Technology-assisted cognitive-behavior therapy delivered by peers versus standard cognitive behavior therapy delivered by community health workers for perinatal depression: study protocol of a cluster randomized controlled non-inferiority trial.

BACKGROUND: The lack of trained mental health professionals is a key barrier to scale-up of evidence-based psychological interventions in low and middle-income countries. We have developed an app that allows a peer with no prior experience of health-care delivery to deliver the cognitive therapy-based intervention for perinatal depression, the Thinking Healthy Programme (THP). This trial aims to assess the effectiveness and cost-effectiveness of this Technology-assisted peer-delivered THP versus standard face-to-face Thinking Healthy Programme delivered by trained health workers. METHODS: We will employ a non-inferiority stratified cluster randomized controlled trial design comparing the two formats of intervention delivery. A total of 980 women in the second or third trimester of pregnancy with a diagnosis of Major Depressive Episode, evaluated with the Structured Clinical Interview for DSM-V Disorders (SCID), will be recruited into the trial. The unit of randomization will be 70 village clusters randomly allocated in a 1:1 ratio to the intervention and control arms. The primary outcome is defined as remission from major depressive episode at 3 months postnatal measured with the SCID. Data will also be collected on symptoms of anxiety, disability, quality of life, service use and costs, and infant-related outcomes such as exclusive breastfeeding and immunization rates. Data will be collected on the primary outcome and selected secondary outcomes (depression and anxiety scores, exclusive breastfeeding) at 6 months postnatal to evaluate if the improvements are sustained in the longer-term. We are especially interested in sustained improvement (recovery) from major depressive episode. DISCUSSION: This trial will evaluate the effectiveness and cost-effectiveness of a technology-assisted peer-delivered cognitive behavioral therapy-based intervention in rural Pakistan. If shown to be effective, the novel delivery format could play a role in reducing the treatment gap for perinatal depression and other common mental disorders in LMIC. TRIAL REGISTRATION: The trial was registered at Clinicaltrials.gov (NCT05353491) on 29 April 2022.

Arterial Versus Venous Blood Gas Analysis Comparisons, Appropriateness, and Alternatives in Different Acid/Base Clinical Settings: A Systematic Review.

Arterial blood gases (ABGs) are routinely done in critical clinical settings to ascertain acid-base status. Due to difficulties and the potential side effects following arterial blood sampling, much research has been done to find the possibility of using venous samples as an alternative. However, this comparison needs to be evaluated in various contexts. Hence, this systematic review aims to explore the differences, appropriateness, and alternatives of arterial versus venous blood gas (VBG) analysis in different acid-base states. A comprehensive literature search was conducted through electronic databases using the terms "ABG," "VBG," "Arterial Blood Gas," "Venous Blood Gas," and "Gas analysis." Studies' qualities were assessed by using Newcastle - Ottawa Quality Assessment Scale. Of 531 articles, 22 were included in the study after title, abstract, and full-text screening. Based on the Newcastle - Ottawa Quality Assessment Scale, 23% of the studies had good quality (score ≥ 7), 77% fair quality (score 2-6), and none of the studies had poor quality (score ≤ 1). Moreover, 22.5% of the included articles found a strong correlation between ABG and VBG. 73% compared arterial and VBG parameters among patients with any clinical contexts, 22.5% in respiratory diseases, and 4.5% in metabolic conditions, and their results had a significant disparity. There was a considerable discrepancy among authors about the appropriateness and utilization of VBG as an alternative to ABG. Our findings suggest that those studies did not consider physiological differences between venous and arterial blood values and obviated the significance of sampling procedures.

Transcriptional profiling of human Vδ1 T cells reveals a pathogen-driven adaptive differentiation program.

γδ T cells are generally considered innate-like lymphocytes, however, an "adaptive-like" γδ compartment has now emerged. To understand transcriptional regulation of adaptive γδ T cell immunobiology, we combined single-cell transcriptomics, T cell receptor (TCR)-clonotype assignment, ATAC-seq, and immunophenotyping. We show that adult Vδ1+ T cells segregate into TCF7+LEF1+Granzyme Bneg (Tnaive) or T-bet+Eomes+BLIMP-1+Granzyme B+ (Teffector) transcriptional subtypes, with clonotypically expanded TCRs detected exclusively in Teffector cells. Transcriptional reprogramming mirrors changes within CD8+ αß T cells following antigen-specific maturation and involves chromatin remodeling, enhancing cytokine production and cytotoxicity. Consistent with this, in vitro TCR engagement induces comparable BLIMP-1, Eomes, and T-bet expression in naive Vδ1+ and CD8+ T cells. Finally, both human cytomegalovirus and Plasmodium falciparum infection in vivo drive adaptive Vδ1 T cell differentiation from Tnaive to Teffector transcriptional status, alongside clonotypic expansion. Contrastingly, semi-invariant Vγ9+Vδ2+ T cells exhibit a distinct "innate-effector" transcriptional program established by early childhood. In summary, adaptive-like γδ subsets undergo a pathogen-driven differentiation process analogous to conventional CD8+ T cells.

