Antidepressants for pain management in adults with chronic pain:a network meta-analysis

Background: Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients’ global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions. Objectives: To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache). Search methods: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022. Selection criteria: We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm. Data collection and analysis: Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal. Main results: This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel−armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Primary efficacy outcomes. Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) −0.31, 95% CI −0.39 to −0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD −0.22, 95% CI −0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD −0.5, 95% CI −0.78 to −0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD −0.16, 95% CI −0.22 to −0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes. Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety. There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes. Authors' conclusions: Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.</p

Decolorization of synthetic melanoidins-containing wastewater by a bacterial consortium

The presence of melanoidins in molasses wastewater leads to water pollution both due to its dark brown color and its COD contents. In this study, a bacterial consortium isolated from waterfall sediment was tested for its decolorization. The identification of culturable bacteria by 16S rDNA based approach showed that the consortium composed of Klebsiella oxytoca, Serratia mercescens, Citrobacter sp. and unknown bacterium. In the context of academic study, prevention on the difficulties of providing effluent as well as its variations in compositions, several synthetic media prepared with respect to color and COD contents based on analysis of molasses wastewater, i.e., Viandox sauce (13.5% v/v), caramel (30% w/v), beet molasses wastewater (41.5% v/v) and sugarcane molasses wastewater (20% v/v) were used for decolorization using consortium with color removal 9.5, 1.13, 8.02 and 17.5%, respectively, within 2 days. However, Viandox sauce was retained for further study. The effect of initial pH and Viandox concentration on decolorization and growth of bacterial consortium were further determined. The highest decolorization of 18.3% was achieved at pH 4 after 2 day of incubation. Experiments on fresh or used medium and used or fresh bacterial cells, led to conclusion that the limitation of decolorization was due to nutritional deficiency. The effect of aeration on decolorization was also carried out in 2 L laboratory-scale suspended cell bioreactor. The maximum decolorization was 19.3% with aeration at KLa = 2.5836 h-1 (0.1 vvm)

A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice

Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells. This cell population is abundant and conserved in the human and murine colon and endowed with polyfunctional effector properties spanning classic Th1- and Th17-cytokines, cytotoxic molecules, and regulators of epithelial homeostasis. T cells with this phenotype are increased in ulcerative colitis patients, and their presence aggravates pathology in dextran sodium sulphate-treated mice, pointing towards a pathogenic role in colitis. Our findings add to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu

The VLA/ALMA Nascent Disk and Multiplicity (VANDAM) Survey of Orion Protostars. I. Identifying and Characterizing the Protostellar Content of the OMC-2 FIR4 and OMC-2 FIR3 Regions

We present ALMA (0.87~mm) and VLA (9~mm) observations toward OMC2-FIR4 and OMC2-FIR3 within the Orion integral-shaped filament that are thought to be the nearest regions of intermediate mass star formation. We characterize the continuum sources within these regions on $\sim$40~AU (0\farcs1) scales and associated molecular line emission at a factor of $\sim$30 better resolution than previous observations at similar wavelengths. We identify six compact continuum sources within OMC2-FIR4, four in OMC2-FIR3, and one additional source just outside OMC2-FIR4. This continuum emission is tracing the inner envelope and/or disk emission on less than 100~AU scales. HOPS-108 is the only protostar in OMC2-FIR4 that exhibits emission from high-excitation transitions of complex organic molecules (e.g., methanol and other lines) coincident with the continuum emission. HOPS-370 in OMC2-FIR3 with L~$\sim$~360~\lsun, also exhibits emission from high-excitation methanol and other lines. The methanol emission toward these two protostars is indicative of temperatures high enough to thermally evaporate methanol from icy dust grains; overall these protostars have characteristics similar to hot corinos. We do not identify a clear outflow from HOPS-108 in \twco, but find evidence of interaction between the outflow/jet from HOPS-370 and the OMC2-FIR4 region. The multitude of observational constraints indicate that HOPS-108 is likely a low to intermediate-mass protostar in its main mass accretion phase and it is the most luminous protostar in OMC2-FIR4. The high resolution data presented here are essential for disentangling the embedded protostars from their surrounding dusty environments and characterizing them

Accumulation of copy number alterations and clinical progression across advanced prostate cancer

