Waldenström macroglobulinemia: a review of pathogenesis, current treatment, and future prospects.

Waldenström macroglobulinemia (WM) is a chronic B-cell lymphoproliferative disorder characterized by lymphoplasmacytic cell overgrowth in the bone marrow and increased secretion of IgM immunoglobulins into the serum. Patients with WM have a variety of clinical outcomes, including long-term survival but inevitable recurrence. Recent advances in disease knowledge, including molecular and genetic principles with the discovery of MYD88 and CXCR4 mutations, have rapidly increased patient-tolerable treatment options. WM patients may benefit from chemotherapy regimens that include rituximab-based regimens, alkylating drugs, proteasome inhibitors, monoclonal antibodies, and drugs targeting Bruton tyrosine kinase inhibitors. In light of these advancements, patients can now receive treatment customized to their specific clinical characteristics, focusing on enhancing the depth and durability of their response while limiting the adverse effects. Despite the rapidly developing therapeutic armament against WM, a lack of high-quality evidence from extensive phase 3 trials remains a significant challenge in the research. We believe clinical outcomes will keep improving when new medicines are introduced while preserving efficacy and minimizing toxicity.

Impact of autologous transplantation on survival in patients with newly diagnosed multiple myeloma who have high-risk cytogenetics: A meta-analysis of randomized controlled trials.

BACKGROUND: Despite routine evaluation of cytogenetics in myeloma, little is known regarding the impact of high-dose therapy (HDT) consolidation on overall survival (OS) or progression-free survival (PFS) in patients who have high-risk cytogenetics. The authors performed a meta-analysis of randomized controlled trials (RCTs) to assess the heterogeneity of HDT efficacy according to cytogenetic risk. METHODS: All RCTs in patients who had newly diagnosed myeloma from 2000 to 2021 that compared upfront HDT versus standard-dose therapy (SDT) consolidation were included. The primary objective was to assess the difference in HDT efficacy between standard-risk and high-risk cytogenetics in terms of the OS or PFS log(hazard ratio) (HR). The pooled OS and PFS HR was calculated according to cytogenetic-risk subgroup using a random-effects model, and heterogeneity (I2 ) (the percentage of total observed variability explained by between-study differences) was assessed using an interaction test. RESULTS: After screening 3307 citations, 6 RCTs were included for PFS analysis, and 4 were included for OS analysis. The median follow-up ranged from 3.1 to 7.8 years. The pooled OS HR for HDT versus SDT consolidation in patients with standard-risk and high-risk cytogenetics was 0.90 (95% confidence interval [CI], 0.70-1.17; I2 = 0%) and 0.66 (95% CI, 0.45-0.97; I2 = 0%), respectively. The difference in HDT efficacy in terms of OS between standard-risk and high-risk patients was statistically significant in favor of the high-risk group (P for interaction = .03). The pooled PFS HR for HDT versus SDT was 0.65 (95% CI 0.56-0.76; I2 = 0%) versus 0.52 (95% CI, 0.33-0.83; I2 = 55%), respectively. The difference in HDT efficacy in terms of PFS between standard-risk and high-risk patients was not significant (P for interaction = .25). CONCLUSIONS: The magnitude of OS benefit with upfront HDT is cytogenetics-dependent. Patients with high-risk cytogenetics should preferably receive upfront rather than delayed HDT consolidation. LAY SUMMARY: Upfront autologous stem cell transplantation improves overall survival in patients with newly diagnosed myeloma harboring high-risk cytogenetics.

A gender-specific assessment of tobacco use risk factors: evidence from the latest Pakistan demographic and health survey.

