Mental health and quality of life in patients with chronic liver disease: a single-center structural equation model.

BACKGROUND: Chronic liver disease (CLD) is one of the leading disease burdens in Pakistan. Until now, there has only been limited focus in the country on providing health services through tertiary services in urban cities, whereas there is almost no research in Pakistan on the mental health and quality of life of CLD patients. This study aimed to understand which predictors influence the mental health and quality of life of CLD patients in order to advise better policy protection. METHODS: Data was collected from CLD patients at the Pakistan Kidney and Liver Institute and Research Centre, Lahore, Pakistan. A total of 850 respondents were part of the final sample. The age of respondents ranged from 18 to 79 years and included the following diagnosis: (i) Chronic Viral Hepatitis (n = 271), (ii) Cirrhosis (n = 259), (iii) Hepatocellular Carcinoma (n = 193), and (iv) Non-viral Liver Disease (n = 127). RESULTS: Mean results reveal that females as well as illiterate patients need more support for mental health and communication with their physician; whereas men need more support to develop coping strategies. Structural equation modelling results reveal that the severity of symptoms (ß = 0.24, p < 0.001), coping strategies (ß=-0.51, p < 0.001), and doctor communication (ß=-0.35, p < 0.001) predict mental health. Quality of life is associated with the severity of symptoms (ß=-0.36, p < 0.001), coping strategies (ß = 0.26, p < 0.05), and doctor communication (ß = 0.09, p < 0.05). CONCLUSIONS: A 'bio-psycho-social-spiritual' model is recommended for Pakistan's CLD patients which includes the integration of social officers to provide support in four key areas to secure mental health and quality of life of patients.

Risk factors leading to pulmonary exacerbation in patients with cystic fibrosis: A systematic review.

OBJECTIVE: To ascertain major risk factors associated with pulmonary exacerbation and pulmonary function decline in cystic fibrosis. METHODS: The systematic review was conducted at Aga Khan University, Karachi, in September 2018, and comprised electronic search of PubMed, Ovid, Science Direct and Cumulative Index of Nursing and Allied Health Literature databases of studies conducted from January 1990 to September 2018 which were categorised into 3 sets; 1990-98, 1999-2007 and 2008-18. Studies included for review focussed on articles with pulmonary exacerbation as the health outcome indicator, and had diagnosis of cystic fibrosis as the inclusion criteria, while risk factors were the exposure terms used in the search process. References in bibliographies of the included studies were also systematically searched for relevant documents. RESULTS: Of the 60 studies obtained, 31(51.7%) were selected; 2(6.45%) from 1990-98, 7(22.58%) from 1999-2007 and 22(70.96%) from 2008-18. Overall, 17(54.83%) were cohort studies, 7(22.5%) were cross-sectional studies, 3(9.6%) were case-control studies, 3(9.6%) were randomised controlled trials and 1(3.2%) was systematic review and meta-analysis. In terms of major risk factors, genetic mutations were cited by 4(12.9%) studies, infections and inflammatory biomarkers by 15(48.4%), nutritional deficiencies by 9(29%) and geographical and socioeconomic status by 3(9.6%) studies. CONCLUSIONS: Early identification and recognition of risk factors associated with pulmonary exacerbation can have an explicit impact on its management, leading to decreased morbidity and mortality burden in cystic fibrosis cases.

Health challenges of mothers with special needs children in Pakistan and the importance of integrating health social workers.

There is concern that mothers of special needs children in developing countries like Pakistan are neglected populations facing hidden health challenges. The aim of this study was to investigate the kinds of health challenges mothers experience and to highlight the role of health social workers in supporting the needs of mothers. Twenty-one mothers were sampled across three cities and findings were analyzed through a thematic content analysis approach. Findings revealed that mothers faced significant and salient challenges under eight sub-categories of mental health and six sub-categories of physical health. We recommend that health social workers collaborate with healthcare practitioners to improve health services for mothers and also coordinate with other social workers, community members, and policymakers for improving both social and structural support for special needs families.

Inhibition of Prenylation Promotes Caspase 3 Activation, Lamin B Degradation and Loss in Metabolic Cell Viability in Pancreatic ß-Cells.