Background: Genomic copy number alterations commonly occur in prostate cancer and are one measure of genomic instability. The clinical implication of copy number change in advanced prostate cancer, which defines a wide spectrum of disease from high-risk localised to metastatic, is unknown. Methods: We performed copy number profiling on 688 tumour regions from 300 patients, who presented with advanced prostate cancer prior to the start of long-term androgen deprivation therapy (ADT), in the control arm of the prospective randomised STAMPEDE trial. Patients were categorised into metastatic states as follows; high-risk non-metastatic with or without local lymph node involvement, or metastatic low/high volume. We followed up patients for a median of 7 years. Univariable and multivariable Cox survival models were fitted to estimate the association between the burden of copy number alteration as a continuous variable and the hazard of death or disease progression. Results: The burden of copy number alterations positively associated with radiologically evident distant metastases at diagnosis (P=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P=0.003) and death (P=0.045) for each unit increase, stabilising into more modest increases with higher copy number burdens. This association between copy number burden and outcome was similar in each metastatic state. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1 × 10−6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC occurred more frequently in cases with higher copy number alteration (for either region: Kolmogorov–Smirnov distance, 0.5; adjusted P<0.0001). Copy number alterations showed variability across tumour regions in the same prostate. This variance associated with increased risk of distant metastases (Kruskal-Wallis test P=0.037). Conclusions: Copy number alteration in advanced prostate cancer associates with increased risk of metastases at diagnosis. Accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death. The increased likelihood of involvement of specific segments in high copy number alteration burden cancers may suggest an order underlying the accumulation of copy number changes

Trivalent Adenovirus Type 5 HIV Recombinant Vaccine Primes for Modest Cytotoxic Capacity That Is Greatest in Humans with Protective HLA Class I Alleles

If future HIV vaccine design strategies are to succeed, improved understanding of the mechanisms underlying protection from infection or immune control over HIV replication remains essential. Increased cytotoxic capacity of HIV-specific CD8+ T-cells associated with efficient elimination of HIV-infected CD4+ T-cell targets has been shown to distinguish long-term nonprogressors (LTNP), patients with durable control over HIV replication, from those experiencing progressive disease. Here, measurements of granzyme B target cell activity and HIV-1-infected CD4+ T-cell elimination were applied for the first time to identify antiviral activities in recipients of a replication incompetent adenovirus serotype 5 (Ad5) HIV-1 recombinant vaccine and were compared with HIV-negative individuals and chronically infected patients, including a group of LTNP. We observed readily detectable HIV-specific CD8+ T-cell recall cytotoxic responses in vaccinees at a median of 331 days following the last immunization. The magnitude of these responses was not related to the number of vaccinations, nor did it correlate with the percentages of cytokine-secreting T-cells determined by ICS assays. Although the recall cytotoxic capacity of the CD8+ T-cells of the vaccinee group was significantly less than that of LTNP and overlapped with that of progressors, we observed significantly higher cytotoxic responses in vaccine recipients carrying the HLA class I alleles B*27, B*57 or B*58, which have been associated with immune control over HIV replication in chronic infection. These findings suggest protective HLA class I alleles might lead to better outcomes in both chronic infection and following immunization due to more efficient priming of HIV-specific CD8+ T-cell cytotoxic responses

The E Sibling Project - exploratory randomised controlled trial of an online multi-component psychoeducational intervention for siblings of individuals with first episode psychosis

Background:Siblings of individuals with first episode psychosis are natural partners to promote service users’recovery and are themselves vulnerable to mental ill health due to the negative impact of psychosis withinthe family. This study aims to develop and undertake a preliminary evaluation of the efficacy of an onlinemulti-component psychoeducational intervention for siblings of individuals with first episode psychosis. Theimpetus for the intervention arose from siblings' expressed needs for peer support and information on psychosis,coping and management strategies for common symptoms and ways to promote recovery. Methods/Design:The project design draws on the Medical Research Council framework for the design andevaluation of complex interventions. Mixed methods comprising collection of qualitative focus group data,systematic review and expert advisory group consultation are used to develop the theoretical basis for and designof the intervention. This protocol focuses on the modelling and piloting phase which uses a randomised controlledtrial with factorial design to test the efficacy of the intervention. Outcome data on participants’mental wellbeing,knowledge, perceived self-efficacy and experiences of caregiving will be assessed at baseline, at end of theintervention (10 weeks later) and at 10 week follow-up. In addition, a post-intervention semi-structured interviewwith 20% of the participants will explore their experiences and acceptability of the intervention. Discussion:This multi-component online psychoeducational intervention aims to enhance siblings' knowledgeabout psychosis and their coping capacity, thus potentially improving their own mental wellbeing and promotingtheir contribution to service users’recovery. The factorial design randomised controlled trial with a supplementaryprocess evaluation using semi-structured interviews and usage-monitoring will collect preliminary evidence ofefficacy, feasibility and acceptability, as well as feedback about the barriers and strategies to using such aninnovative resource. The RCT will provide data for estimating the likely effect size of the intervention on outcomesfor siblings and inform the development of a definitive future trial

