Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis.

BACKGROUND: First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival. PATIENTS AND METHODS: Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed. RESULTS: In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, ≥1%, 1%-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction ≥80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population. CONCLUSION: Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC.

Transcriptomic and clinical heterogeneity of metastatic disease timing within metastatic castration-sensitive prostate cancer.

BACKGROUND: Metastatic castration-sensitive prostate cancer (mCSPC) is commonly classified into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes; however, less is known about any underlying biologic differences between these disease states. Herein, we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy. PATIENTS AND METHODS: We performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous versus metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease timing. The median transcriptomic scores between groups were compared with the Mann-Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from the time of metastasis. Survival analysis was carried out with the Kaplan-Meier method and multivariable Cox regression. RESULTS: A total of 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-year OS (39% versus 79%; P < 0.01) and demonstrated lower median androgen receptor (AR) activity (11.78 versus 12.64; P < 0.01) and hallmark androgen response (HAR; 3.15 versus 3.32; P < 0.01). Multivariable Cox regression identified only high-volume disease [hazard ratio (HR) = 4.97, 95% confidence interval (CI) 2.71-9.10; P < 0.01] and HAR score (HR = 0.51, 95% CI 0.28-0.88; P = 0.02) significantly associated with OS. Finally, patients with synchronous (HR = 0.47, 95% CI 0.30-0.72; P < 0.01) but not metachronous (HR = 1.37, 95% CI 0.50-3.92; P = 0.56) disease were found to have better OS with AR and non-AR combination therapy as compared with monotherapy (P value for interaction = 0.05). CONCLUSIONS: We have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low-volume disease, those with metachronous low-volume disease have a more hormone-dependent transcriptional profile and exhibit a better prognosis than synchronous low-volume disease.

The impact of waiting time for orthopaedic consultation on pain levels in individuals with osteoarthritis: a systematic review and meta-analysis.

OBJECTIVE: Time spent waiting for access to orthopaedic specialist health services has been suggested to result in increased pain in individuals with osteoarthritis (OA). We assessed whether time spent on an orthopaedic waiting list resulted in a detrimental effect on pain levels in patients with knee or hip OA. METHODS: We searched Ovid MEDLINE, EMBASE and EBSCOhost databases from inception until September 2021. Eligible articles included individuals with OA on an orthopaedic waitlist and not receiving active treatment, and reported pain measures at two or more time points. Random-effects meta-analysis was used to estimate the pooled effect of waiting time on pain levels. Meta-regression was used to determine predictors of effect size. RESULTS: Thirty-three articles were included (n = 2,490 participants, 67 ± 3 years and 62% female). The range of waiting time was 2 weeks to 2 years (20.8 ± 18.8 weeks). There was no significant change in pain over time (effect size = 0.082, 95% CI = -0.009, 0.172), nor was the length of time associated with longitudinal changes in pain over time (ß = 0.004, 95% CI = -0.005, 0.012). Body mass index was a significant predictor of pain (ß = -0.043, 95% CI = -0.079, 0.006), whereas age and sex were not. CONCLUSIONS: Pain remained stable for up to 1 year in patients with OA on an orthopaedic waitlist. Future research is required to understand whether pain increases in patients waiting longer than 1 year.

Development of a post-treatment system using a downflow hanging sponge reactor - an upflow anaerobic reactor for natural rubber processing wastewater treatment.

This study aimed to evaluate the nitrogen removal of a post-treatment system for natural rubber processing wastewater (NRPW) under low chemical oxygen demand to total nitrogen (COD/TN) ratios without any supplemental external carbon source. The system including a downflow hanging sponge (DHS) reactor and an upflow anaerobic reactor (UAR) was operated in two phases. In phase 1 (day 0-102), under a nitrogen loading rate (NLR) of 0.23 ± 0.06 kgN m-3 d-1 and COD/TN ratio of 0.63 ± 0.47, the DHS-UAR system removed 82.5 ± 11.8% and 83.9 ± 7.6% of TN and ammonium concentrations, respectively. In phase 2 (day 103-229), higher COD/TN ratio of 1.96 ± 0.28 was applied to remove increasing NLRs. At the highest NLR of 0.51 kgN m-3 d-1, the system achieved TN and ammonium removal efficiencies of 93.2% and 93.7%, respectively. Nitrogen profiles and the 16S rRNA high-throughput sequencing data suggested that ammonium, a major nitrogen compound in NRPW, was utilized by nitrifying and ammonium assimilation bacteria in DHS, then removed by heterotrophic denitrifying and anammox bacteria in the UAR. The predominance of Acinetobacter detected in both reactors suggested its essential role for the nitrogen conversion.

Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial.

BACKGROUND: The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined. PATIENTS AND METHODS: Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC. RESULTS: The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015). CONCLUSION: This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

Enrichment of marine manganese-oxidizing microorganisms using polycaprolactone as a solid organic substrate.

OBJECTIVE: Heterotrophic manganese (Mn)-oxidizing microorganisms responsible for biogenic manganese oxide (Bio-MnOx) production are fastidious. Their enrichment is not easily accomplished by merely adding a soluble organic substrate to non-sterile mixed cultures. The objective of this study was to evaluate polycaprolactone (PCL), an aliphatic polyester, as an effective solid organic substrate for the enrichment of marine Mn-oxidizing microorganisms. RESULTS: We successfully obtained marine microbial enrichment with the capacity for dissolved Mn removal and MnOx production using PCL as a solid organic substrate. The removal of dissolved Mn by the Mn-oxidizing enrichment culture followed first-order kinetics with a rate constant of 0.014 h-1. 16S rRNA gene amplicon sequencing analysis revealed that the Mn-oxidizing enrichment culture was highly dominated by operational taxonomic units related to the bacterial phyla Cyanobacteria, Planctomycetes, and Proteobacteria. CONCLUSIONS: Our data demonstrate that PCL can serve as a potential substrate to enrich Mn-oxidizing microorganisms with the ability to produce MnOx under marine conditions.

High prevalence of syphilis in women, minors and precarious patients: a cross-sectional study in a Reunion Island sexually transmitted infection clinic, 2017-2020.

BACKGROUND: Syphilis is a sexually transmitted infection (STI) with a global prevalence estimated at 0.5% in 2012. Syphilis has been on the rise among men who have sex with men (MSM) in high-income countries and remains at endemic levels in low- and middle-income countries. This trend, however, has not been observed in Reunion Island. OBJECTIVES: To determine the prevalence, clinical characteristics and risk factors of syphilis in at-risk patients visiting the South Reunion STI clinic in Reunion Island. METHODS: This monocentric cross-sectional study included all patients who visited our STI clinic between 2017 and 2020. Syphilis serology was performed on all included patients, and data were collected using a standardized self-administered questionnaire. RESULTS: Over the 3-year study period, 2593 patients were enrolled. The prevalence of syphilis was 7.52% (n = 195, 95% CI, 6.50-8.65%) in the overall study population, 11.76% (n = 18, 95% CI, 6.97-18.59%) in minors (aged under 18 years) and 36.36% (n = 16, 95% CI, 21-59%) in pregnant women. The risk factors identified in multivariate analysis were being female [adjusted Prevalence Ratio (aPR) 1.85, 95% CI, 1.10-3.11], being MSM (aPR 2.87, 95% CI, 1.71-4.80), being aged under 18 years (aPR 3.54, 95% CI, 1.90-6.57), living in precarious conditions [aPR 3.12, 95% CI, 2.11-4.62] and being born in Reunion Island (aPR 2.43, 95% CI, 1.42-4.13). The clinical presentation was heterogeneous (plaques and papules, chancre, atypical ulcerations, multiple ulcerations, condyloma lata, etc.). CONCLUSIONS: These findings suggest a high prevalence of syphilis in at-risk patients visiting our STI clinic. Unlike the situation in other high-income countries, the people most at risk of syphilis in Reunion Island are local-born residents, minors, women and precarious patients. This is a source of concern, especially given the risk of resurgence of congenital syphilis on the island.

A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis.

