazard ratios (HR) for OS of belamaf (DREAMM-2) versus sel + dex (STORM Part 2) and a HR adjusted for refractoriness to carfilzomib and high-risk cytogenetics of sel + dex (STORM) versus SoC (MAMMOTH). RESULTS: Belamaf demonstrated improved OS (HR 0.53; 95% confidence interval 0.34, 0.83; p = 0.005) and DoR (0.41; 0.21, 0.83; p = 0.013) versus sel + dex. There were no statistically significant differences in ORR, TTR, and PFS. Belamaf had a favorable safety profile for most evaluable hematologic (any-grade, Grade 3-4) and non-hematologic (any-grade) adverse events versus sel + dex. Significantly improved OS was observed with belamaf versus SoC (0.29; 0.16, 0.54; p < 0.001). CONCLUSION: Single-agent belamaf represents a new treatment option for triple-class refractory patients with RRMM.

Network meta-analysis of eribulin versus other chemotherapies used as second- or later-line treatment in locally advanced or metastatic breast cancer.

BACKGROUND: Eribulin mesylate (ERI; Halaven®) is a microtubule inhibitor approved in the United States for metastatic breast cancer patients with at least two prior chemotherapy regimens for metastatic breast cancer, and in the European Union in locally advanced breast cancer or metastatic breast cancer patients who progressed after at least one chemotherapy for advanced disease. This network meta-analysis compared the efficacy and safety of ERI versus other chemotherapies in this setting. METHODS: Systematic searches conducted in MEDLINE, Embase, and the Cochrane Central Register of Clinical Trials identified randomized controlled trials of locally advanced breast cancer/metastatic breast cancer chemotherapies in second- or later-line settings. Efficacy assessment included pre-specified subgroup analysis of breast cancer subtypes. Included studies were assessed for quality using the Centre for Reviews and Dissemination tool. Bayesian network meta-analysis estimated primary outcomes of overall survival and progression-free survival using fixed-effect models. Comparators included: capecitabine (CAP), gemcitabine (GEM), ixabepilone (IXA), utidelone (UTI), treatment by physician's choice (TPC), and vinorelbine (VIN). RESULTS: The network meta-analysis included seven trials. Results showed that second- or later-line patients treated with ERI had statistically longer overall survival versus TPC (hazard ratio [HR]: 0.81; credible interval [CrI]: 0.66-0.99) or GEM+VIN (0.62; 0.42-0.90) and statistically longer progression-free survival versus TPC (0.76; 0.64-0.90), but statistically shorter progression-free survival versus CAP+IXA (1.40; 1.17-1.67) and CAP+UTI (1.61; 1.23-2.12). In triple negative breast cancer, ERI had statistically longer overall survival versus CAP (0.70; 0.54-0.90); no statistical differences in progression-free survival were observed in triple negative breast cancer. CONCLUSIONS: This network meta-analysis suggests that ERI may provide an overall survival benefit in the overall locally advanced breast cancer/metastatic breast cancer populations and triple negative breast cancer subgroup compared to standard treatments. These findings support the use of ERI in second- or later-line treatment of patients with locally advanced breast cancer/metastatic breast cancer.

Accelerated theta burst stimulation for the treatment of depression: A randomised controlled trial.

INTRODUCTION: Theta burst pattern repetitive transcranial magnetic stimulation (TBS) is increasingly applied to treat depression. TBS's brevity is well-suited to application in accelerated schedules. Sizeable trials of accelerated TBS are lacking; and optimal TBS parameters such as stimulation intensity are not established. METHODS: We conducted a three arm, single blind, randomised, controlled, multi-site trial comparing accelerated bilateral TBS applied at 80 % or 120 % of the resting motor threshold and left unilateral 10 Hz rTMS. 300 patients with treatment-resistant depression (TRD) were recruited. TBS arms applied 20 bilateral prefrontal TBS sessions over 10 days, while the rTMS arm applied 20 daily sessions of 10 Hz rTMS to the left prefrontal cortex over 4 weeks. Primary outcome was depression treatment response at week 4. RESULTS: The overall treatment response rate was 43.7 % and the remission rate was 28.2 %. There were no significant differences for response (p = 0.180) or remission (p = 0.316) across the three groups. Response rates between accelerated bilateral TBS applied at sub- and supra-threshold intensities were not significantly different (p = 0.319). Linear mixed model analysis showed a significant effect of time (p < 0.01), but not rTMS type (p = 0.680). CONCLUSION: This is the largest accelerated bilateral TBS study to date and provides evidence that it is effective and safe in treating TRD. The accelerated application of TBS was not associated with more rapid antidepressant effects. Bilateral sequential TBS did not have superior antidepressant effect to unilateral 10 Hz rTMS. There was no significant difference in antidepressant efficacy between sub- and supra-threshold accelerated bilateral TBS.