BACKGROUND/AIMS: Lamins are intermediate filament proteins that constitute the main components of the lamina underlying the inner-nuclear membrane and serve to organize chromatin. Lamins (e.g., lamin B) undergo posttranslational modifications (e.g., isoprenylation) at their C-terminal cysteine residues. Such modifications are thought to render optimal association of lamins with the nuclear envelop. Using human islets, rodent islets, and INS-1 832/13 cells, we recently reported significant metabolic defects under glucotoxic and endoplasmic reticulum (ER) stress conditions, including caspase 3 activation and lamin B degradation. The current study is aimed at further understanding the regulatory roles of protein prenylation in the induction of the aforestated metabolic defects. METHODS: Subcellular phase partitioning assay was done using Triton X-114. Cell morphology and metabolic cell viability assays were carried out using standard methodologies. RESULTS: We report that exposure of pancreatic ß-cells to Simvastatin, an inhibitor of mevalonic acid (MVA) biosynthesis, and its downstream isoprenoid derivatives, or FTI-277, an inhibitor of farnesyltransferase that mediates farnesylation of lamins, leads to activation of caspase 3 and lamin B degradation. Furthermore, Simvastatin-treatment increased activation of p38MAPK (a stress kinase) and inhibited ERK1/2 (regulator of cell proliferation). Inhibition of farnesylation also resulted in the release of degraded lamin B into the cytosolic fraction and promoted loss in metabolic cell viability. CONCLUSION: Based on these findings we conclude that protein prenylation plays key roles in islet ß-cell function. These findings affirm further support to the hypothesis that defects in prenylation pathway induce caspase-3 activation and nuclear lamin degradation in pancreatic ß-cells under the duress of metabolic stress (e.g., glucotoxicity).

VAV2, a guanine nucleotide exchange factor for Rac1, regulates glucose-stimulated insulin secretion in pancreatic beta cells.

AIMS/HYPOTHESIS: Rho GTPases (Ras-related C3 botulinum toxin substrate 1 [Rac1] and cell division cycle 42 [Cdc42]) have been shown to regulate glucose-stimulated insulin secretion (GSIS) via cytoskeletal remodelling, trafficking and fusion of insulin-secretory granules with the plasma membrane. GTP loading of these G proteins, which is facilitated by GDP/GTP exchange factors, is a requisite step in the regulation of downstream effector proteins. Guanine nucleotide exchange factor VAV2 (VAV2), a member of the Dbl family of proteins, has been identified as one of the GDP/GTP exchange factors for Rac1. Despite recent evidence on the regulatory roles of VAV2 in different cell types, roles of this guanine nucleotide exchange factor in the signalling events leading to GSIS remain undefined. Using immunological, short interfering RNA (siRNA), pharmacological and microscopic approaches we investigated the role of VAV2 in GSIS from islet beta cells. METHODS: Co-localisation of Rac1 and VAV2 was determined by Triton X-114 phase partition and confocal microscopy. Glucose-induced actin remodelling was quantified by live cell imaging using the LifeAct-GFP fluorescent biosensor. Rac1 activation was determined by G protein linked immunosorbent assay (G-LISA). RESULTS: Western blotting indicated that VAV2 is expressed in INS-1 832/13 beta cells, normal rat islets and human islets. Vav2 siRNA markedly attenuated GSIS in INS-1 832/13 cells. Ehop-016, a newly discovered small molecule inhibitor of the VAV2-Rac1 interaction, or siRNA-mediated knockdown of VAV2 markedly attenuated glucose-induced Rac1 activation and GSIS in INS-1 832/13 cells. Pharmacological findings were recapitulated in primary rat islets. A high glucose concentration promoted co-localisation of Rac1 and VAV2. Real-time imaging in live cells indicated a significant inhibition of glucose-induced cortical actin remodelling by Ehop-016. CONCLUSIONS/INTERPRETATION: Our data provide the first evidence to implicate VAV2 in glucose-induced Rac1 activation, actin remodelling and GSIS in pancreatic beta cells.

The migrant Hazara Shias of Pakistan and their social determinants for PTSD, mental disorders and life satisfaction.

