Ferritin screening and Iron treatment for maternal anemia and fetal growth restriction prevention - A multicenter randomized controlled trial (FAIR Study)

Background: Non-anemic iron deficiency precedes iron deficiency anaemia and has an estimated prevalence of 1-2 billion worldwide. Few studies have comprehensively researched the idea of treating non-anemic iron deficiency (NAID) with iron to improve the outcome of the mother and the offspring. Methods and Analysis: FAIR will be a multicenter randomized controlled trial that will be conducted in multiple clinical academic obstetrics units in Lahore (including Services Institute of Medical Sciences, Lahore, Allama Iqbal Medical College, Lahore and Fatima Jinnah Medical University). Pregnant women at gestational age <20 weeks with hemoglobin 11-13 g/L and ferritin below the threshold (<30 ng/ml) will be invited to take part in the study. Randomization will be done by computer based generated random numbers. One group (usual care or oral group) will be offered routine care prophylactic dose of oral iron (30-45 mg/day) and the other group (intervention arm or IV group) will be offered therapeutic dose of IV iron (dose calculated by Ganzoni formula) in addition to usual care. All patients will be followed up till delivery. Primary maternal outcome will be hemoglobin at 36 weeks’ gestation. Secondary outcomes are fetal birthweight or small for gestational age, preterm birth, preeclampsia, multidimensional fatigue inventory, breast feeding initiation, blood transfusion, and fetal cord ferritin and hemoglobin. Discussion: The study will generate evidence as to whether screening serum ferritin in non-anemic pregnant women and replenishing their iron stores will likely reduce the rate of predelivery anemia in pregnant women, improve birthweight and preventing perinatal complications. Roles and responsibilities: Tayyiba Wasim is principal Investigator and other members of data management team are Natasha Bushra, Shamsa Humayoun, Khalid Saeed Khan, Fatima Shehbaz, Saba Rasool, Anam Riaz and Sonia Irshad. Principal investigator will assume the full responsibility of Fair trial including training of research assistants, administration of informed consent and protecting participants confidentiality. Data management team will help in the management, development and execution of trial. Khadija Irfan Khawaja is the operational lead for fair trial´s technology team comprising of Aziz Fatima and Zubia Zafar, responsible for gathering requirements from study teams and supporting the operational implementation of technology to drive the collection of high-quality study data. Protocol contributors are Gynae unit I of Services Institute of Medical Sciences/ Services hospital, Lahore, Gynae Unit II of Allama Iqbal Medical College/ Jinnah hospital, Lahore and Gynae unit 1 of Fatima Jinnah Medical College/ Sir Ganga Ram hospital, Lahore. These coordinating centres will recruit patients (sample size=600) and will discuss their progress in trial management meetings quarterly. Steering committee has an independent chair Prof Samia Malik, one expert member Prof Faiza Bashir and Ms Neelam to represent patients, public and consumers. Trial steering committee with independent chair and member with a patient representative will oversee the study. Chair of steering committee has the authority to stop the trial whenever needed in case of positive or negative results. Steering committee meetings will be held on annual basis. Independent Data monitoring committee comprises of Dr. Shehnoor Azhar as chair and Prof Ejaz Hussain and Dr. Shehla Javed Akram as members. Data monitoring committee will assess the progress, data safety and if needed critical efficacy points of the clinical study and will show their results quarterly in data interim meetings. The committee will focus on integrity of the whole process and compliance of all sites with all aspects of the protocol. It will perform confidential interim analyses quarterly, which may be used to determine if an effect` is observed and if the study should continue to its planned sample size. Data monitoring committee will report to the Chair of the steering committee

Restraint-induced Corticosterone Secretion and Hypothalamic CRH mRNA Expression are Augmented During Acute Withdrawal from Chronic Cocaine Administration

Stress responses during cocaine withdrawal likely contribute to drug relapse and may be intensified as a consequence of prior cocaine use. The present study examined changes in stressor-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis during acute withdrawal from chronic cocaine administration. Adult male Sprague–Dawley rats received daily administration of cocaine (30 mg/kg, i.p.) or saline for 14 days. Twenty-four hours after the last injection, rats in each group were sacrificed under stress-free conditions or following 30 min of immobilization. Plasma corticosterone (CORT) was measured in trunk-blood using radioimmunoassay, corticotropin-releasing hormone (CRH) mRNA levels in the paraventricularnucleus (PVN) of the hypothalamus were measured using in situ hybridization and glucocorticoid receptor (GR) protein expression in the pituitary gland and dissected brain regions was measured using Western blot analysis. Basal CRH mRNA in the PVN was unaltered as a result of prior cocaine administration. However, a significant increase in CRH mRNA was observed 90 min following the termination of restraint in cocaine withdrawn, but not saline-treated, rats. Basal CORT was also unaffected by prior cocaine administration, but the CORT response measured immediately after restraint was significantly augmented in cocaine-withdrawn rats. Differences in GR protein expression in number of regions implicated in negative feedback regulation of HPA function, including the hypothalamus, were not observed. These findings indicate that the HPA response to stressors is intensified during early withdrawal from cocaine administration and may be independent of changes in GR-mediated negative feedback