BACKGROUND: The high prevalence of tobacco use in Pakistan poses a substantial health and economic burden to Pakistani individuals, families, and society. However, a comprehensive assessment of the key risk factors of tobacco use in Pakistan is very limited in the literature. A better understanding of the key risk factors of tobacco use is needed to identify and implement effective tobacco control measures. OBJECTIVES: To investigate the key socioeconomic, demographic, and psychosocial determinants of tobacco smoking in a recent large nationally representative sample of Pakistani adults. METHODS: N = 18,737 participants (15,057 females and 3680 males) from the 2017-18 Pakistan Demographic Health Survey, aged 15-49 years, with data on smoking use and related factors were included. Characteristics of male and female participants were compared using T-tests (for continuous variables) and χ2-tests (for categorical variables). Multivariable logistic regression models were used to identify gender-specific risk factors of tobacco use. The Receiver Operating Characteristic Curve test was used to evaluate the predictive power of models. RESULTS: We found that the probability of smoking for both males and females is significantly associated with factors such as their age, province/region of usual residence, education level, wealth, and marital status. For instance, the odds of smoking increased with age (from 1.00 [for ages 15-19 years] to 3.01 and 5.78 respectively for females and males aged 45-49 years) and decreased with increasing education (from 1.00 [for no education] to 0.47 and 0.50 for females and males with higher education) and wealth (from 1.00 [poorest] to 0.43 and 0.47 for richest females and males). Whilst the odd ratio of smoking for rural males (0.67) was significantly lower than that of urban males (1.00), the odds did not differ significantly between rural and urban females. Finally, factors such as occupation type, media influence, and domestic violence were associated with the probability of smoking for Pakistani females only. CONCLUSIONS: This study identified gender-specific factors contributing to the risk of tobacco usage in Pakistani adults, suggesting that policy interventions to curb tobacco consumption in Pakistan should be tailored to specific population sub-groups based on their sociodemographic and psychosocial features.

Preventing MQTT Vulnerabilities Using IoT-Enabled Intrusion Detection System.

The advancement in the domain of IoT accelerated the development of new communication technologies such as the Message Queuing Telemetry Transport (MQTT) protocol. Although MQTT servers/brokers are considered the main component of all MQTT-based IoT applications, their openness makes them vulnerable to potential cyber-attacks such as DoS, DDoS, or buffer overflow. As a result of this, an efficient intrusion detection system for MQTT-based applications is still a missing piece of the IoT security context. Unfortunately, existing IDSs do not provide IoT communication protocol support such as MQTT or CoAP to validate crafted or malformed packets for protecting the protocol implementation vulnerabilities of IoT devices. In this paper, we have designed and developed an MQTT parsing engine that can be integrated with network-based IDS as an initial layer for extensive checking against IoT protocol vulnerabilities and improper usage through a rigorous validation of packet fields during the packet-parsing stage. In addition, we evaluate the performance of the proposed solution across different reported vulnerabilities. The experimental results demonstrate the effectiveness of the proposed solution for detecting and preventing the exploitation of vulnerabilities on IoT protocols.

Searching appropriate system boundary for accounting India's emission inventory for the responsibility to reduce carbon emissions.

This paper explores the features of accounting for the national carbon emission inventory under four different system boundaries, including the presently operational territorial production-based accounting (PBA) practised by the UNFCCC. Using a recently published input-output table with the base year for 2013-2014, the study calculates India's 'Nationally Determined Contribution (NDC)' to the mitigation of carbon emissions using production-based, consumption-based, sharing-based and equity-based accounting. The study finds India as a net importer of carbon emissions, especially for its high emission-intensive capital and energy goods import such that the country is bearing the minimum burden of emission reduction responsibility. However, the study intends to analyse this burden of responsibility in terms of the criteria of justice and effectiveness and addresses the future policy priorities for India to become a net exporter of industrial goods. We recommend India for supporting and implementing an alternative system boundary of emission inventory accounting which would be more consistent with the provisions of 'equity' subscribed under the UNFCCC while at the same time, helpful for achieving the climate goals by appropriately trace and track the sources of 'carbon leakage'.

Molecular epidemiology of Coxiella Brunetii in small ruminants in Punjab, Pakistan: a novel reporting analytical cross sectional study.