Background: Ensuring safety and wellbeing of all the minority populations of Pakistan is essential for collective national growth. The Pakistani Hazara Shias are a marginalized non-combative migrant population who face targeted violence in Pakistan, and suffer from great challenges which compromise their life satisfaction and mental health. In this study, we aim to identify the determinants of life satisfaction and mental health disorders in Hazara Shias and ascertain which socio-demographic characteristics are associated with post-traumatic stress disorder (PTSD). Methods: We used a cross-sectional quantitative survey, utilizing internationally standardized instruments; with an additional qualitative item. Seven constructs were measured, including household stability; job satisfaction; financial security; community support; life satisfaction; PTSD; and mental health. Factor analysis was performed showing satisfactory Cronbach alpha results. A total of 251 Hazara Shias from Quetta were sampled at community centers through convenience method based on their willingness to participate. Results: Comparison of mean scores shows significantly higher PTSD in women and unemployed participants. Regression results reveal that people who have low community support, especially from national and ethnic community, religious community, and other community groups, had higher risk of mental health disorders. Structural equation modeling identified that four study variables contribute to greater life satisfaction, including: household satisfaction (ß = 0.25, p < 0.001); community satisfaction (ß = 0.26, p < 0.001); financial security (ß = 0.11, p < 0.05); and job satisfaction (ß = 0.13, p < 0.05). Qualitative findings revealed three broad areas which create barriers to life satisfaction, including: fears of assault and discrimination; employment and education problems; and financial and food security issues. Conclusions: The Hazara Shias need immediate assistance from state and society to improve safety, life opportunities, and mental health. Interventions for poverty alleviation, mental health, and fair education and employment opportunities need to be planned in partnership with the primary security issue.

Characterizing Social Determinants of Maternal and Child Health: A Qualitative Community Health Needs Assessment in Underserved Areas.

This study aimed to identify social determinants of maternal and child health (SDoH) in Pakistan. Using a qualitative study design, data were collected from community members in seven underserved areas of Lahore City, Pakistan. A total of 22 qualitative in-depth interviews and 10 focus group discussions (FGDs) were conducted. The participants included basic health unit healthcare staff, women of reproductive ages, male family members, mothers-in-law, and religious leaders. We found that maternal and child health is adversely affected by the following socioeconomic and environmental barriers: (i) poor housing quality and sanitation; (ii) inadequate food supply and safety; (iii) unsatisfactory public sector school services; (iv) a lack of safety and security; (v) scarce poverty alleviation efforts and loan schemes; (vi) unsatisfactory transport and internet services; and (vii) inadequate health services. The targets for maternal and child health in Pakistan cannot be met without close coordination between the primary health sector, local governance, and macro state structures, which collectively must monitor and improve housing adequacy, food security, public sector services (primary healthcare services, public schooling, public transport, and public internet access), overall safety, and poverty emergence.

Sonographic Findings of a Gynecological Cause of Acute Pelvic Pain - A Systematic Review.

Objective: The purpose of this study was to use ultrasonographic data to rule out and distinguish diseases that cause acute pelvic pain. Material and method: The literature was reviewed using a systematic search of the databases Google Scholars and PubMed, as well as through hand searching. We looked through a total of 35 articles, but only 26 were selected after preliminary screening. Furthermore, 14 articles were left out because they required a membership, copyright clearance, or featured non-English references. There were a total of 12 articles included in the final revuew. Among all the study-related articles, only original research studies and one systematic review that sonographically explored the gynecological etiology of acute pelvic pain were selected. Results: Acute pelvic pain in women might be difficult to identify between gynecologic and non-gynecologic causes based solely on patient history and examination. Advanced imaging, like ultrasound, aids in determining the reason. Pelvic inflammatory disease can be difficult to diagnose, and clinicians should use a low threshold for starting presumptive treatment in order to avoid significant long-term effects such as infertility. Conclusions: Pelvic pain can be acute, chronic or functional. Imaging investigations such as CT, ultrasonography, and MRI can assist in establishing a diagnosis. Particularly ultrasound scanning makes it possible to arrive at a diagnosis with a high degree of precision.

WhatsApp-Delivered Intervention for Continued Learning for Nurses in Pakistan During the COVID-19 Pandemic: Results of a Randomized-Controlled Trial.

The COVID-19 pandemic has necessitated support for continued learning in frontline practitioners through online digital mediums that are convenient and fast to maintain physical distancing. Nurses are already neglected professionals for support in training for infection control, leadership, and communication in Pakistan and other developing countries. For that reason, we aimed to deliver a WhatsApp-based intervention for continued learning in nurses who are currently working in both private and public sector. A 12-week intervention was delivered to 208 nurses (102 in the control group and 106 in the intervention group) who had been employed in the clinical setting during data collection. The analysis reveals that nurses in the intervention group show significantly better results for learning in "infection prevention and control" and "leadership and communication." Results of a content analysis based on participant's feedback also confirm that the WhatsApp-based intervention is a valuable tool for education. This study highlights the effectiveness of online-based digital interventions as a convenient training tool for awareness and management of infectious diseases, leadership, and communication during COVID-19 and beyond. Furthermore, this study emphasizes that group interventions with other healthcare practitioners and the role of on-going longer WhatsApp-based interventions can become integral tools to support continued learning and patient safety practices.