Integration of teaming therapy and mixed-reality simulation as remote learning modality for couple and family therapy graduate training programs.

In response to COVID-19, a couple and family therapy (CFT) graduate training program integrated a teaming therapy model with virtual technology using mixed-reality simulation software. By utilizing teaming therapy--a model with strong roots in systemic theory and practice-- combined with cutting-edge simulation technology, this distance learning modality provides distinctly relational therapy supervision and training for students at a time when their internships sites are struggling to offer remote clinical services due to the pandemic. This integrative framework offers a high degree of both realism and safety, allowing experiential learning to be appropriately scaffolded for optimum creativity and engagement in an online setting. This paper describes the conceptual, systemic basis for the learning modality, steps for implementation, benefits of the model, and the authors plan for further evaluation.

Dimensions of Craving Interact with COMT Genotype to Predict Relapse in Individuals with Alcohol Use Disorder Six Months after Treatment.

(1) Background: Alcohol use disorder (AUD) is associated with poor medical, psychological, and psychosocial outcomes and approximately 60% of individuals with AUD relapse six months after treatment. Craving is a core aspect of AUD and associated with high risk of relapse. One promising avenue to improve outcomes may be in understanding the relationship between COMT genotype, craving, and treatment outcomes. (2) Methods: To this end, we assessed craving, recent drinking history, and impulsivity in 70 individuals with AUD undergoing a standard course of treatment at a regional Veteran Affairs (VA) medical center. Saliva samples were collected to determine COMT genotype. In this prospective observational study, participants were followed for six months to determine who went on to relapse after treatment. (3) Results: Results revealed a significant interaction between craving and catechol-O-methyltransferse (COMT) genotype in predicting relapse. Post hoc exploratory analyses indicated that Met/Met homozygotes reported the highest levels of craving, and craving was associated with recent drinking history. Among Val/Val homozygotes, who had higher rates of relapse, craving was associated with impulsivity. (4) Conclusions: These associations highlight that specific profiles of psychological and biological factors may be important in understanding which individuals are at highest risk of relapse following treatment. Future studies that build on these findings are warranted.

Alterations of Brain Signal Oscillations in Older Individuals with HIV Infection and Parkinson's Disease.

More than 30 years after the human immunodeficiency virus (HIV) epidemic, HIV patients are now aging due to the advances of antiretroviral therapy. With immunosenescence and the susceptibility of dopamine-rich basal ganglia regions to HIV-related injury, older HIV patients may show neurofunctional deficits similar to patients with Parkinson's disease (PD). We examined the amplitudes of low frequency fluctuations (ALFF) across different frequency bands of the BOLD signal in 30 older HIV-infected individuals, 33 older healthy controls, and 36 PD patients. Participants underwent resting-state fMRI, neuropsychological testing, and a clinical motor exam. HIV patients mainly showed abnormalities in cortical ALFF with reduced prefrontal amplitudes and enhanced sensorimotor and inferior temporal amplitudes. Frontal hypoactivation was overlapping for HIV and PD groups and different from controls. PD patients further exhibited reduced pallidum amplitudes compared to the other groups. In the HIV group, lower pallidum amplitudes were associated with lower CD4+ nadir and CD4+ T cell counts. Abnormalities in ALFF dynamics were largely associated with cognitive and motor functioning in HIV and PD groups. The disruption of neurofunctional frequency dynamics in subcortical-cortical circuits could contribute to the development of cognitive and motor dysfunction and serve as a biomarker for monitoring disease progression with immunosenescence. Graphical Abstract.

Correction to: Crisaborole Ointment, 2%, for Treatment of Patients with Mild-to-Moderate Atopic Dermatitis: Systematic Literature Review and Network Meta-Analysis.

The authors would like to replace 2 small sections of the published manuscript that refer to a qualitative review of safety data for included studies (together with an associated safety table), to provide some further clarifications on these safety data and to include some quantitative updates for rates.