Coxiella burnetii, an intracellular zoonotic bacterium, causes query (Q) fever in ruminants. Its role has never been elucidated in small ruminants from Pakistan. The current study is designed to (a) determine the prevalence of coxiellosis in small ruminants, (b) evaluate the association of various potential risk factors and biomarkers in the occurrence of Coxiella burnetii, (c) and determine phylogeny and genetic variability of its various isolates identified during the study. For this purpose, 320 blood samples from sheep (n = 160) and goats (n = 160) were collected from 9 Union Councils of district Kasur, Punjab, and processed for DNA extraction. C. burnetii was confirmed by amplification of IS1111 transposase gene with an amplicon size of 294 bp. The results showed that the overall positive percentage of C. burnetii is 36.87% (sheep: 46.9% and goats: 30%). The phylogenetic tree was also constructed which described the possible origin of this pathogen from environment. Besides, after translation into amino acid, the resultant alignment showed several unique changes at position numbers 18 and 27 in the isolates from goats and at 27 and 66 from those of sheep. These mutations can have major impact on the infectious characteristics of this pathogen. Furthermore, different potential risk factors and clinical biomarkers like age, tick infestation, abortion, mastitis, and infertility were also studied and found that these are significantly (p < 0.05) associated with the occurrence of coxiellosis. It is concluded from the study that C. burnetii is endemic in small ruminants in Punjab, Pakistan. The outcomes of this study are alarming for scientific community as well as for policy makers because coxiellosis is an emerging threat to both humans and animals in this region due to its interspecies transmission ability.

Betalains: Potential Drugs with Versatile Phytochemistry.

Currently, the demand for natural colorants is increasing instead of synthetic colorants for foodstuff, because they are harmless to human health. Betalain is group of compounds containing nitrogen and water soluble pigment. Betalain is classified into two main classes, betacyanin which is the condensation of betalamic acid with cyclo-DOPA and betaxanthin which is the conjugation of amino acid or amines with betalamic acid. They are used to color various foods and medicines. Betalain is different from anthocyanin because betalains contain nitrogen in their structures. It is interesting to hear that betalains and anthocyanins are individually significant but they have not seen together in the same plant. Their stability influenced by various factors such as, temperature, pH, water activity and light. In this review basic chemistry of betalains, classes, subclasses, their sources and biosynthesis, factors affecting their stability, health and food industry applications are discussed. Moreover, mentioned work signifies the potent anticancer, antioxidant and antimalarial activities of betalains, furthermore provides a help to do more scientific work on it.

Short survival and frequent transformation in extranodal marginal zone lymphoma with multiple mucosal sites presentation.

Between 11 and 37% of extranodal marginal zone lymphoma (EMZL) patients present with disease involvement in multiple mucosal sites (MMS). We analyzed 405 EMZL patients seen between 1995 and 2017: 265 (65.4%) patients presented with stage I disease, 49 of 309 (15.8%) patients with bone marrow involvement, and 35 of 328 (10.7%) patients with monoclonal gammopathy (MG). Forty-three (10.6%) patients had MMS presentation, which was more frequently seen in patients aged >60 years (55.8%). Five (17.9%) of 28 MMS patients had MG. MMS patients commonly exhibited the International Prognostic Index (IPI) >2 (79.1%), Follicular Lymphoma International Prognostic Index (FLIPI) >2 (39.5%), and Mucosa-Associated Lymphoid Tissue Lymphoma International Prognostic Index (MALT-IPI) 2-3 (60.5%). Both MMS presentation and MG were associated with shorter survival univariately. In multivariable Cox regression models, shorter progression-free survival (PFS) and overall survival (OS) were observed in patients with MMS (hazard ratio [HR] = 3.08 and 2.92, respectively), age ≥60 years (HR = 1.52 and 2.45, respectively), and in patients who failed to attain a complete remission following initial therapy (HR = 3.27 and 2.13, respectively). Elevated lactate dehydrogenase was associated with shorter PFS (HR = 1.92), while anemia (HR = 2.46) was associated with shortened OS. MALT-IPI ≥2 (HR = 2.47 and 4.75), FLIPI >2 (HR = 1.65 and 2.09), and IPI >2 (HR = 2.09 and 1.73) were associated with shorter PFS and OS, respectively. Higher grade transformation (HGT) occurred in 11 (25.6%) MMS patients with a 5-year cumulative incidence of 13.2% (95% CI 4.7-26.1%). EMZL patients with MMS presentation represent a novel clinical subset associated with shorter PFS, OS, and higher incidence of HGT that needs novel therapeutic approaches.

Comprehensive Analysis of Phytochemical Constituents and Ethnopharmacological Investigation of Genus Datura.