Vitamin D status and pulmonary exacerbations in children and adolescents with cystic fibrosis: Experience from a tertiary care center.

BACKGROUND: The function of Vitamin D in preventing inflammation and infection has been studied previously for different pathologies in different populations globally. Relationships between serum Vitamin D levels and its effect on pulmonary exacerbations in the cystic fibrosis (CF) population are not well studied in our part of the world. Therefore, we aimed to ascertain the Vitamin D status in pediatric and adolescent CF patients and its association with pulmonary exacerbations. MATERIALS AND METHODS: A retrospective study was conducted at The Aga Khan University Hospital from 2015 to 2018. Patients of CF with sweat chloride value >60 mmol/l and who had at least one measurement of 25 hydroxy Vitamin D (25 OHD) were included in the study. Annual serum Vitamin D levels were documented for enrolled patients and their past 1-year data were analyzed for pulmonary exacerbations, average length of stay, and tracheal/airway colonization with organisms. RESULTS: 69 patients were included in the study. 28 patients (40.57%) were found to be Vitamin D deficient, 22 patients (31.88%) were Vitamin D insufficient and 19 patients (27.53%) were labeled as Vitamin D insufficient. The average number of exacerbations per year was significantly high in Vitamin D deficient group (3.71 ± 0.96) in comparison with insufficient (3.18 ± 1.09) and sufficient groups (2.26 ± 0.93) (P < 0.001). CONCLUSION: Vitamin D deficiency is related to an increased number of annual pulmonary exacerbations and pseudomonas infections.

EHT 1864, a small molecule inhibitor of Ras-related C3 botulinum toxin substrate 1 (Rac1), attenuates glucose-stimulated insulin secretion in pancreatic ß-cells.

Glucose-stimulated insulin secretion (GSIS) in the pancreatic ß-cells entails a variety of signaling mechanisms including activation of small GTP-binding proteins (G-proteins). Previous studies from our laboratory in human islets, rodent islets and clonal ß-cells have demonstrated that G-proteins (e.g., Arf6, Cdc42 and Rac1) play novel roles in cytoskeletal remodeling, which is a critical step in the trafficking of insulin-laden secretory granules for fusion with plasma membrane and release of insulin. To further understand regulatory roles of Rac1 in GSIS, we utilized, herein, EHT 1864, a small molecule inhibitor, which attenuates Rac1 activation by retaining the G-protein in an inert/inactive state, thereby preventing activation of its downstream effector proteins. We demonstrate that EHT 1864 markedly attenuated GSIS in INS-1 832/13 cells. In addition, EHT 1864 significantly reduced glucose-induced activation and membrane targeting of Rac1 in INS-1 832/13 cells. This Rac1 inhibitor also suppressed glucose-induced activation of ERK1/2 and p53, but not Akt. Lastly, unlike the inhibitors of protein prenylation (simvastatin), EHT 1864 did not exert any significant effects on cell morphology (cell rounding) under the conditions it attenuated Rac1-sensitive signaling steps leading to GSIS. Based on these findings, we conclude that EHT 1864 specifically inhibits glucose-induced Rac1 activation and membrane association and associated downstream signaling events culminating in inhibition of GSIS.

Phagocyte-like NADPH oxidase (Nox2) promotes activation of p38MAPK in pancreatic ß-cells under glucotoxic conditions: Evidence for a requisite role of Ras-related C3 botulinum toxin substrate 1 (Rac1).