Predictors of Prenatal Depression: A Cross-Sectional Study in Rural Pakistan.

Objective: To determine the prevalence and association of prenatal depression with socioeconomic, demographic and personal factors among pregnant women living in Kallar Syedan, Rawalpindi, Pakistan. Methods: Five hundred women in the second and third trimester of pregnancy, living in Kallar Syedan, a rural area of district Rawalpindi Pakistan, were included in the study. Depression was assessed using "Patient health questionnaire" (PHQ9) in Urdu, with a cut-off score of 10. Multi-dimensional scale of perceived social support (MSPSS) was used to assess perceived social support. Life Events and Difficulties Schedule (LEDS) were used to measure stressful life events in past 1 year. Tool to assess intimate partner violence (IPV) was based on WHO Multi Country Study on "Women's Health and Domestic Violence against Women." Results: Prevalence of prenatal depression was found to be 27%. Number of pregnancies was significantly associated with prenatal depression (p < 0.01). Women living in a joint family and those who perceived themselves as moderately satisfied or not satisfied with their life in the next 4 years were found to be depressed (p < 0.01, OR 6.9, CI 1.77-26.73). Depressive symptomatology in women who experienced more than five stressful life events in last 1 year was three times higher (p < 0.001, OR 3.2, CI 1.68-5.98) than in women with 1-2 stressful events. Women who were supported by their significant others or their family members had 0.9 times (p < 0.01, OR 0.9, CI 0.85-0.96) less chance of getting depressed. Pregnant women who were psychologically abused by their partners were 1.5 times more depressed (p < 0.05 CI 1.12-2.51). Odds of having depression was also high in women who had less mean score of MSSI (p < 0.05, OR 1.1, CI 1.01-1.09). Women who had suitable accommodation had 0.5 times less chance of having depression than others (p < 0.05, OR 0.5, CI 0.27-0.92). Conclusion: Over a quarter of the women in the study population reported prenatal depression, which were predicted predominantly by psychosocial variables.

Psychometric Validation of the Multidimensional Scale of Perceived Social Support During Pregnancy in Rural Pakistan.

Background: The Multidimensional Scale of Perceived Social Support (MSPSS) is a short and reliable instrument that assesses perceived social support from the social network of an individual. A previous study in Pakistan among postpartum women has demonstrated a unidimensional factor structure in contrast to the original three-factor structure. The emergence of a one-factor structure for postpartum women in Pakistan may be due to traditional postpartum practices unique to the women of the subcontinent. Building upon the previous evidence, this study aims to explore the psychometric properties of MSPSS among pregnant women in their third trimester in rural Pakistan. Methods: A cross-sectional survey was conducted from October 2014 to February 2016, in rural Pakistan. A sample of 1,154 pregnant women (aged ≥ 18 years) in their third trimester who were registered with the local Lady Health Worker Program and were living in the north of the Punjab Province was included in this study. They were assessed using Urdu translated scales of Patient Health Questionnaire, MSPSS, Maternal Social Support Index, and Perceived Stress Scale. Principal Axis Factoring was used to assess the construct validity of the MSPSS. Results: The MSPSS scale showed an excellent internal consistency, yielding a Cronbach's α-value of 0.933. The MSPSS scale exhibited an excellent construct validity, and confirmatory factor analysis retained three factors (family, friends, and significant others) for both the depressed and non-depressed samples. Internal reliability and construct validity were also established. Conclusion: The psychometric findings suggest that the tridimensional structure of MSPSS is a valid and reliable measure of perceived social support among the Pakistani population with and without perinatal depression. The perceived social support is an important predictor of maternal mental well-being and psychopathologies, and the MSPSS can serve as a useful tool in mental health research in Pakistan.

Generation of Stable Isopentenyl Monophosphate Aryloxy Triester Phosphoramidates as Activators of Vγ9Vδ2 T Cells.