The genus Datura comprises wild shrub plants that belong to the Solanaceae family. Naturally, they possess both medicinal and poisonous properties due to the presence of many biologically active phytochemical constituents. Traditionally, Datura had been used for mystic and religious purposes, as a natural drug to treat asthma, pain, gout, boils, abscesses, and wounds, and as psychoactive infusions and fumitories. Different Datura species exhibit diverse ethnopharmacological activities against different diseases, and many ancient and traditional cultures have used various forms of Datura to treat ailments and to prevent many diseases. In this article, we comprehensively summarize various phytochemical constituents isolated from Datura, their pharmacological properties against different diseases, parts of the plants used as traditional therapeutic agents, regions where they are located, and botanical descriptions of different Datura species. The ethnopharmacological properties of Datura may provide new insights for discovery and development of natural drugs. Further research is needed for the investigation of mechanisms of action and to develop safety profiles of the phytochemical constituents isolated from Datura species.

Decision-making for birth location among women in Pakistan: evidence from national survey.

BACKGROUND: Pakistan ranks 149th in the maternal mortality ratio (MMR) and has failed to keep pace with other countries in the region, except Afghanistan, with respect to health indicators. Home deliveries are linked to a higher risk of maternal death; therefore, discouraging home deliveries is imperative to improve maternal health. This study provides a holistic view and analyses factors affecting home birth decisions within the context of maternal socio-demographic characteristics in Pakistan. METHODS: The study exploits the latest data from the Pakistan Demographic and Health Survey (2012-2013), which includes a nationally representative sample of 13,558 women aged 15-49 years. However, the sample was reduced to 6977 women who had given birth in the 5 years preceding the survey. Statistical techniques, including bi-variate and multivariate logistic regression, were used to analyse the data. The dependent variable was dichotomous and coded as 0 for home deliveries and 1 for deliveries at a health facility. The dependent variable was constructed based on information regarding the most recent birth in the 5 years preceding the survey. RESULTS: The study reveals that giving birth at home is highly prevalent among mothers in Pakistan (Baluchistan, 74%; Khyber-Pakhtunkhwa, 53%; Gilgit Baltistan, 46%; Punjab, 45% and Sindh, 34%) because of their difficulty obtaining permission to visit a health facility, financial barriers, the distance to health facilities and transportation. Substantial variation is observed when geo-demographic characteristics are considered. Higher home childbirth rates have been recorded in rural areas compared with those in urban areas (OR 1.32; p ≤ 0.000). The likelihood of home birth is highest (OR 2.67; p = 0.000) among women in Baluchistan province and lowest (OR 0.48; p = 0.000) among mothers in Punjab province. After controlling for all odds ratios and demographic characteristics, the parents' education levels remain a significant factor (p = 0.000) that affects women's decisions to deliver at home rather than at a health facility. CONCLUSION: The study findings provide a better understanding of why women prefer to give birth at home. These results can help policymakers to introduce appropriate interventions to increase the number of deliveries at health facilities. These findings are expected to reduce maternal and neonatal mortality in Pakistan.

Clinical outcomes associated with per-operative discontinuation of aspirin in patients with coronary artery disease: A systematic review and meta-analysis.

BACKGROUND: Postoperative state is characterized by increased thrombotic risk by virtue of platelet activation. Whether aspirin ameliorates this risk in patients with established coronary artery disease undergoing cardiac or noncardiac surgery is unknown. We conducted a systematic review and meta-analysis to compare the risk of major adverse cardiac events (MACE) and the risk of bleeding in patients with early (3-5 or more days before surgery) vs. late discontinuation(<3-5 days)/no discontinuation of aspirin. METHODS: Multiple databases were searched from inception of these databases until March 2015 to identify studies that reported discontinuation of aspirin in patients undergoing surgery. The outcomes measured were all cause mortality, nonfatal myocardial infarction and other relevant thrombotic events (MACE) which also may include, fatal and nonfatal MI, stent thrombosis and restenosis, stroke, perioperative cardiovascular complications (heart failure, MI, VTE, acute stroke) and perioperative bleeding during the perioperative period to up to 30 days after surgery. RESULTS: A total of 1,018 titles were screened, after which six observational studies met the inclusion criteria. Our analysis suggests that there is no difference in MACE with planned discontinuation of aspirin (OR = 1.17, 95% CI = 0.76-1.81; P = 0.05; I2 = 55%). Early discontinuation of aspirin showed a decreased risk of peri-operative bleeding (OR 0.82, 95% CI = 0.67-0.99; P = 0.04; I2 = 42%). CONCLUSION: Our analysis suggests that planned short-term discontinuation in the appropriate clinical setting appears to be safe in the correct clinical setting with no increased risk of thrombotic events and with a decreased risk of bleeding. © 2016 Wiley Periodicals, Inc.