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Epidemiology of potential drug-drug interactions in elderly population admitted to critical care units of Peshawar, Pakistan

Abstract Background Aging population, is a reality in many countries because of improvement in the health care, patient safety and other supplemental factors. Pharmacotherapy in this population must be evaluated due to their higher susceptibility to adverse drug outcomes, like potential drug-drug interactions (PDDIs). Research in this regard is limited particularly in developing countries. The aim of the study was to evaluate the prevalence and associated factors in this population. Methods The multicentered study evaluated the prevalence of potential drug-drug interactions and associated factors in elderly population at critical care units in Peshawar, Pakistan. Potential drug-drug interactions were evaluated using Micromedex DrugReax, while statistical analysis was performed using SPSS. Results A total of 70.17% elderly patients were observed to have at least one PDDI. A significant association was observed between presence of PDDIs and number of prescribed drugs, duration of stay and age (p < 0.05). A total of 3019 PDDIs were observed, attributing to 225 drug pairs. Prevalent PDDIs were of moderate severity, good documentation and pharmacodynamic in nature. One-way ANOVA revealed a significant difference in the means of PDDIs between Northwest general hospital and the rest of the hospitals. Moreover, there was a significant difference in the means of PDDIs of CCU and SU with rest of the units. Conclusion The prevalence of PDDIs was observed to be high in elderly population which can be managed by avoiding or managing a limited number of drug combinations. Such studies are necessary to evaluate the risks of these PDDIs in a population which is already physiologically compromised

Impact of dark triad personality traits on turnover intention and mental health of employees through cyberbullying

AbstractThe increased usage of technology has engendered different forms of bullying. While scholars affirm that cyberbullying is considered to exhibit the most harmful impacts on individuals among the different types of bullying. It needs to be underscored that the multifaceted and recurring nature of cyberbullying, particularly in the workplace, has a more hazardous effect on employees. It is urged that the highly competitive working environment has exacerbated the problems of rivalry among employees, which subsequently pushes them towards cyberbullying. Despite an extensive body of knowledge on traditional bullying, research still lacks the effect of cyberbullying in the workplace context. This research addresses the gaps by explaining the impact of the dark triad of personality traits (DTPT) on turnover intention and employees’ mental health through cyberbullying. It incorporated a unique multistage sampling approach in which data were gathered through self-administered questionnaires from the banking sector. The analyses showed a direct relationship between the DTPT and turnover intention. Cyberbullying partially mediates the relationship between DTPT and turnover intention. Findings also indicate that the DTPT negatively affects employees’ mental health. A vital facet of this research is testing the mediating role of cyberbullying between DTPT and employees’ mental health and turnover intention. The findings are of great value to organizational stakeholders, where management can adopt various strategies and training programs to reduce the detrimental effects of cyberbullying. Such initiatives enable employees to cope with mental health issues, mitigating negative workplace behaviour and minimizing turnover intention

Risk of bleeding in patients on single and dual antiplatelet therapy undergoing dental extractions

We assessed the impact of single and dual antiplatelet therapy on postoperative bleeding in dental extraction patients. The study involved 160 patients on antiplatelet medication and a control group of 105 healthy subjects undergoing extractions. Bleeding was considered an "event" if it persisted over 12 hours or met other specific criteria. A total of 115 teeth were extracted from control, 48 teeth were extracted from the dual drug group and 122 from the single drug group, with no significant difference in postoperative bleeding incidence (χ2 = 4.3, p = 0.11). Dental extractions for patients on single or dual antiplatelet therapy can be performed safely using local haemostatic measures without treatment interruption

Daily versus stat vitamin D supplementation during pregnancy; A prospective cohort study.

