Epigenetic reader SP140 loss of function drives Crohn's disease due to uncontrolled macrophage topoisomerases.

How mis-regulated chromatin directly impacts human immune disorders is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing epigenetic "reader," and SP140 loss-of-function mutations associate with Crohn's disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). However, the relevance of these mutations and mechanisms underlying SP140-driven pathogenicity remains unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOPs) that maintains heterochromatin and macrophage fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, de-repression of developmentally silenced genes, and ultimately defective microbe-inducible macrophage transcriptional programs and bacterial killing that drive intestinal pathology. Pharmacological inhibition of TOP1/2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1/2 inhibitors in Sp140-/- mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a TOP repressor and reveal repurposing of TOP inhibition to reverse immune diseases driven by SP140 loss.

Brain motor and fear circuits regulate leukocytes during acute stress.

The nervous and immune systems are intricately linked1. Although psychological stress is known to modulate immune function, mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood2. Here we show that distinct brain regions shape leukocyte distribution and function throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that motor circuits induce rapid neutrophil mobilization from the bone marrow to peripheral tissues through skeletal-muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow through direct, cell-intrinsic glucocorticoid signalling. These stress-induced, counter-directional, population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and directing their recruitment to sites of injury. On the other hand, corticotropin-releasing hormone neuron-mediated leukocyte shifts protect against the acquisition of autoimmunity, but impair immunity to SARS-CoV-2 and influenza infection. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, therefore calibrating the ability of the immune system to respond to physical threats.

Astrocytic interleukin-3 programs microglia and limits Alzheimer's disease.

Communication within the glial cell ecosystem is essential for neuronal and brain health1-3. The influence of glial cells on the accumulation and clearance of ß-amyloid (Aß) and neurofibrillary tau in the brains of individuals with Alzheimer's disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aß deposits, microglia increase their expression of IL-3Rα-the specific receptor for IL-3 (also known as CD123)-making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aß and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte-microglia cross-talk and a node for therapeutic intervention in AD.

Limited plasticity of monocyte fate and function associated with epigenetic scripting at the level of progenitors.

Myeloid cell heterogeneity is known, but whether it is cell-intrinsic or environmentally-directed remains unclear. Here, an inducible/reversible system pausing myeloid differentiation allowed the definition of clone-specific functions that clustered monocytes into subsets with distinctive molecular features. These subsets were orthogonal to the classical/nonclassical categorization and had inherent, restricted characteristics that did not shift under homeostasis, after irradiation, or with infectious stress. Rather, their functional fate was constrained by chromatin accessibility established at or before the granulocyte-monocyte or monocyte-dendritic progenitor level. Subsets of primary monocytes had differential ability to control distinct infectious agents in vivo. Therefore, monocytes are a heterogeneous population of functionally restricted subtypes defined by the epigenome of their progenitors that are differentially selected by physiologic challenges with limited plasticity to transition from one subset to another.

Shrimp SIRT4 promotes white spot syndrome virus replication.

In WSSV pathogenesis, the molecular mechanisms and the key host factors that regulate the viral replication and morphogenesis remain unclear. However, like most viruses, WSSV is known to induce metabolic reprogramming in several metabolic pathways including the host glutamine metabolism, and several recent reports have suggested that the sirtuins SIRT3, SIRT4, and SIRT5, which belong to a family of NAD+-dependent deacetylases, play an important role in this regulation. Here we focus on characterizing LvSIRT4 from Litopenaeus vannamei and investigate its role in regulating glutamine dehydrogenase (GDH), an important enzyme that promotes glutaminolysis and viral replication. We found that LvSIRT4 silencing led to significant decreases in both WSSV gene expression and the number of viral genome copies. Conversely, overexpression of LvSIRT4 led to significant increases in the expression of WSSV genes and the WSSV genome copy number. Immunostaining in Sf9 insect cells confirmed the presence of LvSIRT4 in the mitochondria and the co-localization of LvSIRT4 and LvGDH in the same cellular locations. In vivo gene silencing of LvSIRT4 significantly reduced the gene expression of LvGDH whereas LvSIRT4 overexpression had no effect. However, neither silencing nor overexpression had any effect on the protein expression levels of LvGDH. Lastly, although GDH activity in uninfected shrimp was unchanged, the GDH enzyme activity in WSSV-infected shrimp was significantly increased after both LvSIRT4 silencing and overexpression. This suggests that although there may be no direct regulation, LvSIRT4 might still be able to indirectly regulate LvGDH via the mediation of one or more WSSV proteins that have yet to be identified.