Bone lymphoma with multiple negative bone biopsies.

This article describes a 71-year-old man with right knee pain, prerenal azotemia, hypercalcemia, and a mass in the distal femur. Although testing, including bone marrow biopsy, initially ruled out myeloma, an open surgical biopsy eventually confirmed the diagnosis as lymphoma involving the bone with classic histologic findings of mature B-cell neoplasm of germinal cell origin.

Temporal Trends in Strut-Level Optical Coherence Tomography Evaluation of Coronary Stent Coverage: A Systematic Review and Meta-Analysis.

OBJECTIVES: We sought to pool data from all studies with reported strut-level data in human subjects evaluated by optical coherence tomography (OCT) surveillance and to compare the aggregate data of stent strut coverage on a longitudinal temporal timeline from initial implantation for different coronary stent subtypes. BACKGROUND: Delayed strut coverage following drug-eluting stent (DES) implantation is an important contributor to late stent thrombosis (LST). OCT can detect stent strut coverage. METHODS: We conducted a systematic search of published or presented studies reporting OCT stent strut coverage of bare-metal stents (BMS) and DES in PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials to June 2014. Data from 3,515 patients with strut-level data on 731,761 struts were analyzed. RESULTS: The temporal kinetics of strut coverage differed according to stent type. The rate of strut coverage, reflected by the calculated regression coefficient, was found to be the highest in BMS, followed by early generation zotarolimus-eluting stent, everolimus-eluting stent, newer-generation zotarolimus-eluting stent, paclitaxel-eluting stent, and sirolimus-eluting stent (p < 0.0001). CONCLUSIONS: Aggregate rates of stent strut coverage assessed by OCT surveillance differed according to stent type. The clinical implications of these differences require further study but may underlie the differences in rates of stent thrombosis observed in clinical trials with different stent types. © 2015 Wiley Periodicals, Inc.

The Hidden Toll of Psychological Distress in Australian Adults and Its Impact on Health-Related Quality of Life Measured as Health State Utilities.

BACKGROUND: Psychological distress (PD) is a major health problem that affects all aspects of health-related quality of life including physical, mental and social health, leading to a substantial human and economic burden. Studies have revealed a concerning rise in the prevalence of PD and various mental health conditions among Australians, particularly in female individuals. There is a scarcity of studies that estimate health state utilities (HSUs), which reflect the overall health-related quality of life in individuals with PD. No such studies have been conducted in Australia thus far. OBJECTIVE: We aimed to evaluate the age-specific, sex-specific and PD category-specific HSUs (disutilities) in Australian adults with PD to inform healthcare decision making in the management of PD. METHODS: Data on age, sex, SF-36/SF6D responses, Kessler psychological distress (K10) scale scores and other characteristics of N = 15,139 participants (n = 8149 female individuals) aged >15 years were derived from the latest wave (21) of the nationally representative Household, Income and Labor Dynamics in Australia survey. Participants were grouped into the severity categories of no (K10 score: 10-19), mild (K10: 20-24), moderate (K10: 25-29) and severe PD (K10: 30-50). Both crude and adjusted HSUs were calculated from participants' SF-36 profiles, considering potential confounders such as smoking, marital status, remoteness, education and income levels. The calculations were based on the SF-6D algorithm and aligned with Australian population norms. Additionally, the HSUs were stratified by age, sex and PD categories. Disutilities of PD, representing the mean difference between HSUs of people with PD and those without, were also calculated for each group. RESULTS: The average age of individuals was 46.130 years (46% male), and 31% experienced PD in the last 4 weeks. Overall, individuals with PD had significantly lower mean HSUs than those likely to be no PD, 0.637 (95% confidence interval [CI] 0.636, 0.640) vs 0.776 (95% CI 0.775, 0.777) i.e. disutility: -0.139 [95% CI -0.139, -0.138]). Mean disutilities of -0.108 (95% CI -0.110, -0.104), -0.140 (95% CI -0.142, -0.138), and -0.188 (95% CI -0.190, -0.187) were observed for mild PD, moderate PD and severe PD, respectively. Disutilities of PD also differed by age and sex groups. For instance, female individuals had up to 0.049 points lower mean HSUs than male individuals across the three classifications of PD. There was a clear decline in health-related quality of life with increasing age, demonstrated by lower mean HSUs in older population age groups, that ranged from 0.818 (95% CI 0.817, 0.818) for the 15-24 years age group with no PD to 0.496 (95% CI 0.491, 0.500) for the 65+ years age group with severe PD). Across all ages and genders, respondents were more likely to report issues in certain dimensions, notably vitality, and these responses did not uniformly align with ageing. CONCLUSIONS: The burden of PD in Australia is substantial, with a significant impact on female individuals and older individuals. Implementing age-specific and sex-specific healthcare interventions to address PD among Australian adults may greatly alleviate this burden. The PD state-specific HSUs calculated in our study can serve as valuable inputs for future health economic evaluations of PD in Australia and similar populations.