BACKGROUND: Talaromyces marneffei infection is a major cause of human immunodeficiency virus (HIV)-related death in South and Southeast Asia. Guidelines recommend initial treatment with amphotericin B deoxycholate, but this drug has substantial side effects, a high cost, and limited availability. Itraconazole is available in oral form, is associated with fewer unacceptable side effects than amphotericin, and is widely used in place of amphotericin; however, clinical trials comparing these two treatments are lacking. METHODS: In this open-label, noninferiority trial, we randomly assigned 440 HIV-infected adults who had talaromycosis, confirmed by either microscopy or culture, to receive either intravenous amphotericin B deoxycholate (amphotericin) (219 patients), at a dose of 0.7 to 1.0 mg per kilogram of body weight per day, or itraconazole capsules (221 patients), at a dose of 600 mg per day for 3 days, followed by 400 mg per day, for 11 days; thereafter, all the patients received maintenance therapy with itraconazole. The primary outcome was all-cause mortality at week 2. Secondary outcomes included all-cause mortality at week 24, the time to clinical resolution of talaromycosis, early fungicidal activity, relapse of talaromycosis, development of the immune reconstitution inflammatory syndrome (IRIS), and the side-effect profile. RESULTS: The risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], -3.9 to 5.6; P<0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P=0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and IRIS than itraconazole. The patients who received amphotericin had significantly higher rates of infusion-related reactions, renal failure, hypokalemia, hypomagnesemia, and anemia than patients in the itraconazole group. CONCLUSIONS: Amphotericin was superior to itraconazole as initial treatment for talaromycosis with respect to 6-month mortality, clinical response, and fungicidal activity. (Funded by the Medical Research Council and others; IVAP Current Controlled Trials number, ISRCTN59144167 .).

Microarray analyses of the dorsal root ganglia support a role for innate neuro-immune pathways in persistent pain in experimental osteoarthritis.

OBJECTIVE: Following destabilization of the medial meniscus (DMM), mice develop experimental osteoarthritis (OA) and associated pain behaviors that are dependent on the stage of disease. We aimed to describe changes in gene expression in knee-innervating dorsal root ganglia (DRG) after surgery, in order to identify molecular pathways associated with three pre-defined pain phenotypes: "post-surgical pain", "early-stage OA pain", and "persistent OA pain". DESIGN: We performed DMM or sham surgery in 10-week old male C57BL/6 mice and harvested L3-L5 DRG 4, 8, and 16 weeks after surgery or from age-matched naïve mice (n = 3/group). RNA was extracted and an Affymetrix Mouse Transcriptome Array 1.0 was performed. Three pain phenotypes were defined: "post-surgical pain" (sham and DMM 4-week vs 14-week old naïve), "early OA pain" (DMM 4-week vs sham 4-week), and "persistent OA pain" (DMM 8- and 16-week vs naïve and sham 8- and 16-week). 'Top hit' genes were defined as P < 0.001. Pathway analysis (Ingenuity Pathway Analysis) was conducted using differentially expressed genes defined as P < 0.05. In addition, we performed qPCR for Ngf and immunohistochemistry for F4/80+ macrophages in the DRG. RESULTS: For each phenotype, top hit genes identified a small number of differentially expressed genes, some of which have been previously associated with pain (7/67 for "post-surgical pain"; 2/14 for "early OA pain"; 8/37 for "persistent OA pain"). Overlap between groups was limited, with 8 genes differentially regulated (P < 0.05) in all three phenotypes. Pathway analysis showed that in the persistent OA pain phase many of the functions of differentially regulated genes are related to immune cell recruitment and activation. Genes previously linked to OA pain (CX3CL1, CCL2, TLR1, and NGF) were upregulated in this phenotype and contributed to activation of the neuroinflammation canonical pathway. In separate sets of mice, we confirmed that Ngf was elevated in the DRG 8 weeks after DMM (P = 0.03), and numbers of F4/80+ macrophages were increased 16 weeks after DMM (P = 0.002 vs Sham). CONCLUSION: These transcriptomics findings support the idea that distinct molecular pathways discriminate early from persistent OA pain. Pathway analysis suggests neuroimmune interactions in the DRG contribute to initiation and maintenance of pain in OA.

Clinical calculator predictive of chemotherapy benefit in stage 1A uterine papillary serous cancers.

OBJECTIVE: Determine the utility of a clinical calculator to predict the benefit of chemotherapy in stage IA uterine papillary serous cancer (UPSC). PATIENTS AND METHODS: Data were collected from NCDB from years 2010-2014. Based on demographic and surgical characteristics, a clinical score was developed using the random survival forest machine learning algorithm. RESULTS: Of 1,751 patients with stage IA UPSC, 1,012 (58%) received chemotherapy and 739 (42%) did not. Older age (HR 1.06), comorbidities (HR 1.31), larger tumor size (HR 1.27), lymphovascular invasion (HR 1.86), positive peritoneal cytology (HR 2.62), no pelvic lymph node dissection (HR 1.51), and no chemotherapy (HR 2.16) were associated with poorer prognosis. Compared to no chemotherapy, patients who underwent chemotherapy had a 5-year overall survival of 80% vs. 67%. To better delineate those who may derive more benefit from chemotherapy, we designed a clinical calculator capable of dividing patients into low, moderate, and high-risk groups with associated 5-year OS of 86%, 73%, and 53%, respectively. Using the calculator to assess the relative benefit of chemotherapy in each risk group, chemotherapy improved the 5-year OS in the high (42% to 64%; p < 0.001) and moderate risk group (66% to 79%; p < 0.001) but did not benefit the low risk group (84% to 87%; p = 0.29). CONCLUSION: Our results suggest a clinical calculator is useful for counseling and personalizing chemotherapy for stage IA UPSC.