VSSP-activated macrophages mediate senescence and tumor inhibition in a preclinical model of advanced prostate cancer.

Androgen deprivation therapy (ADT) is a standard therapy for prostate cancer (PCa). Though disseminated disease is initially sensitive to ADT, an important fraction of the patients progresses to castration-resistant prostate cancer (CRPC). For this reason, the identification of novel effective therapies for treating CRPC is needed. Immunotherapeutic strategies focused on macrophages as antitumor effectors, directly enhancing their tumoricidal potential at the tumor microenvironment or their adoptive transfer after ex vivo activation, have arisen as promising therapies in several cancer types. Despite several approaches centered on the activation of tumor-associated macrophages (TAMs) in PCa are under investigation, to date there is no evidence of clinical benefit in patients. In addition, the evidence of the effectiveness of macrophage adoptive transfer on PCa is poor. Here we find that VSSP, an immunomodulator of the myeloid system, decreases TAMs and inhibits prostatic tumor growth when administered to castrated Pten-deficient prostate tumor-bearing mice. In mice bearing castration-resistant Ptenpc-/-; Trp53pc-/- tumors, VSSP administration showed no effect. Nevertheless, adoptive transfer of macrophages activated ex vivo with VSSP inhibited Ptenpc-/-; Trp53pc-/- tumor growth through reduction of angiogenesis and tumor cell proliferation and induction of senescence. Taken together, our results highlight the rationale of exploiting macrophage functional programming as a promising strategy for CRPC therapy, with particular emphasis on ex vivo-activated proinflammatory macrophage adoptive transfer. Video abstract.

Comparison of the 12-month impact of COVID-19 and SARS on physiological capacity and health-related quality of life.

BACKGROUND: Little is known about the differences in medium to long-term recovery on spirometry, 6-minute walking distance (6MWD) and health-related quality of life (HRQoL) between COVID-19 and SARS. METHODS: We performed a 12-month prospective study on COVID-19 survivors. The changes in dynamic lung volumes at spirometry (%predicted FEV1, %predicted FVC), 6MWD and HRQoL at 1-3, 6 to 12 months were compared against a historical cohort of SARS survivors using the same study protocol. The residual radiological changes in HRCT in COVID-19 survivors were correlated with their functional capacity. RESULTS: 108 COVID-19 survivors of various disease severity (asymptomatic 2.9%, mild 33.3%, moderate 47.2%, severe 8.3%, critical 8.3%) were recruited. When compared with 97 SARS survivors, 108 COVID-19 survivors were older (48.1 ± 16.4 vs. 36.1 ± 9.5 years, p < 0.001) and required less additional support during hospitalization; with lower dynamic lung volumes, shorter 6MWD and better physical component score. Both groups of survivors had comparable changes in these parameters at subsequent follow-ups. Both COVID-19 and SARS survivors had similar mental component score (MCS) at 6 and 12 months. COVID-19 survivors initially experienced less (between-group difference, -3.1, 95% confidence interval [CI] -5.5 to -0.7, p = 0.012) and then more improvement (between-group difference 2.9, 95%, CI 0.8 to 5.1, p = 0.007) than SARS survivors in the MCS at 1-3 to 6 months and 6 to 12 months respectively. Forty (44.0%) out of 91 COVID-19 survivors had residual abnormalities on HRCT at 12 months, with a negative correlation between the severity scores of parenchymal changes and 6MWD (r=-0.239, p < 0.05). CONCLUSIONS: COVID-19 survivors demonstrated a similar recovery speed in dynamic lung volumes and exercise capacity, but different paces of psychological recovery as SARS survivors in the convalescent phase. The severity of parenchymal changes in HRCT is negatively correlated with the 6MWD of COVID-19 survivors. TRIAL REGISTRATION: This prospective study was registered at ClinicalTrials.gov on 2 November 2020 (Identifier: NCT04611243).

"Decoding MH"-A de-stigmatization campaign in the Hong Kong Police Force.