An environmental perspective of energy consumption, overpopulation, and human capital barriers in South Asia.

Prior literature is substantive in highlighting the nexus between pollutant and socio-economic predictors; however, the role of human interaction has not been sufficiently explored. Thus, the present study examines the validity of the environmental Kuznets Curve (EKC) hypothesis in the presence of energy consumption, overpopulation, and human capital index in five South Asian countries. It employs fixed effects, random effects, and dynamic panel causality techniques with a set of panel data from 1972 to 2021. The baseline results validate the existence of the EKC hypothesis in the recipient panel. Nevertheless, the findings reveal that energy consumption and population density have positive effects, while human capital has negative impacts on CO2 emissions. Furthermore, the study observes that energy consumption and per capita GDP have a significant causal link with CO2 emissions, whereas CO2 emissions are evident to have causality with population density and human capital index. The results are robust and suggest that the consolidation of an effective regulatory framework and technological improvements are substantial measures to improve environmental quality in South Asia. Moreover, allocating sufficient resources to uplift contemporary educational and health status would be imperative to improving environmental quality as aspired to by the Paris Agreement.

Comparable Efficacy of Oral Bendamustine versus Intravenous Administration in Treating Hematologic Malignancies.

Purpose: The purpose of this study was to analyze potential differences in antitumor efficacy and pharmacokinetics between intravenous (IV) bendamustine (BEN) and a novel orally administered bendamustine agent (PO) that is utilizing the beneficial properties of superstaturated solid dispersions formulated in nanoparticles. Methods: Pharmacokinetics of IV versus PO BEN were determined by analysis of plasma samples collected from NSG mice treated with either IV or PO BEN. Plasma samples were analyzed using liquid chromatography-mass spectrometry (LC/MS/MS) following a liquid-liquid extraction to determine peak BEN concentration (Cmax), area under the concentration-time curve (AUC) and the half-life (t1/2) in-vivo. in-vitro cytotoxicity of BEN against human non-Hodgkin's Burkitt's Lymphoma (Raji), multiple myeloma (MM.1s), and B-cell acute lymphoblastic leukemia (RS4;11) cell lines was determined over time using MTS assays. Luciferase-tagged versions of the aforementioned cell lines were used to determine in-vivo BEN cytotoxicity of IV versus PO BEN at two different doses. Results: Bendamustine at a high dose in-vitro causes cell death. There was no significant difference in antitumor efficacy between IV and novel PO BEN at a physiologically relevant concentration in all three xenograft models. In-vivo pharmacokinetics showed the oral bioavailability of BEN in mice to be 51.4%. Conclusions: The novel oral BEN agent tested exhibits good oral bioavailability and systemic exposure for in-vivo antitumor efficacy comparable to IV BEN. An oral BEN formulation offers exciting clinical potential as an additional method of administration for bendamustine and warrants further evaluation in clinical studies.

Comparable efficacy of oral bendamustine versus intravenous administration in treating hematologic malignancies.