Shame, self-discrepancies, and adjustment after acquired brain injury.

OBJECTIVES: To explore the relationship between shame and self-discrepancies and the extent that these factors predict adjustment after an acquired brain injury (ABI). METHOD: 62 participants with an ABI completed the following self-report qualitative questionnaires: the Hospital Anxiety and Depression Scale, the Quality of Life after Brain Injury Scale, the Internalized Shame Scale, and the Head Injury Semantic Differential Scale - III. Data was analyzed using correlations, repeated ANOVA, and multiple regression models. RESULTS: A significant self-discrepancy was found between the present self and the pre-injury self, with the present self-being rated more negatively. This self-discrepancy was found to be positively correlated to shame, and these two variables were found to predict adjustment (emotional distress and quality of life). CONCLUSIONS: Shame and self-discrepancies both appear to play a crucial role in adjustment following an ABI. However, the relationship between shame and self-discrepancies needs more consideration to understand how these variables may interact to predict adjustment.

Crisaborole Ointment, 2%, for Treatment of Patients with Mild-to-Moderate Atopic Dermatitis: Systematic Literature Review and Network Meta-Analysis.

INTRODUCTION: There is a need to compare efficacy and safety profiles of crisaborole ointment, 2%, versus other topical treatments across randomized clinical trials (RCTs). We performed this review/network meta-analysis to evaluate the comparative efficacy and safety of crisaborole versus other topical pharmacologic therapies for mild-to-moderate atopic dermatitis (AD) among patients aged ≥ 2 years. METHODS: Searches were conducted in MEDLINE, Embase, the Cochrane Collection Central Register of Clinical Trials, and the Database of Abstracts of Reviews of Effects using Ovid to identify English language articles reporting RCTs of topical anti-inflammatory agents in patients aged ≥ 2 years with mild-to-moderate AD published between inception and 10 March 2020. This review used a prespecified protocol with eligibility criteria for population, interventions, comparisons, outcomes, and study design. Efficacy was evaluated using the Investigator's Static Global Assessment (ISGA) of clear (0) or almost clear (1) and expressed by hazard ratios (HR) with 95% credible intervals. RESULTS: Patients treated with crisaborole or tacrolimus ointment, 0.1% or 0.03%, versus vehicle alone were significantly more likely to achieve ISGA 0/1 at 28-42 days, with the greatest point estimate observed for the crisaborole comparison (hazard ratio: 2.07; 95% credible interval 1.76 to - 2.36; probability HR above 1 [p better]: 100.0%). Patients were also more likely to achieve ISGA 0/1 with crisaborole than with pimecrolimus cream, 1% (HR: 1.62; 95% credible interval 1.04-2.48; p better: 98.3%). While network meta-analysis for safety was not feasible because of data limitations, crisaborole pivotal studies (AD-301/AD-302) showed crisaborole was well tolerated. CONCLUSIONS: Crisaborole was shown to be superior to vehicle and pimecrolimus and comparable to tacrolimus, 0.1% or 0.03%, with respect to ISGA 0/1 at 28-42 days in patients aged ≥ 2 years with mild-to-moderate AD. This evaluation of comparative efficacy of crisaborole further supports use of crisaborole as an effective therapeutic option in this population.

Peer support groups after acquired brain injury: a systematic review.

BACKGROUND: Peer support groups can be a way to obtain support, problem solve, and widen social networks. However, there has been no systematic literature review examining the evidence for the use of peer support groups after an acquired brain injury (ABI). OBJECTIVE: This review sought to systematically evaluate the evidence for (1) the psychosocial effectiveness, and (2) the experience of peer support groups in adults who had experienced ABI's. METHODS: The systematic literature search was conducted across the following four databases: PsycINFO, PsycARTICLES, MEDLINE, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) in October 2019. The mixed methods appraisal tool was used to examine the quality of the research. RESULTS: 13 papers were included in this review. Limited evidence was found for the psychosocial effectiveness of peer support groups in ABI, although the experience of partaking in a peer support group was largely found to be positive. The benefits and helping factors of taking part in a peer support group can be summarized as: being connected, interacting with others, and providing and receiving support. CONCLUSIONS: The findings of this review suggest that peer support groups could be a promising intervention to support individuals and promote adjustment following an ABI.

Genetic Influences of the Microbiota on the Life Span of Drosophila melanogaster.