It is well established that glucotoxicity (caused by high glucose concentrations; HG) underlies pathogenesis of islet dysfunction in diabetes. We have recently demonstrated that Nox2 plays a requisite role in the generation of reactive oxygen species (ROS) under HG conditions, resulting in mitochondrial dysregulation and loss of islet ß-cell function. Herein, we investigated roles of Nox2 in the regulation of downstream stress kinase (p38MAPK) activation under HG conditions (20mM; 24h) in normal rodent islets and INS-1 832/13 cells. We observed that gp91-ds-tat, a specific inhibitor of Nox2, but not its inactive analog, significantly attenuated HG-induced Nox2 activation, ROS generation and p38MAPK activation, thus suggesting that Nox2 activation couples with p38MAPK activation. Since Rac1, is an integral member of the Nox2 holoenzyme, we also assessed the effects of Rac1 inhibitors (EHT 1864, NSC23766 and Ehop-016) on HG-induced p38MAPK activation in isolated ß-cells. We report a significant inhibition of p38MAPK phosphorylation by Rac1 inhibitors, implying a regulatory role for Rac1 in promoting the Nox2-p38MAPK signaling axis in the ß-cell under the duress of HG. 2-Bromopalmitate, a known inhibitor of protein (Rac1) palmitoylation, significantly reduced HG-induced p38MAPK phosphorylation. However, GGTI-2147, a specific inhibitor of geranylgeranylation of Rac1, failed to exert any significant effects on HG-induced p38MAPK activation. In conclusion, we present the first evidence that the Rac1-Nox2 signaling module plays novel regulatory roles in HG-induced p38MAPK activation and loss in glucose-stimulated insulin secretion (GSIS) culminating in metabolic dysfunction and the onset of diabetes.

Upregulation of phagocyte-like NADPH oxidase by cytokines in pancreatic beta-cells: attenuation of oxidative and nitrosative stress by 2-bromopalmitate.

Phagocyte-like NADPH oxidase (Nox2) has been shown to play regulatory roles in the metabolic dysfunction of the islet ß-cell under the duress of glucolipotoxic conditions and exposure to proinflammatory cytokines. However, the precise mechanisms underlying Nox2 activation by these stimuli remain less understood. To this end, we report a time-dependent phosphorylation of p47phox, a cytosolic subunit of Nox2, by cytomix (IL-1ß+TNFα+IFNγ) in insulin-secreting INS-1 832/13 cells. Furthermore, cytomix induced the expression of gp91phox, a membrane component of Nox2. 2-Bromopalmitate (2-BP), a known inhibitor of protein palmitoylation, markedly attenuated cytokine-induced, Nox2-mediated reactive oxygen species (ROS) generation and inducible nitric oxide synthase (iNOS)-mediated nitric oxide (NO) generation. However, 2-BP failed to exert any significant effects on cytomix-induced CHOP expression, a marker for endoplasmic reticulum stress. Together, our findings identify palmitoyltransferase as a target for inhibition of cytomix-induced oxidative (ROS generation) and nitrosative (NO generation) stress in the pancreatic ß-cell.

Glucotoxic conditions induce endoplasmic reticulum stress to cause caspase 3 mediated lamin B degradation in pancreatic ß-cells: protection by nifedipine.

Nuclear lamins form the lamina on the interior of the nuclear envelope, and are involved in the regulation of various cellular processes, including DNA replication and chromatin organization. Despite this evidence, little is known about potential alterations in nuclear metabolism, specifically lamin structure and integrity in isolated ß-cells subjected to stress conditions, including chronic exposure to hyperglycemia (i.e., glucotoxicity). Herein, we investigated effects of glucotoxic conditions on the catalytic activation of caspase 3 and the associated degradation of one of its substrate proteins, namely lamin-B. We report that incubation of insulin-secreting INS-1 832/13 cells, normal rat islets or human islets under glucotoxic conditions (20 mM; 12-48 h) results in the degradation of native lamin B leading to accumulation of the degraded products in non-relevant cellular compartments, including cytosol. Moreover, the effects of high glucose on caspase 3 activation and lamin B degradation were mimicked by thapsigargin, a known inducer of endoplasmic reticulum stress (ER stress). Nifedipine, a known blocker of calcium channel activation, inhibited high glucose-induced caspase 3 activation and lamin B degradation in these cells. 4-Phenyl butyric acid, a known inhibitor of ER stress, markedly attenuated glucose-induced CHOP expression (ER stress marker), caspase 3 activation and lamin B degradation. We conclude that glucotoxic conditions promote caspase 3 activation and lamin B degradation, which may, in part, be due to increased ER stress under these conditions. We also provide further evidence to support beneficial effects of calcium channel blockers against metabolic dysfunction of the islet ß-cell induced by hyperglycemic conditions.