Police officers are under high level of stress given the intense and emergent work nature. If left untreated, their mental wellbeing would be at risk and work performance compromised. However, mental health stigma is common among police officers and is perpetuated by factors like police cultures emphasizing toughness and self-reliance. In view of this, since 2016, the Hong Kong Police Force had launched a holistic campaign for Force members which was the first among law enforcement organizations in Hong Kong, aiming to reduce stigma, by enhancing mental health knowledge and decreasing negative attitudes and behaviors towards mental health issues. The programme incorporated standardised trainings of the Mental Health First Aid course with examples modified to the local police context, and psychoeducation via the use of digital medium and sharing by public figures. Positive feedback was received. It was foreseen that the campaign effects would increase Force members' awareness of their mental health, encourage help-seeking and facilitate officers' decision making when encountering crises in the community.

Dysregulation of Immune Cell Subpopulations in Atypical Hemolytic Uremic Syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy. Definitive biomarkers for disease diagnosis and activity remain elusive, making the exploration of molecular markers paramount. We conducted single-cell sequencing on peripheral blood mononuclear cells from 13 aHUS patients, 3 unaffected family members of aHUS patients, and 4 healthy controls. We identified 32 distinct subpopulations encompassing 5 B-cell types, 16 T- and natural killer (NK) cell types, 7 monocyte types, and 4 other cell types. Notably, we observed a significant increase in intermediate monocytes in unstable aHUS patients. Subclustering analysis revealed seven elevated expression genes, including NEAT1, MT-ATP6, MT-CYB, VIM, ACTG1, RPL13, and KLRB1, in unstable aHUS patients, and four heightened expression genes, including RPS27, RPS4X, RPL23, and GZMH genes, in stable aHUS patients. Additionally, an increase in the expression of mitochondria-related genes suggested a potential influence of cell metabolism on the clinical progression of the disease. Pseudotime trajectory analysis revealed a unique immune cell differentiation pattern, while cell-cell interaction profiling highlighted distinctive signaling pathways among patients, family members, and controls. This single-cell sequencing study is the first to confirm immune cell dysregulation in aHUS pathogenesis, offering valuable insights into molecular mechanisms and potential new diagnostic and disease activity markers.

Impact of moist wound dressing on wound healing time: A meta-analysis.

Among the assortment of available dressings aimed at promoting wound healing, moist dressings have gained significant popularity because of their ability to create an optimal environment for wound recovery. This meta-analysis seeks to compare the effects of moist dressing versus gauze dressing on wound healing time. A comprehensive literature search was conducted, encompassing publications up until April 1, 2023, across multiple databases including PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Cochrane Library. Stringent criteria were used to determine study inclusion and evaluate methodological quality. Statistical analyses were performed utilizing Stata 17.0. A total of 13 articles, encompassing 866 participants, were included in the analysis. The findings indicate that moist dressing surpasses gauze dressing in terms of wound healing time (standard mean difference [SMD] -2.50, 95% confidence interval [CI] -3.35 to -1.66, p < 0.01; I2 = 97.24%), wound site infection rate (odds ratio [OR] 0.30, 95% CI 0.17 to 0.54, p < 0.01; I2 = 39.91%), dressing change times (SMD -3.65, 95% CI -5.34 to -1.97, p < 0.01; I2 = 96.48%), and cost (SMD -2.66, 95% CI -4.24 to -1.09, p < 0.01; I2 = 94.90%). Subgroup analyses revealed possible variations in wound healing time based on wound types and regions. This study underscores the significant advantages associated with the use of moist dressings, including expedited wound healing, reduced infection rates, decreased frequency of dressing changes, and lower overall treatment costs.

Mechanism of sensitivity to cisplatin, docetaxel, and 5-fluorouracil chemoagents and potential erbB2 alternatives in oral cancer with growth differentiation factor 15 overexpression.