To better understand how associated microorganisms ("microbiota") influence organismal aging, we focused on the model organism Drosophila melanogaster We conducted a metagenome-wide association (MGWA) as a screen to identify bacterial genes associated with variation in the D. melanogaster life span. The results of the MGWA predicted that bacterial cysteine and methionine metabolism genes influence fruit fly longevity. A mutant analysis, in which flies were inoculated with Escherichia coli strains bearing mutations in various methionine cycle genes, confirmed a role for some methionine cycle genes in extending or shortening fruit fly life span. Initially, we predicted these genes might influence longevity by mimicking or opposing methionine restriction, an established mechanism for life span extension in fruit flies. However, follow-up transcriptome sequencing (RNA-seq) and metabolomic experiments were generally inconsistent with this conclusion and instead implicated glucose and vitamin B6 metabolism in these influences. We then tested if bacteria could influence life span through methionine restriction using a different set of bacterial strains. Flies reared with a bacterial strain that ectopically expressed bacterial transsulfuration genes and lowered the methionine content of the fly diet also extended female D. melanogaster life span. Taken together, the microbial influences shown here overlap with established host genetic mechanisms for aging and therefore suggest overlapping roles for host and microbial metabolism genes in organismal aging.IMPORTANCE Associated microorganisms ("microbiota") are intimately connected to the behavior and physiology of their animal hosts, and defining the mechanisms of these interactions is an urgent imperative. This study focuses on how microorganisms influence the life span of a model host, the fruit fly Drosophila melanogaster First, we performed a screen that suggested a strong influence of bacterial methionine metabolism on host life span. Follow-up analyses of gene expression and metabolite abundance identified stronger roles for vitamin B6 and glucose than methionine metabolism among the tested mutants, possibly suggesting a more limited role for bacterial methionine metabolism genes in host life span effects. In a parallel set of experiments, we created a distinct bacterial strain that expressed life span-extending methionine metabolism genes and showed that this strain can extend fly life span. Therefore, this work identifies specific bacterial genes that influence host life span, including in ways that are consistent with the expectations of methionine restriction.

Reasons for voriconazole prophylaxis discontinuation in allogeneic hematopoietic cell transplant recipients: A real-life paradigm.

We sought to describe the clinical experience of voriconazole as primary antifungal prophylaxis (AFP) in allogeneic hematopoietic cell transplant recipients (allo-HCTr). This was a single-center retrospective study of adult allo-HCTr (1 January 2014 to 31 December 2016) who received ≥two doses of voriconazole-AFP. Voriconazole-AFP was started on day +7 post-HCT and continued at least through day +60 post-HCT, or longer as clinically indicated. We reviewed the rate, reasons, and risk factors of voriconazole-AFP discontinuation until day-100 post-HCT. A total of 327 patients were included. Voriconazole-AFP was continued for a median of 69 days (mean: 57.9; range 1, 100): for a median of 90 days (mean :84; range 2, 100) in 180/327 (55%) in the standard-of-care (SOC) group and 20 days (mean :25.6 ; range 1, 89; P-value < .001) in 147/327 (45%) patients in the early-discontinuation-group. Early-voriconazole-AFP discontinuation was due to adverse events, drug interactions, insurance coverage, and other reasons in 101/147 (68.7%), 27 (18.4%), 13 (8.8%), and 6 (4.1%) patients, respectively. Early-voriconazole-AFP discontinuation occurred in 73/327 (22.3%) patients due to hepatotoxicity. Important predictors for early-voriconazole-AFP discontinuation included: graft-versus-host disease grade ≥2 (odds ratio [OR]: 1.9, P-value: .02), alanine-aminotransferase ≥75 IU/ml on voriconazole-administration day-14 (OR: 5.6, P-value: .02) and total bilirubin ≥1.3 mg/dl on voriconazole-administration day-7 (OR: 3.0, P-value: .03). There were 13 proven/probable invasive fungal infections by day-180 post-HCT (8/147, 5.4%, and 5/180, 2.8% in the early-discontinuation and SOC-groups, respectively; log-rank:0.13). By day-180 post HCT, 23/147 (15.6%) and 14/180 (7.8%) patients in the early-discontinuation and SOC-groups had died, respectively (log-rank:0.03). Voriconazole-AFP was discontinued in up to 45% of allo-HCTr. Hepatotoxicity during the first 2 weeks post-HCT is a significant predictor of early-voriconazole-AFP discontinuation.