Biodegradation of natural rubber and deproteinized natural rubber by enrichment bacterial consortia.

This study examined the biodegradation of natural rubber (NR) and deproteinized natural rubber (DPNR) by bacterial consortia enriched from a rubber-processing factory's waste in Vietnam. The results reveal the degradation in both NR and DPNR, and the DPNR was degraded easier than NR. The highest weight loss of 48.37% was obtained in the fourth enrichment consortium with DPNR, while 35.39% was obtained in the fifth enrichment consortium with NR after 14 days of incubation. Nitrogen content and fatty acid content determined by Kjeldahl method and fourier transform infrared spectroscopy (FTIR), respectively, were decreased significantly after being incubated with the consortia. Structure of degraded rubber film analyzed by nuclear magnetic resonance spectroscopy showed the presence of aldehyde group, a sign of rubber degradation. Bacterial cells tightly adhering and embedding into NR and DPNR films were observed by scanning electron microscopy. There were differences in the bacterial composition of the consortia with NR and DPNR, which were determined by metagenomic analysis using 16S rRNA gene sequencing. The phyla Bacteroidetes and Proteobacteria may play a role in the degradation of non-isoprene compounds such as protein or lipid, while the phylum Actinobacteria plays a crucial role in the degradation of rubber hydrocarbon in all consortia.

Modified Folfox6 as Adjuvant Chemotherapy in Vietnamese Patients With Colorectal Cancer.

Colorectal cancer is the third most common cancer and the second leading cause of death from cancer worldwide. In Vietnam, the disease is the fifth leading cancer (8.9%), with 14 733 new cases in 2018. In recent years, the mFolfox6 regimen has been indicated commonly as the adjuvant chemotherapy after curative resection for patients with colorectal cancer. However, the efficacy of the regimen in Vietnamese patients has not been assessed and reported. In this retrospective study, we reviewed medical records of 83 patients with stage II or stage III colorectal cancer who received mFOLFOX6 regimen in order to investigate simultaneously survival and safety of this chemotherapy regimen. Three-year overall and disease-free survival were 84.3% and 79.5%, respectively. Our data revealed that postoperative Carcinoma Embryonic Antigen (CEA) level was a significant prognostic factor for survival, with hazard ratio of 3.83 and 3.67, respectively (P < .05), for overall survival and disease-free survival in the elevated CEA level group when compared to the normal CEA level group. The regimen also demonstrated to be well tolerated and can be used in routine practice as an adjuvant chemotherapy.

Spinal microglial activation in a murine surgical model of knee osteoarthritis.

OBJECTIVE: Microgliosis, the activation of microglial cells, is thought to contribute to synaptic transmission in the dorsal horn and thereby promote chronic pain. The primary aim of this study was to document the temporal profile of dorsal horn microgliosis after destabilization of the medial meniscus (DMM) in wild type (WT) and Adamts5 null mice. Since neuronal fractalkine (CX3CL1) contributes to microgliosis, we assessed its release from dorsal root ganglia (DRG) cultures after DMM. DESIGN: DMM or sham surgery was performed in the right knee of 10-week old male WT, CX3CR1-green fluorescent protein (GFP), or Adamts5 null C57BL/6 mice. Hind paw mechanical allodynia was monitored using von Frey fibers. L4 dorsal horn microgliosis was assessed 4, 8 and 16 weeks after surgery, based on the morphology of Iba1-immunoreactive microglia. DRG cells (L3-L5) were cultured and supernatants collected for fractalkine (FKN) ELISA. RESULTS: In WT mice, numbers of activated microglia were increased 8 and 16 weeks, but not 4 weeks, after DMM but not sham surgery. DRG cultures showed increased basal FKN release at 8 and 16 weeks. Adamts5 null mice did not develop mechanical allodynia up to 16 weeks after DMM. Accordingly, DRG cultures from these mice did not exhibit increased FKN release and dorsal horn microgliosis did not occur. CONCLUSION: DMM surgery leads to late stage dorsal horn microgliosis. The temporal correlation with DRG FKN release suggests it may contribute to microgliosis. Reduced microgliosis in Adamts5 null mice, which are protected from joint damage and associated mechanical allodynia after DMM, suggests that microgliosis is associated with joint damage and accompanying persistent pain.