Aryloxy triester phosphoramidate prodrugs of the monophosphate derivatives of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) were synthesized as lipophilic derivatives that can improve cell uptake. Despite the structural similarity of IPP and DMAPP, it was noted that their phosphoramidate prodrugs exhibited distinct stability profiles in aqueous environments, which we show is due to the position of the allyl bond in the backbones of the IPP and DMAPP monophosphates. As the IPP monophosphate aryloxy triester phosphoramidates showed favorable stability, they were subsequently investigated for their ability to activate Vγ9/Vδ2 T cells and they showed promising activation of this subset of T cells. Together, these findings represent the first report of IPP and DMAPP monophosphate prodrugs and the ability of IPP aryloxy triester phosphoramidate prodrugs to activate Vγ9/Vδ2 T cells highlighting their potential as possible immunotherapeutics.

Accuracy of Community Informant Led Detection of Maternal Depression in Rural Pakistan.

Maternal depression is a global mental health and a public health priority. Despite the priority its active detection is still a challenge. We tested the accuracy of an adapted version of Community Informant Detection Tool for Maternal Depression (CIDT-MD) in rural settings of Pakistan. Using a single stage design, trained community informants (lady health workers and lay peers) identified women (pregnant and/or with children) with symptoms of probable depression using CIDT-MD. This was immediately followed by diagnostic interviews of all the women using the Structured Clinical Interview for the Diagnostic and Statistical Manual (SCID-V) for current major depressive episode by trained assessors, blinded to the outcome of CIDT-MD. Data were analyzed using Statistical Package for Social Sciences (Version 25.0, IBM Corp., Armonk, NY, USA) and FACTOR software (Version. 10.3.01, Virgili University, Tarragona, Spain). Descriptive statistics, factor analysis, validity, reliability and known group validity was conducted to evaluate the psychometric properties of the adapted CIDT-MD. In all, 425 women, with mean age of 28 years (SD = 4.7), participated. Nearly 10% were illiterate, while the rest (90%) had an education ranging from eight to 15 years of schooling. The majority (73.2%) of the participants had 1-3 children while only 17.4% had >3 children. The sensitivity and specificity of CIDT-MD in detecting depressive symptoms was 97.5% (95% CI: 94.2-99.1) and 82.4% (95% CI: 77.8-86.4) respectively. It's positive predictive value (PPV), 77.3% (95% CI: 72.9-81.2) and the negative predictive value (NPV) was 98.17% (95% CI: 95.7-99.2). While factor analysis revealed high inter-item correlation for most items (0.62-0.77) with an adequately fair Kaiser-Meyer-Olkin (KMO) sampling adequacy (0.73), significant Bartlett's test of sphericity (p < 0.001). Uni-dimensionality for the CIDT-MD based on one-dimensional congruence (0.97), explained common variance (0.85), excellent internal consistency (0.90), good criterion validity (Area Under Curve = 81%), tester-test reliability (0.87-0.89) and statistically significant known group analysis (p < 0.001). The adapted version of the Community Informant Detection Tool for Maternal Depression is a valid and a reliable tool for active case detection of maternal depression in rural settings of Pakistan.

Aryloxy Diester Phosphonamidate Prodrugs of Phosphoantigens (ProPAgens) as Potent Activators of Vγ9/Vδ2 T-Cell Immune Responses.

Vγ9/Vδ2 T-cells are activated by pyrophosphate-containing small molecules known as phosphoantigens (PAgs). The presence of the pyrophosphate group in these PAgs has limited their drug-like properties because of its instability and polar nature. In this work, we report a novel and short Grubbs olefin metathesis-mediated synthesis of methylene and difluoromethylene monophosphonate derivatives of the PAg (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBP) as well as their aryloxy diester phosphonamidate prodrugs, termed ProPAgens. These prodrugs showed excellent stability in human serum (t1/2 > 12 h) and potent activation of Vγ9/Vδ2 T-cells (EC50 ranging from 5 fM to 73 nM), which translated into sub-nanomolar γδ T-cell-mediated eradication of bladder cancer cells in vitro. Additionally, a combination of in silico and in vitro enzymatic assays demonstrated the metabolism of these phosphonamidates to release the unmasked PAg monophosphonate species. Collectively, this work establishes HMBP monophosphonate ProPAgens as ideal candidates for further investigation as novel cancer immunotherapeutic agents.

Effectiveness of a peer-delivered, psychosocial intervention on maternal depression and child development at 3 years postnatal: a cluster randomised trial in Pakistan.