BACKGROUND:Despite favorable climatic conditions, vitamin D deficiency (VDD) is widespread in Pakistan. Current study was aimed to evaluate the prevalence of VDD in Pakistani pregnant women and effectiveness of various regimen of Vitamin D supplementation. METHODOLOGY:This hospital-based prospective cohort study included pregnant women at 12th to 24th weeks of gestation attending Gynae clinic from October 2018 to April 2019. Patients were classified into control and treatment groups (Groups: G1, G2 and G3) according to the dose of vitamin D supplementation. Patients received various regimens of vitamin D including 2000 IU/day (G1), 5000 IU/day (G2) and stat 200000 IU (G3). The levels of vitamin D were measured before and after supplementation. The effectiveness of dosages were compared between and within the groups. Moreover, factors associated with vitamin D sufficiency and insufficiency were ascertained using appropriate statistical methods. RESULTS:Among 281 pregnant women (mean age: 28.22 ± 4.61 years), VDD was prevalent in 47.3% cases. Vitamin D supplementation caused significant rise in the levels 25(OH)D in treatment groups, while there was no significant difference in control group. The highest mean increment in vitamin D (23.14 ± 11.18 ng/ml) was observed with dose 5000 IU/day followed by doses 200000 IU stat (21.06 ± 13.73 ng/ml) and 2000 IU/day (10.24 ± 5.65 ng/ml). Vitamin D toxicity was observed in one patient who received 200000 IU stat of vitamin D. The frequency of VDD following the supplementation was 5.7%. Education status, duration of sun exposure and use of sunblock was substantially associated with vitamin D sufficiency in the current study. CONCLUSION:Our findings underscore the high proportion of VDD among pregnant women in Pakistan. Maternal vitamin D supplementation substantially improved the levels of 25(OH)D. Of three used regimens, the dose of 5000 IU/day is considered safe and equally effective as of 200000 IU stat. Since pregnancy is a time of tremendous growth and physiological changes for mother and her developing fetus with lifelong implications for the child, gestational vitamin D supplementation should be considered to ensure the optimal vitamin D accrual in pregnant women. This study generates the hypothesis that vitamin D supplementation at a dose of 5000 IU/day during pregnancy is superior to the other regimens. However, well-controlled randomized trials are needed to confirm these findings

Cytokine-Mediated Dysregulation of Signaling Pathways in the Pathogenesis of Multiple Myeloma

Multiple myeloma (MM) is a hematologic disorder of B lymphocytes characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow. The altered plasma cells overproduce abnormal monoclonal immunoglobulins and also stimulate osteoclasts. The host&rsquo;s immune system and microenvironment are of paramount importance in the growth of PCs and, thus, in the pathogenesis of the disease. The interaction of MM cells with the bone marrow (BM) microenvironment through soluble factors and cell adhesion molecules causes pathogenesis of the disease through activation of multiple signaling pathways, including NF-&kappa;&beta;, PI3K/AKT and JAK/STAT. These activated pathways play a critical role in the inhibition of apoptosis, sustained proliferation, survival and migration of MM cells. Besides, these pathways also participate in developing resistance against the chemotherapeutic drugs in MM. The imbalance between inflammatory and anti-inflammatory cytokines in MM leads to an increased level of pro-inflammatory cytokines, which in turn play a significant role in dysregulation of signaling pathways and proliferation of MM cells; however, the association appears to be inadequate and needs more research. In this review, we are highlighting the recent findings on the roles of various cytokines and growth factors in the pathogenesis of MM and the potential therapeutic utility of aberrantly activated signaling pathways to manage the MM disease

Greensporone A, a Fungal Secondary Metabolite Suppressed Constitutively Activated AKT via ROS Generation and Induced Apoptosis in Leukemic Cell Lines

Greensporone A is a fungal secondary metabolite that has exhibited potential in vitro for anti-proliferative activity in vitro. We studied the anticancer activity of greensporone A in a panel of leukemic cell lines. Greensporone A-mediated inhibition of proliferation is found to be associated with the induction of apoptotic cell death. Greensporone A treatment of leukemic cells causes inactivation of constitutively activated AKT and its downstream targets, including members GSK3 and FOXO1, and causes downregulation of antiapoptotic genes such as Inhibitor of Apoptosis (IAPs) and Bcl-2. Furthermore, Bax, a proapoptotic member of the Bcl-2 family, was found to be upregulated in leukemic cell lines treated with greensporone A. Interestingly, gene silencing of AKT using AKT specific siRNA suppressed the expression of Bcl-2 with enhanced expression of Bax. Greensporone A-mediated increase in Bax/Bcl-2 ratio causes permeabilization of the mitochondrial membrane leading to the accumulation of cytochrome c in the cytoplasm. Greensporone A-induced cytochrome c accumulation causes the activation of caspase cascade and cleavage of its effector, poly(ADP-ribose) polymerase (PARP), leading to apoptosis. Greensporone A-mediated apoptosis in leukemic cells occurs through the generation of reactive oxygen species (ROS) due to depletion of glutathione (GSH) levels. Finally, greensporone A potentiated the anticancer activity of imatinib in leukemic cells. In summary, our study showed that greensporone A suppressed the growth of leukemic cells via induction of apoptotic cell death. The apoptotic cell death occurs by inhibition of AKT signaling and activation of the intrinsic apoptotic/caspase pathways. These results raise the possibility that greensporone A could be developed as a therapeutic agent for the treatment of leukemia and other hematological malignancies