The aim of this study was to: (a) explore the potential mechanism of cancer cell sensitivity to cisplatin, docetaxel, and 5-fluorouracil (TPF) in oral squamous cell carcinoma (OSCC) patients overexpressing growth differentiation factor 15 (GDF15); and (b) identify potential alternative agents for patients who might not benefit from inductive TPF chemotherapy. The results indicated that OSCC cells overexpressing GDF15 were sensitive to TPF through a caspase-9-dependent pathway both in vitro and in vivo. Immunoprecipitation combined with mass spectrometry revealed that the erbB2 protein was a potential GDF15-binding protein, which was verified by coimmunoprecipitation. Growth differentiation factor 15 overexpression promoted OSCC cell proliferation through erbB2 phosphorylation, as well as downstream AKT and Erk signaling pathways. When GDF15 expression was blocked, the phosphorylation of both the erbB2 and AKT/Erk pathways was downregulated. When OSCC cells with GDF15 overexpression were treated with the erbB2 phosphorylation inhibitor, CI-1033, cell proliferation and xenograft growth colony formation were significantly blocked (P < .05). Thus, GDF15-overexpressing OSCC tumors are sensitive to TPF chemoagents through caspase-9-dependent pathways. Growth differentiation factor 15 overexpression promotes OSCC proliferation through erbB2 phosphorylation. Thus, ErbB2 inhibitors could represent potential targeted drugs or an alternative therapy for OSCC patients with GDF15 overexpression.

Grazoprevir/Elbasvir Treatment in Liver or Kidney Transplant Recipients with Genotype 1b Hepatitis C Virus Infection.

More options regarding the choice of direct-acting antivirals (DAAs) are helpful for avoiding individual limitations in treating hepatitis C virus (HCV) infection. We aimed to assess the efficacy and tolerability of grazoprevir (GZR)/elbasvir (EBR) treatment in genotype-1b (GT-1b) HCV-infected liver or kidney transplant recipients. In this phase 4, single-arm, open-label, multicenter trial, patients received GZR 100 mg/EBR 50 mg daily for 12 weeks. Patients with any HCV infection other than GT-1b, liver decompensation, human immunodeficiency virus, or hepatitis B virus co-infection, a history of NS5A inhibitor exposure, or any severe drug-drug interactions (DDIs), was excluded. The primary endpoint was sustained virologic response at 12 weeks posttreatment (SVR12). Of the 14 patients (10 kidney and 4 liver transplant subjects) enrolled in this study, 9 (64%) were females; the median age was 64.0 (range: 43-73) years. The regularly used immunosuppressants were tacrolimus (93%), everolimus (29%), and sirolimus (7%), with patient blood levels easily managed and generally stable (all P > 0.05 in quantile regression analysis). The rate of SVR12 was 100% in intent-to-treat analysis. Only one patient discontinued GZR/EBR therapy at 6 weeks posttreatment, due to a treatment-unrelated adverse event (AE); however, this patient remained, achieving SVR12. Most AEs were mild in severity and deemed to be not treatment-related. No organ rejection episodes or deaths occurred during the study period. The single-tablet regimen of GZR/EBR for 12 weeks is highly effective and well tolerated in GT-1b HCV-infected liver or kidney transplant recipients, and its DDIs are generally easy to manage. (This study has been registered at ClinicalTrials.gov under identifier NCT03723824.).

Lewy Body-like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α-Synuclein Mutations.

OBJECTIVE: We utilized human midbrain-like organoids (hMLOs) generated from human pluripotent stem cells carrying glucocerebrosidase gene (GBA1) and α-synuclein (α-syn; SNCA) perturbations to investigate genotype-to-phenotype relationships in Parkinson disease, with the particular aim of recapitulating α-syn- and Lewy body-related pathologies and the process of neurodegeneration in the hMLO model. METHODS: We generated and characterized hMLOs from GBA1-/- and SNCA overexpressing isogenic embryonic stem cells and also generated Lewy body-like inclusions in GBA1/SNCA dual perturbation hMLOs and conduritol-b-epoxide-treated SNCA triplication hMLOs. RESULTS: We identified for the first time that the loss of glucocerebrosidase, coupled with wild-type α-syn overexpression, results in a substantial accumulation of detergent-resistant, ß-sheet-rich α-syn aggregates and Lewy body-like inclusions in hMLOs. These Lewy body-like inclusions exhibit a spherically symmetric morphology with an eosinophilic core, containing α-syn with ubiquitin, and can also be formed in Parkinson disease patient-derived hMLOs. We also demonstrate that impaired glucocerebrosidase function promotes the formation of Lewy body-like inclusions in hMLOs derived from patients carrying the SNCA triplication. INTERPRETATION: Taken together, the data indicate that our hMLOs harboring 2 major risk factors (glucocerebrosidase deficiency and wild-type α-syn overproduction) of Parkinson disease provide a tractable model to further elucidate the underlying mechanisms for progressive Lewy body formation. ANN NEUROL 2021;90:490-505.