Determinants of Depressive Symptoms at 1 Year Following ICU Discharge in Survivors of $ 7 Days of Mechanical Ventilation : Results From the RECOVER Program, a Secondary Analysis of a Prospective Multicenter Cohort Study

Abstract : Background: Moderate to severe depressive symptoms occur in up to one-third of patients at 1 year following ICU discharge, negatively affecting patient outcomes. This study evaluated patient and caregiver factors associated with the development of these symptoms. Methods: This study used the Rehabilitation and Recovery in Patients after Critical Illness and Their Family Caregivers (RECOVER) Program (Phase 1) cohort of 391 patients from 10 medical/surgical university-affiliated ICUs across Canada. We determined the association between patient depressive symptoms (captured by using the Beck Depression Inventory II [BDI-II]), patient characteristics (age, sex, socioeconomic status, Charlson score, and ICU length of stay [LOS]), functional independence measure (FIM) motor subscale score, and caregiver characteristics (Caregiver Assistance Scale and Center for Epidemiologic Studies-Depression Scale) by using linear mixed models at time points 3, 6, and 12 months. Results: BDI-II data were available for 246 patients. Median age at ICU admission was 56 years (interquartile range, 45-65 years), 143 (58%) were male, and median ICU LOS was 19 days (interquartile range, 13-32 days). During the 12-month follow-up, 67 of 246 (27.2%) patients had a BDI-II score ≥ 20, indicating moderate to severe depressive symptoms. Mixed models showed worse depressive symptoms in patients with lower FIM motor subscale scores (1.1 BDI-II points per 10 FIM points), lower income status (by 3.7 BDI-II points; P = .007), and incomplete secondary education (by 3.8 BDI-II points; P = .009); a curvilinear relation with age (P = .001) was also reported, with highest BDI-II at ages 45 to 50 years. No associations were found between patient BDI-II and comorbidities (P = .92), sex (P = .25), ICU LOS (P = .51), or caregiver variables (Caregiver Assistance Scale [P = .28] and Center for Epidemiologic Studies Depression Scale [P = .74]). Conclusions: Increased functional dependence, lower income, and lower education are associated with increased severity of post-ICU depressive symptoms, whereas age has a curvilinear relation with symptom severity. Knowledge of risk factors may inform surveillance and targeted mental health follow-up. Early mobilization and rehabilitation aiming to improve function may serve to modify mood disorders

Wellbeing, mental health knowledge and caregiving experiences of siblings of people with psychosis, compared to their peers and parents: An exploratory study

Purpose The wellbeing and caregiving experiences of family carers supporting people with psychosis has garnered increasing interest. Evidence indicates that the burden of caregiving can adversely impact on parents’ wellbeing, few studies have investigated whether this is also the case for siblings, who often take on caregiving responsibilities. This exploratory study investigated the wellbeing, mental health knowledge, and appraisals of caregiving in siblings of individuals with psychosis. Method Using a cross-sectional design, 90 siblings completed three validated questionnaires: Warwick–Edinburgh Mental Wellbeing Scale (WEMWBS), Mental Health Knowledge Schedule (MAKS), and Experience of Caregiving Inventory (ECI). Data obtained were compared to general population norms and parent-carers’ scores. Multi-variable regression analyses were conducted to examine relationships between questionnaire scores and demographic characteristics including age, sex, birth order, marital status, accommodation and educational level. Results Siblings, especially sisters, had significantly poorer mental wellbeing, compared to normative scores. Conversely, they had better mental health knowledge. Siblings and parent-carers had comparable high levels of negative appraisals of caregiving experiences, but siblings reported more satisfaction with personal experiences and relationships. Education level was a significant predictor for better mental health knowledge; there were no other relationships between siblings’ demographic factors and outcomes. Conclusion Study findings suggest that siblings have overlapping as well as distinct needs, compared to parent-carers. Further research is required to better understand siblings’ experiences so as to inform development of targeted interventions that enhance wellbeing and caregiving capacity