BACKGROUND: Maternal depression has a recurring course that can influence offspring outcomes. Evidence on how to treat maternal depression to improve longer-term maternal outcomes and reduce intergenerational transmission of psychopathology is scarce, particularly for task-shifted, low-intensity, and scalable psychosocial interventions. We evaluated the effects of a peer-delivered, psychosocial intervention on maternal depression and child development at 3 years postnatal. METHODS: 40 village clusters in Pakistan were randomly allocated using a computerised randomisation sequence to receive a group-based, psychosocial intervention and enhanced usual care for 36 months, or enhanced usual care alone. Pregnant women (≥18 years) were screened for moderate or severe symptoms of depression (patient health questionnaire-9 [PHQ-9] score ≥10) and were recruited into the trial (570 participants), and a cohort without depression (PHQ-9 score <10) was also enrolled (584 participants). Including the non-depressed dyads enabled us to determine how much of the excess risk due to maternal depression exposure the intervention could mitigate. Research teams responsible for identifying, obtaining consent, and recruiting trial participants were blind to the allocation status throughout the duration of the study, and principal investigators, site coordinators, statisticians, and members of the trial steering committee were also blinded to the allocation status until the analysis of 6-month data for the intervention. Primary outcomes were maternal depression symptoms and remission (PHQ-9 score <10) and child socioemotional skills (strengths and difficulties questionnaire [SDQ-TD]) at 36-months postnatal. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02658994. FINDINGS: From Oct 15, 2014 to Feb 25, 2016 46 village clusters were assessed for eligibility, of which 40 (including 1910 mothers were enrolled. After exclusions, 288 women were randomly assigned to the enhanced usual care group and 284 to the intervention group, and 1159 women were included in a group without prenatal depression. At 36-months postnatal, complete data were available from 889 mother-child dyads: 206 (72·5%) in the intervention group, 216 (75·3%) in the enhanced usual care group, and 467 (80·0%) women who did not have prenatal-depression. We did not observe significant outcome differences between the intervention group and the enhanced usual care group for the primary outcomes. The standardised mean difference of PHQ-9 total score was -0·13 (95% CI -0·33 to 0·07), relative risk of patient health questionnaire-9 remission was 1·00 (95% CI 0·88 to 1·14), and the SDQ-TD treatment estimate was -0·10 (95% CI -1·39 to 1·19). INTERPRETATION: Reduced symptom severity and high remission rates were seen across both the intervention and enhanced usual care groups, possibly masking any effects of the intervention. A multi-year, psychosocial intervention can be task-shifted via peers but might be susceptible to reductions in fidelity and dosage over time (which were not among the outcomes of this trial). Early intervention efforts might need to rely on multiple models (eg, collaborative care), be of greater intensity, and potentially targeted at mothers who are at high risk for depression to reduce the intergenerational transmission of psychopathology from mothers to children. FUNDING: National Institutes of Health.

Effectiveness of the Thinking Healthy Programme for perinatal depression delivered through peers: Pooled analysis of two randomized controlled trials in India and Pakistan.

BACKGROUND: The Thinking Healthy Programme (THP) is recommended to treat perinatal depression in resource-limited settings, but scale-up is hampered by a paucity of community health workers. THP was adapted for peer-delivery (THPP) and evaluated in two randomized controlled trials in India and Pakistan. Our aim was to estimate the effectiveness of THPP on maternal outcomes across these two settings, and evaluate effect-modification by country and other pre-defined covariates. METHODS: Participants were pregnant women aged≥18 years with depression (Patient Health Questionnaire (PHQ-9) score≥10), randomized to THPP plus enhanced usual care (EUC) or EUC-only. Primary outcomes were symptom severity and remission (PHQ-9 score<5) 6 months post-childbirth. Secondary outcomes included further measures of depression, disability and social support at 3 and 6 months post-childbirth. RESULTS: Among 850 women (280 India; 570 Pakistan), 704 (83%) attended 6-month follow-up. Participants in the intervention arm had lower symptom severity (PHQ-9 score adjusted mean difference -0.78 (95% confidence interval -1.47,-0.09)) and higher odds of remission (adjusted odds ratio 1.35 (1.02,1.78)) versus EUC-only. There was a greater intervention effect on remission among women with short chronicity of depression, and those primiparous. There were beneficial intervention effects across multiple secondary outcomes. LIMITATIONS: The trials were not powered to assess effect-modifications. 10-20% of participants were missing outcome data. CONCLUSIONS: This pooled analysis demonstrates the effectiveness, acceptability and feasibility of THPP, which can be scaled-up within a stepped-care approach by engaging with the existing health care systems and the communities to address the treatment gap for perinatal depression in resource-limited settings.