Impact of mind-body intervention on proinflammatory cytokines interleukin 6 and 1ß: A three-arm randomized controlled trial for persons with sleep disturbance and depression.

Depressed people are prone to sleep disturbance, which may in return perpetuate the depression. Both depression and sleep disturbance influence proinflammatory cytokines interleukin (IL) 6 and 1ß. Thus interventions for depression should consider the effect on sleep disturbance, and vice versa. Integrative Body-Mind-Spirit (IBMS) and Qigong interventions have been applied in a wide range of health and mental health conditions, including depression and sleep disturbance. This study aimed to evaluate the effect of these two mind-body therapies for persons with both depressive symptoms and sleep disturbance. A three-arm randomized controlled trial was conducted among 281 participants, who were randomly assigned to either IBMS, Qigong or wait list control group. Participants in IBMS and Qigong groups received eight weekly sessions of intervention. Outcome measures were plasma concentrations of IL-6 and IL-1ß, and a questionnaire containing Pittsburgh Sleep Quality Index, Center for Epidemiologic Studies Depression Scale, Somatic Symptom Inventory, Perceived Stress Scale and Body-Mind-Spirit Holistic Well-being Scale. Outcomes were assessed at baseline (T0), immediate post-intervention (T1) and at three-months post-intervention (T2). Besides intervention efficacy analysis, path analysis was performed to explore the relations among perceived stress, depression, sleep disturbance, and IL-6 and IL-1ß values. The study found both IBMS and Qigong reduced depression, sleep disturbance, painful and painless somatic symptoms, IL-6 and IL-1ß levels, and increased holistic well-being. The effect sizes of IBMS and Qigong, mostly in the medium magnitude range, were approximatively equivalent. Path analysis models revealed a predictive role of perceived stress in depression and sleep disturbance, a bidirectional relationship between depression and sleep disturbance, and significant influence of depression and sleep disturbance on IL-6 and IL-1ß. Compared with control, the findings support the efficacy of IBMS and Qigong interventions in relieving depression and sleep disturbance, and in reducing IL-6 and IL-1ß levels.

The impact of multidisciplinary pre-dialysis care on the outcomes of incident peritoneal dialysis patients.

BACKGROUND: This study aims to evaluate the impact of multidisciplinary pre-dialysis care (MDPC) on the risks of peritonitis, technique failure and mortality in peritoneal dialysis (PD) patients. METHODS: Incident end-stage kidney disease patients who received peritoneal dialysis (PD) for more than 90 days were recruited in this study from 1 January 1, 2007 to December 31, 2018. Patients were classified into two groups, the MDPC group and the control group, that received the usual care by nephrologists. Risks of the first episode of peritonitis, technique failure and mortality were compared between the two groups. RESULTS: There were 126 patients under the usual care and 546 patients under the MDPC. Patients in the MDPC group initiated dialysis earlier than those in the non-MDPC group. There was no significant difference between these two groups in time to the first episode of peritonitis. Compared to the non-MDPC group, the MDPC group was at similar risks of technique failure (adjusted HR = 0.85, 95% CI = 0.64-1.15) and mortality (adjusted HR = 0.66, 95% CI = 0.42-1.02). Among patients with diabetes, the risk of mortality was significantly reduced in the MDPC group with an adjusted HR of 0.45 (95% CI = 0.25-0.80). CONCLUSIONS: There was no significant difference in time to develop the first episode of peritonitis, and risks of technique failure and mortality between these two groups. Diabetic PD patients under MDPC had a lower risk of mortality than those under the usual care.

Type I, II, and III Interferon Signatures Correspond to Coronavirus Disease 2019 Severity.

