A meta-analysis and experimental data for multidrug resistance genes in breast cancer

Background: Increasing trend of breast cancer incidence worldwide is a known fact. This curable disease may become fatal if drug resistance is developed leading to metastatic cancerous tissue. Objective: This is a two parts study; a meta-analysis exploring association of drug resistance (mdr1 and ABCG2) genes with breast cancer and mutational association with molecular subtypes of cancer. Methods: PCR-SSCP for genomic polymorphisms and RT-PCR for expression analysis were performed. Results: C3435T polymorphism of mdr1 gene was most commonly studied mutation with contradictory results. Association of ABCG2 gene mutations with untreated breast cancer was reported only by one study so far. Regarding current genomic analysis of mdr1 gene, three novel mutations were found in exon 12 and 2 mutations were found in exon 26. In ABCG2 gene, addition of C and T were found in intron 8 at the intron-exon junction. A positive correlation was observed between these mutations and tumor grade. Levels of mRNA expression revealed that they were over expressed in cancerous tissues compared with controls. Conclusion: These findings suggest that these genes are associated with breast cancer. Keywords: Expression; mutations; mdr1; ABCG2; breast cancer

Comparison between Mesh Hernioplasty and Simple Suture Repair in the treatment of Paraumbilical Hernias at Bahawalpur Hospitals

To compare the rate of recurrence between mesh hernioplasty and simple suture repair in the management of paraumbilical hernias. Total 215 patients were selected in medical ward of Bahawal Victoria Hospital Bahawalpur. They were subdivided into three groups. Group A 112 patients were repaired in traditional way and group B 88 patients underwent mesh repair and the in third group C 15 patients undergone other ways of repair which we did not covered in our study. And the patients who showed the recurrence of hernia were selected and those were subject of interest. A comparison was made between two groups in terms of, complications and rate of recurrence. In Group A, 12(10.71%) patients had recurrence which was quite high compared to the group B which had only 2(2.27%) patients. Rate of infection was higher in group B (12%). There were incidences of postoperative hematomas and seromas formation in group A but none in group B. Mesh hernioplasty significantly reduced the recurrence rate as compared to the traditional suture repair. Unlike results of the other studies, infection rate was not high in mesh group. Keywords: Paraumbilical hernia, Mesh repair, Simple suture repair

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

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

Gut modulator effect of methanolic extract of Solanum surattense explains its traditional use in constipation and diarrhea

Papar has been withdrawn by the editor

Natural killer cells enhance the immune surveillance of cancer

Immune system (IS) is comprised of molecules, cells, tissues and organs involved in host defense mechanism from infectious agents or tumor cells. On crossing the cell barriers by these infectious agents, the defense mechanism is alerted by the immune system to respond against these invading microbes. Innate immune response (IIR) and acquired immune response (AIR) are working in parallel to control these invading microbes. IIR is composed of various types of phagocytes and lymphocytes, while AIR is comprised of T and B lymphocytes. All the cells of the immune system cooperatively work against infectious agents and cancerous cells but Natural killer (NK) cells are playing an important role to respond to tumor by enhancing the expression of complementary domain (CD86) on dendritic cells (DCs) and production of IL-12. NK cells demolished tumor through perforin and granzyme, which are important for immune surveillance and death of tumor cells induced by cytokines such as tumor necrosis factor (TNF), Fas ligand (CD178), interferon-γ (IFN-γ) and IL-10. These cytokines have inhibited proliferation of tumor by inducing anti-angiogenic factors and maintaining cross talk with other immune cells. Natural products like transfer factor plus, immune modulator mix, ascorbic acid, Ganoderma lucidum, Agaricus blazei teas, nitrogenated soy extract, Andrographis paniculata and several phytochemicals enhanced the efficiency of NK cells in controlling cancers. Further studies will unravel the impact of NK cells in cancer control and how NK efficiency can be further enhanced

Breast Cancer: Epidemiology, Risk Factors and Survival Analysis in the Pakistani Population

Objective: To find out the association of genetic, reproductive and socio demographic factors with breast cancer in Pakistani women along with the sur- vival percentage of patients having breast cancer. Methodology: A case control study was carried out for a period of 3 years. Data were collected from different hospitals in Pakistan and the survival rate was determined by having direct contact with patients through telephone calls. For the estimation of survival probability Kaplan-Meier curve was used. Association of various demographic and epidemiological factors with breast cancer occurrence was estimated by using the odds ratio (OR) and 95% confidence interval (CI). Various tests used to find out the significance of results included student t-test, chi-square test, Fisher exact test and ANOVA. A statistical tool SPSS version 22 was used to analyze the data and results orientation. Results: The mean age for breast cancer diagnosis 47.3±11.8 years of age was found as mean age for breast cancer diagnosis. Higher BMI was the major contributing factors in developing breast cancer (OR=3.5, 95% CI=2.6-4.5). Significant risk factors found to be associated with the breast cancer included long reproductive period (menarche to menopause), family history of disease and habit of passive smoking (P<0.05). Out of 448 married patients, 23% were nulliparous and 26% of patients did not have a lactation history. Chemotherapy along with radiotherapy and surgery have been found to be effective methods for breast cancer treatment (80% survival). Conclusion: Present study concluded that age, body mass index, oral contraceptives usage, lactation duration, reproductive duration and marital status of the female are significant factors in developing breast cancer in Pakistani women. Keywords: Breast Cancer, Nulliparous, Chemotherapy, Radiotherapy

Comparative Suitability of Ear Notch Biopsy and Serum Pairs for Detecting Nature of Bovine Viral Diarrhoea Virus Infection in Dairy Herds

Suitability of ear notch biopsy (EN) and serum pairs (n= 307) collected from 10 Holstein dairy herds located in Charlottetown, Canada was evaluated for simultaneous detection, nature of bovine viral diarrhea virus (BVDV) infection and genotype of the prevailing BVDV through Real time RT-PCR. Depending upon vaccination status and age, the sampled animals were categorized into two groups, A (n=123, ≤ 6 month of age) and B (n=184, ≥ 6 months of age) originating from 4 vaccinated (n=108) and 3 non-vaccinated (n=76) animal herds. On first round of testing a discrepancy between ear notch biopsies and sera pairs (3.25 and 6.50%; P<0.05) of groups A was observed, however, a complete harmony (50% for EN and sera each, P<0.01 was found on second round of testing that confirmed the presence of 4 persistent infection (PI) animals harboring genotype 1 of BVDV. Complete concordance between EN and sera pairs (P<0.01) on first and follow up testing in group B was observed (2.77%, each), depicting 3 PI animals with the same genotype as in group A. In the study, ear notch biopsies did not detect any transient infection (TI) but sera samples detected 3.25% transiently infected animals in group A that was 1.30 % among all the test samples (n=307) while no TI animal was found in group B. It may be concluded that both the serum and ear notch biopsy can be used to detect PI animals and that, serum samples are more sensitive than ear notch (P < 0.05) for detection of TI using real time RT-PCR