Delivering the Thinking Healthy Programme for perinatal depression through volunteer peers: a cluster randomised controlled trial in Pakistan.

BACKGROUND: The Thinking Healthy Programme (THP), which is endorsed by WHO, is an evidence-based intervention for perinatal depression. We adapted THP for delivery by volunteer peers (laywomen from the community) to address the human resource needs in bridging the treatment gap, and we aimed to assess its effectiveness and cost-effectiveness in Rawalpindi, Pakistan. METHODS: In this cluster randomised controlled trial, we randomly assigned 40 village clusters (1:1) to provide either THP peer-delivered (THPP) and enhanced usual care (EUC; intervention group) or EUC only (control group) to the participants within clusters. These villages were randomly selected from eligible villages by an independent researcher. The participants were pregnant women aged 18 years or older who had scored at least 10 on the Patient Health Questionnaire-9 (PHQ-9), who we recruited from households within communities in Rawalpindi, Pakistan. The research teams who were responsible for recruiting trial participants were masked to treatment allocations. Participants attended follow-up visits at 3 and 6 months after childbirth. The primary outcomes were the severity of depressive symptoms (assessed by PHQ-9 score) and the prevalence of remission (defined as a PHQ-9 score of less than 5) in participants with available data 6 months after childbirth, which was assessed by researchers who were masked to treatment allocations. We analysed outcomes by intention to treat, adjusting for covariates that were defined a priori or that showed imbalance at baseline. The trial was registered with ClinicalTrials.gov, number NCT02111915. FINDINGS: Between April 15 and July 30, 2014, we randomly selected 40 of 46 eligible village clusters for assessment, as per sample size calculations. Between Oct 15, 2014, and Feb 25, 2016, we identified and screened 971 women from 20 village clusters that had been randomly assigned to the THPP and EUC group and 939 women from 20 village clusters that had been randomly assigned to the EUC only group. In the intervention group, 79 women were ineligible for inclusion, 11 women refused screening, 597 women screened negative on the PHQ-9, and one woman did not consent to participate. In the control group, 75 women were ineligible for inclusion, 14 women refused screening, 562 women screened negative on the PHQ-9, and one woman did not consent to participate. We enrolled 283 (29%) women in the intervention group and 287 (31%) women in the control group. At 6 months after childbirth, 227 (80%) women in the THPP and EUC group and 226 (79%) women in the EUC only group were assessed for the primary outcome. The severity of depression (assessed by PHQ-9 scores; standardised mean difference -0·13, 95% CI -0·31 to 0·06; p=0·07) and prevalence of remission (49% in the intervention group vs 45% in the control group; prevalence ratio 1·12, 95% CI 0·95 to 1·29; p=0·14) did not significantly differ between the groups 6 months after childbirth. There was no evidence of significant differences in serious adverse events between the groups. INTERPRETATION: THPP had no effect on symptom severity or remission from perinatal depression at 6 months after childbirth, but we found that it was beneficial on some other metrics of severity and disability and that it was cost-effective. THPP could be a step towards use of an unused human resource to address the treatment gap in perinatal depression. FUNDING: National Institute of Mental Health (USA).

MCE domain proteins: conserved inner membrane lipid-binding proteins required for outer membrane homeostasis.

Bacterial proteins with MCE domains were first described as being important for Mammalian Cell Entry. More recent evidence suggests they are components of lipid ABC transporters. In Escherichia coli, the single-domain protein MlaD is known to be part of an inner membrane transporter that is important for maintenance of outer membrane lipid asymmetry. Here we describe two multi MCE domain-containing proteins in Escherichia coli, PqiB and YebT, the latter of which is an orthologue of MAM-7 that was previously reported to be an outer membrane protein. We show that all three MCE domain-containing proteins localise to the inner membrane. Bioinformatic analyses revealed that MCE domains are widely distributed across bacterial phyla but multi MCE domain-containing proteins evolved in Proteobacteria from single-domain proteins. Mutants defective in mlaD, pqiAB and yebST were shown to have distinct but partially overlapping phenotypes, but the primary functions of PqiB and YebT differ from MlaD. Complementing our previous findings that all three proteins bind phospholipids, results presented here indicate that multi-domain proteins evolved in Proteobacteria for specific functions in maintaining cell envelope homeostasis.