ARE SSRIs RESPONSIBLE FOR PRECIPITATING SUICIDAL IDEATION IN TEENAGERS WITH ‘SUBSYNDROMAL’ BIPOLAR AFFECTIVE DISORDER WHO HAVE BEEN MISDIAGNOSED WITH UNIPOLAR DEPRESSION?

Concerns have recently been raised about a possible link between suicidal ideation and the use of SSRIs in teenagers diagnosed with unipolar depression, such that the USA FDA and UK CSM have issued warnings regarding the use of SSRIs in adolescents with depression. We investigated this phenomenon first by recognizing that the initial presentation of unipolar and bipolar depression may only differ in subtle ways and with the result being that a significant number of patients are misdiagnosed at the expense of patient outcomes. This is especially pertinent as patients with bipolar disorder have increased lifetime rates of suicide as compared with those patients with unipolar depression. The normal developmental trajectory of bipolar disorder often involves recurrent depressive episodes in early adolescence before the development of hypomanic/manic episodes. Therefore, a misdiagnosis of bipolar disorder as unipolar depression in teenagers could explain the failure of SSRIs to adequately treat depressive episodes. A suboptimal response to SSRIs and so a lack of control of the depression is a risk factor for suicide. One reason for this suboptimal response is the markedly different neurotransmission involved in bipolar depression as compared to the neurotransmitter systems operated on by SSRIs. In bipolar disorder, dopamine is the principal neurotransmitter disrupted and we marshal structural, pharmacological and biochemical evidence to support this claim. One important strand of evidence involves polymorphisms in D1 and D2 dopamine receptors being implicated in the pathogenesis of bipolar affective disorder. Serotonin neurotransmission is affected by SSRIs, however the role of serotonin in bipolar disorder is much more ambiguous. The conclusion we arrive at is that the link between suicidality and SSRI use in adolescents diagnosed with unipolar depression may in fact be due to inappropriate treatment of misdiagnosed bipolar disorder that has yet to manifest with hypomanic/manic symptoms

A Novel Dual Ultrawideband CPW-Fed Printed Antenna for Internet of Things (IoT) Applications

This paper presents a dual-band coplanar waveguide (CPW) fed printed antenna with rectangular shape design blocks having ultrawideband characteristics, proposed and implemented on an FR4 substrate. The size of the proposed antenna is just 25 mm × 35 mm. A novel rounded corners technique is used to enhance not only the impedance bandwidth but also the gain of the antenna. The proposed antenna design covers two ultrawide bands which include 1.1–2.7 GHz and 3.15–3.65 GHz, thus covering 2.4 GHz Bluetooth/Wi-Fi band and most of the bands of 3G, 4G, and a future expected 5G band, that is, 3.4–3.6 GHz. Being a very low-profile antenna makes it very suitable for the future 5G Internet of Things (IoT) portable applications. A step-by-step design process is carried out to obtain an optimized design for good impedance matching in the two bands. The current densities and the reflection coefficients at different stages of the design process are plotted and discussed to get a good insight into the final proposed antenna design. This antenna exhibits stable radiation patterns on both planes, having low cross polarization and low back lobes with a maximum gain of 8.9 dB. The measurements are found to be in good accordance with the simulated results

Extrapulmonary tuberculosis in Pakistan- A nation-wide multicenter retrospective study

Background Pakistan is fifth among high burden countries for tuberculosis. A steady increase is seen in extrapulmonary tuberculosis (EPTB), which now accounts for 20% of all notified TB cases. There is very limited information on the epidemiology of EPTB. This study was performed with the aim to describe the demographic characteristics, clinical manifestations and treatment outcomes of EPTB patients in Pakistan. Method We performed descriptive analysis on routinely collected data for cohorts of TB patients registered nationwide in 2016 at health facilities selected using stratified convenient sampling. Findings Altogether 54092 TB including 15790 (29.2%) EPTB cases were registered in 2016 at 50 study sites. The median age was 24 years for EPTB and 30 years for PTB patients. The crude prevalence of EPTB in females was 30.5% (95%CI; 29.9–31.0) compared to 27.9% (95%CI; 27.3–28.4) in males. The likelihood of having EPTB (OR), was 1.1 times greater for females, 2.0 times for children, and 3.3 times for residents of provinces in the North-West. The most common forms of EPTB were pleural (29.6%), lymphatic (22.7%) and abdominal TB (21.0%). Pleural TB was the most common clinical manifestation in adults (34.2%) and abdominal TB in children (38.4%). An increase in the prevalence of pleural and osteoarticular and decline in lymphatic and abdominal TB was observed with advancing age. Diversity in demography and clinical manifestations were noted between provinces. The treatment success rate for all type EPTB was significantly high compared to bacteriology confirmed PTB with the exception of EPTB affecting CNS with a high mortality rate. Conclusions The study provides an insight into demography, clinical manifestations and treatment outcomes of EPTB. Further studies are needed to explain significant diversities observed between provinces, specific risk factors and challenges concerning EPTB management.publishedVersio