We analyzed plasma levels of interferons (IFNs) and cytokines, and expression of IFN-stimulated genes in peripheral blood mononuclear cells in patients with coronavirus disease 2019 of varying disease severity. Patients hospitalized with mild disease exhibited transient type I IFN responses, while intensive care unit patients had prolonged type I IFN responses. Type II IFN responses were compromised in intensive care unit patients. Type III IFN responses were induced in the early phase of infection, even in convalescent patients. These results highlight the importance of early type I and III IFN responses in controlling coronavirus disease 2019 progression.

Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.

BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

Impact of Age on Outcome of Rifapentine-Based Weekly Therapy for Latent Tuberculosis Infection.

BACKGROUND: Weekly rifapentine and isoniazid (3HP) is gaining popularity for latent tuberculosis infection treatment because of its short course and high completion rate. Prior to widespread use, comprehensive 3HP treatment assessment covering an all-age population is essential. METHODS: Participants receiving ≥1 3HP dose from September 2014 to December 2019 were stratified into elderly (≥65 years), middle-aged (>35 & <65 years), and younger (≤35 years) age groups. This study investigated the impact of age on treatment outcome, particularly systemic drug reactions (SDRs) and 3HP discontinuation. RESULTS: Overall, 134 of 579 (23.1%) participants were elderly. The completion rate was 83.1% overall and was highest and lowest in the younger group (94.5%) and elderly (73.9%) group, respectively. However, the 3HP discontinuation rate was not significantly different among the 3 groups in multivariate logistic regression analysis. In total, 362 (62.5%) participants experienced 1 or more adverse drug reactions (ADRs), of which 38 (10.5%) and 98 (27.1%) required temporary and permanent treatment interruption, respectively. The SDR risk was 11.2% in overall and 17.1% in the middle-aged group, 3.04-fold higher than that in the elderly group (P = .025). This finding was consistently observed in different clinical settings. Hypertensive events accompanied with flu-like symptoms occurred in 11.2% of elderly participants, and accounted for 50% of grade ≥3 ADRs. CONCLUSIONS: With proper medical support and programmatic follow-up, the 3HP completion rate is >70% even in elderly participants. In middle-aged and elderly individuals, 3HP should be employed with caution because of risk of SDRs and hypertensive events, respectively. Summary: Under programmatic medical support, widespread use of weekly rifapentine and isoniazid (3HP) for latent tuberculosis treatment is possible for its high completion rate. 3HP should be employed with caution for risk of systemic drug reactions and hypertensive events in middle-aged and elderly individuals, respectively.

Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-infection and Nonalcoholic Fatty Liver Disease.

BACKGROUND: The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modulates critical metabolic pathways; however, little is known regarding effects of augmenting pulsatile GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and liver tissue in people with human immunodeficiency virus (HIV) (PWH) and nonalcoholic fatty liver disease (NAFLD). METHODS: 92 biomarkers associated with immunity, chemotaxis, and metabolism were measured in plasma samples from 61 PWH with NAFLD who participated in a double-blind, randomized trial of tesamorelin versus placebo for 12 months. Gene set enrichment analysis was performed on serial liver biopsies targeted to immune pathways. RESULTS: Tesamorelin, compared to placebo, decreased interconnected proteins related to cytotoxic T-cell and monocyte activation. Circulating concentrations of 13 proteins were significantly decreased, and no proteins increased, by tesamorelin. These included 4 chemokines (CCL3, CCL4, CCL13 [MCP4], IL8 [CXCL8]), 2 cytokines (IL-10 and CSF-1), and 4 T-cell associated molecules (CD8A, CRTAM, GZMA, ADGRG1), as well as ARG1, Gal-9, and HGF. Network analysis indicated close interaction among the gene pathways responsible for these proteins, with imputational analyses suggesting down-regulation of a closely related cluster of immune pathways. Targeted transcriptomics using liver tissue confirmed a significant end-organ signal of down-regulated immune activation pathways. CONCLUSIONS: Long-term treatment with a GHRH analog reduced markers of T-cell and monocyte/macrophage activity, suggesting that augmentation of the GH axis may ameliorate immune activation in an HIV population with metabolic dysregulation, systemic and end organ inflammation. Clinical Trials Registration. NCT02196831.

Assisted reproduction technology and long-term cardiometabolic health in the offspring.

Ronald Ma and co-authors discuss Emma Norrman and colleagues' accompanying research study on the health of children born with assisted reproductive technology.