A spatial and temporal analysis of paediatric central nervous system infections from 2005 to 2015 in Ho Chi Minh City, Vietnam.

Central nervous system infections (CNSI) are a leading cause of death and long-term disability in children. Using ICD-10 data from 2005 to 2015 from three central hospitals in Ho Chi Minh City (HCMC), Vietnam, we exploited generalized additive mixed models (GAMM) to examine the spatial-temporal distribution and spatial and climatic risk factors of paediatric CNSI, excluding tuberculous meningitis, in this setting. From 2005 to 2015, there were 9469 cases of paediatric CNSI; 33% were ⩽1 year old at admission and were mainly diagnosed with presumed bacterial CNSI (BI) (79%), the remainder were >1 year old and mainly diagnosed with presumed non-bacterial CNSI (non-BI) (59%). The urban districts of HCMC in proximity to the hospitals as well as some outer districts had the highest incidences of BI and non-BI; BI incidence was higher in the dry season. Monthly BI incidence exhibited a significant decreasing trend over the study. Both BI and non-BI were significantly associated with lags in monthly average temperature, rainfall, and river water level. Our findings add new insights into this important group of infections in Vietnam, and highlight where resources for the prevention and control of paediatric CNSI should be allocated.

De novo hepatocellular carcinoma post-multivisceral transplantation in a child.

De novo hepatocellular carcinoma (HCC) post-transplantation in patients without viral hepatitis is extremely rare, with only three reported adult cases in the English literature. Here, we present a case of de novo HCC that developed in a 7-year-old female, who at 8 months of age received a liver, small bowel, spleen, and pancreas transplantation 6.5 years ago for gastroschisis and total parenteral nutrition (TPN)-related cirrhosis. The post-transplant course was complicated by Epstein-Barr virus (EBV) infection, post-transplant lymphoproliferative disease, and subsequent development of multifocal EBV-associated post-transplant smooth muscle tumors (EBV-PTSMT) in the small bowel 1 year and 10 months after transplantation, respectively. This was managed by reducing immunosuppression with rituximab and EBV-specific cytotoxic T-cell therapy. She was noted to have a new lesion in her transplanted liver graft 6.5 years post-transplantation that was diagnosed as HCC. The HCC was resected, and the patient remained clinically stable for 7 months. At that time, recurrence of the HCC was discovered on MRI. She passed away 6 months after. To the best of our knowledge, this is the first reported occurrence of de novo HCC post-transplantation in the pediatric population that is unrelated to viral hepatitis in either recipient or donor.

Everolimus-induced nephrotic syndrome precipitated by interaction with voriconazole in a patient with Hodgkin's lymphoma.

WHAT IS KNOWN AND OBJECTIVES: Everolimus is a small molecule that inhibits the mammalian target of rapamycin (mTOR) and is used for treatment of various solid tumours and renal transplant rejection prophylaxis. Whereas everolimus-induced proteinuria was previously observed in 3%-36% renal transplant recipients, nephrotic syndrome was not reported in cancer patients taking everolimus. However, nephrotic syndrome was reported in patients taking sirolimus. CASE SUMMARY: We report the case of a 32-year-old female with relapsed Hodgkin's lymphoma who was on everolimus for 5 years and developed nephrotic syndrome about 2 months after initiation of voriconazole. She was on 10 mg everolimus once a day and 200 mg voriconazole twice a day orally. Renal biopsy revealed thrombotic microangiopathic vasculopathy and thin basement membrane nephropathy. Discontinuation of everolimus and voriconazole rapidly improved her nephrotic syndrome. WHAT IS NEW AND CONCLUSION: We provide in-depth analysis of the underlying mechanisms of everolimus-induced nephrotic syndrome and hypothesize that voriconazole likely decreased everolimus metabolism. In the era of targeted therapy for cancer, healthcare providers should be aware of the drug-drug interaction between everolimus (as well as tyrosine kinase inhibitors) and cytochrome P450 CYP3A4 inhibitors (ie voriconazole).

Taking culture seriously: Can we improve the developmental health and well-being of Australian Aboriginal children in out-of-home care?