Celiac Disease and its Association with Socio-Demographic Parameters in Patients with Diabetes Mellitus Type-1

Objective: To determine the frequency of Celiac disease in patients with Type-1 Diabetes Mellitus (DM) and its association with socio-demographic parameters. Study Design: Cross-sectional study. Place and Duration: Medical Departments of Dr Ruth K. M. Pfau, Civil Hospital, Karachi Pakistan, from Apr to Sep 2019. Methodology: Patients diagnosed with type-1 DM were enrolled in the study. Patients underwent blood testing for Celiac Serology. IgA level greater than 10U/m1 was taken as positive for celiac disease. If IgA levels were low, then Anti-tTG IgG was tested. Results: One hundred seventy-seven patients diagnosed with type-1 diabetes mellitus were included in this study. The average age of patients was 36.39±6.81 years. There were 109(61.58%) males and 68(38.2%) females. The frequency of celiac disease in patients with type-1 DM was observed at 8.47%. The frequency of celiac disease was not statistically significant among different age groups (p=0.644), gender and disease duration (p>0.05). However, celiac disease was more frequent in patients with a family history, but it was not statistically significant (25% vs 7.7%; p=0.086). Conclusion: This study showed a higher frequency of celiac disease in patients with T1DM than in the general population in our country, and the data lend support to recommend regular screening for Celiac disease in all patients with Type-1 DM

Oxidative Stress Diminishing Perspectives of Green and Black Tea Polyphenols: A Mechanistic Approach

Polyphenols have credentials to tackle the oxidative stress. Oxidative stress is the imbalance between free radicals production and antioxidant enzymes ability to tackle these radicals resulting the onset various metabolic related disorders. Polyphenols based foods have credential as a shield against these glitches mainly owing to their antioxidant potential. In this context, tea polyphenols have gained paramount attention of scientific community as therapeutic agents for the prevention and treatment of various oxidative stress induce maladies owing to their structural diversity, strong antioxidant ability and capacity to modulate various expression involved in the pathogenesis of these maladies. The notable polyphenols are catechins which are mainly present in green tea and further subdivided into various compounds like ECG, EGC, EGCG which has their unique therapeutic potential. The catechins undergo various structural changes and transformed into theaflavins and thearubigins in the process of black tea formation. These are high molecular weight polyphenols and promising candidates in obesity, diabetes and cancer treatment. Mechanistically, these polyphenols ameliorate oxidative stress by trapping the noxious radicals like superoxide and peroxyl, promote the activity of glutathione, suppressing the malondialdehyde (MDA) activity. The current chapter is an attempt to highlight the therapeutic potential of tea polyphenols

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

PRODUCTIVITY MEASUREMENT AND ANALYSIS OF A PUBLIC SECTOR AUTOMOBILE REBUILD ORGANIZATION

Public sector automobile rebuild organizations have comparatively low productivity as compared to private sector organizations especially in developing countries. Despite gigantic budgetary allotments, public sector rebuild organizations remain non-productive, ineffective and inefficient as they are not exposed to aggressive market competition and profitability. These organizations are administered by government rules and procedures unlike private sector organizations which are driven solely on profitability factor. Therefore, conventional productivity improvement models are as such not fully applicable to public sector rebuild organizations. In this context, data of a public sector automobile rebuild organization has been collected. Total and partial productivities of the organization have been measured and analyzed by using Total Productivity Model (TPM). Detailed productivity analysis of the selected organization has been carried out with specific focus on limitations of model when applied to public sector organizations alongside reasons for low productivity. Results indicate that public sector organizations need to focus on cost minimization and resource optimization to enhance productivity and output as compared to private sector organizations which focus on cost minimization and profit maximization