BACKGROUND: Children in out-of-home care have well-documented health and developmental needs. Research suggests that Aboriginal children in care have unmet health and intervention needs. In metropolitan Sydney, Kari Aboriginal Resources Inc. (KARI), an Aboriginal organization, provides support to indigenous children in care, including clinical assessment and intervention. We wanted to determine the health and developmental needs of a subset of children in out-of-home care with KARI, who had been in stable care for at least a year. We wanted to identify child, carer, and intervention characteristics that contributed to children doing well. We also wanted to identify enablers and barriers to providing culturally competent intervention. METHODS: We used mixed methods. From the KARI clinic database over the past 3 years, we identified children who had been in stable care with KARI for >12 months. We compared clinical measures and outcomes for these children with results from previous audits. We carried out a group discussion and key informant interviews with therapists and caseworkers to identify risk and resilience factors for each child, as well as enablers and barriers to culturally competent intervention. RESULTS: The health and developmental profile of the 26 children identified as being in stable care was similar to that of previous audits. Most (88%) were getting speech pathology intervention; one third were getting occupational therapy and psychological intervention; most children and their carers attended cultural programmes. The majority of children (25/26) improved in their developmental health. Caseworkers and therapists identified risk and resilience factors related to child, carer, and home characteristics. They also identified elements of good practice; systemic issues prevented some interventions from being carried out. CONCLUSIONS: There are challenges delivering a trauma-informed, culturally respectful service to Aboriginal children in out-of-home care in an urban setting, but it can be done if attention is paid to culture and the enablers and barriers are identified.

The ability of a colloidal silver gel wound dressing to kill bacteria in vitro and in vivo.

OBJECTIVE: Inhibiting bacterial biofilms is of major significance for proper wound healing. The choice of the dressing material plays a key role, as bacteria can live in dressings and keep reinfecting the wound. This study examines the effectiveness of a colloidal silver gel (Ag-gel) wound dressing in inhibiting the growth of bacteria in a mouse wound model. METHOD: Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii and two different meticillin-resistant Staphylococcus aureus (MRSA) strains were examined. Bacteria were measured in vitro on the dressing, and in vivo studies were carried out to analyses both the dressing and the infected tissue. RESULTS: Using colony-forming unit (CFU) assays, over 7 logs of inhibition (100%) were found for Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumannii for the Ag-gel dressing when compared with the control dressing. In vivo, complete inhibition was observered for the three most common bacteria on the Ag-gel dressing and the tissue under that dressing. These results were confirmed by an in vivo live imaging system. However, with MRSA strains, only 2-3 logs of inhibition were recorded. CONCLUSION: The Ag-gel was effective in preventing biofilm infections caused by both Gram-negative and Gram-positive bacteria.

Oral administration of a medium containing both D-aspartate-producing live bacteria and D-aspartate reduces rectal temperature in chicks.

1. The aim of this study was to investigate the effects on the rectal temperature of young chicks of the oral administration of a medium that contained both live bacteria that produce D-aspartate (D-Asp) and D-Asp. 2. In Experiment 1, chicks were subjected to chronic oral administration of either the medium (containing live bacteria and 2.46 µmol D-Asp) or water from 7 to 14 d of age. Plasma-free amino acids as well as mitochondrial biogenic gene expression in the breast muscle were analysed. In Experiment 2, 7-d-old chicks were subjected to acute oral administration of the above medium or of an equimolar amount of D-Asp to examine their effect on changes in rectal temperature. In Experiment 3, after 1 week of chronic oral administration of the medium, 14-d-old chicks were exposed to either high ambient temperature (HT; 40 ± 1°C, 3 h) or control thermoneutral temperature (CT; 30 ± 1°C, 3 h) to monitor the changes in rectal temperature. 3. Chronic, but not acute, oral administration of the medium significantly reduced rectal temperature in chicks, and a chronic effect also appeared under HT conditions. 4. Chronic oral administration of the medium significantly reduced the mRNA abundance of the avian uncoupling protein (avUCP) in the breast muscle, but led to a significant increase in avian adenine nucleotide translocator (avANT) mRNA in the same muscle. 5. (a) These results indicate that the medium can reduce body temperature through the decline in avUCP mRNA expression in the breast muscle that may be involved in reduced mitochondrial proton leaks and heat production. (b) The increase in avANT further suggests a possible enhancement of adenosine triphosphate (ATP) synthesis.

Combination antifungal therapy for cryptococcal meningitis.

BACKGROUND: Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. METHODS: We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. RESULTS: A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P=0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P=0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P=0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (-0.42 log10 colony-forming units [CFU] per milliliter per day vs. -0.31 and -0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy. CONCLUSIONS: Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.).