PURPOSE: The purpose of this study was to analyze potential differences in antitumor efficacy and pharmacokinetics between intravenous (IV) bendamustine and a novel orally administered (PO) bendamustine agent that is utilizing the beneficial properties of superstaturated solid dispersions formulated in nanoparticles. METHODS: Pharmacokinetics of IV versus PO bendamustine were determined by analysis of plasma samples collected from NSG mice treated with either IV or PO bendamustine. Plasma samples were analyzed using liquid chromatography-mass spectrometry following a liquid-liquid extraction to determine peak bendamustine concentration, area under the concentration-time curve, and the half-life in-vivo. In-vitro cytotoxicity of bendamustine against human non-Hodgkin Burkitt's Lymphoma (Raji), multiple myeloma (MM.1s), and B-cell acute lymphoblastic leukemia (RS4;11) cell lines was determined over time using MTS assays. Luciferase-tagged versions of the aforementioned cell lines were used to determine in-vivo bendamustine cytotoxicity of IV versus PO bendamustine at two different doses. RESULTS: Bendamustine at a high dose in-vitro causes cell death. There was no significant difference in antitumor activity between IV and novel PO bendamustine at a physiologically relevant concentration in all three xenograft models. In-vivo pharmacokinetics showed the oral bioavailability of bendamustine in mice to be 51.4%. CONCLUSIONS: The novel oral bendamustine agent tested exhibits good oral bioavailability and systemic exposure for in-vivo antitumor efficacy comparable to IV bendamustine. An oral bendamustine formulation offers exciting clinical potential as an additional method of administration for bendamustine and warrants further evaluation in clinical studies.

Transcatheter patent foramen ovale closure versus medical therapy for cryptogenic stroke: a meta-analysis of randomized clinical trials.

BACKGROUND: There is an association between cryptogenic stroke and patent foramen ovale (PFO). The optimal treatment strategy for secondary prevention remains unclear. The purpose of this study was to analyze aggregate data examining the safety and efficacy of transcatheter device closure versus standard medical therapy in patients with PFO and cryptogenic stroke. METHODS: A search of published data identified 3 randomized clinical trials for inclusion. The primary outcome was a composite end-point of death, stroke and transient-ischemic attack (TIA). Pre-defined subgroup analysis was performed with respect to baseline characteristics including age, sex, atrial septal aneurysm and shunt size. Data was synthesized using a random effects model and results presented as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: A cohort of 2,303 patients with a history of cryptogenic stroke and PFO were randomized to device closure (n = 1150) and medical therapy (n = 1153). Mean follow-up was 2.5 years. Transcatheter closure was not superior to medical therapy in the secondary prevention of stroke or TIA in intention-to-treat analysis (HR: 0.66, 95% CI: 0.43 to 1.01; p = 0.056). However, the results were statistically significant using per-protocol analysis (HR: 0.64, 95% CI: 0.41 to 0.98; p = 0.043). Males had significant benefit with device closure (HR: 0.48, 95% CI: 0.24 to 0.96; p = 0.038). CONCLUSIONS: In this meta-analysis, using intention-to-treat analysis, transcatheter device closure of PFO was not superior to standard medical therapy in the secondary prevention of cryptogenic stroke. Transcatheter closure was superior using per-protocol analysis.

Correlates of preferences for home or hospital confinement in Pakistan: evidence from a national survey.

BACKGROUND: Despite the pregnancy complications related to home births, homes remain yet major place of delivery in Pakistan and 65 percent of totals births take place at home. This work analyses the determinants of place of delivery in Pakistan. METHODS: Multivariate Logistic regression is used for analysis. Data are extracted from Pakistan Demographic and Health Survey (2006-07). Based on information on last birth preceding 5 years of survey, we construct dichotomous dependent variable i.e. whether women deliver at home (Coded=1) or at health facility (coded=2). RESULTS: Bivariate analysis shows that 72% (p≤0.000) women from rural area and 81% women residing in Baluchistan delivered babies at home. Furthermore 75% women with no formal education, 81% (p≤0.000) women working in agricultural sector, 75% (p≤0.000) of Women who have 5 and more children and almost 77% (p≤0.000) who do not discussed pregnancy related issues with their husbands are found delivering babies at home. Multivariate analysis documents that mothers having lower levels of education, economic status and empowerment, belonging to rural area, residing in provinces other than Punjab, working in agriculture sector and mothers who are young are more likely to give births at home. CONCLUSION: A trend for home births, among Pakistani women, can be traced in lower levels of education, lower autonomy, poverty driven working in agriculture sector, higher costs of using health facilities and regional backwardness.

Investigating the energy-environmental Kuznets curve under panel quantile regression: a global perspective.

Energy is regarded as an engine of economic growth and an important ingredient of human survival and development, but it can lead to deterioration of environmental quality. The study investigates the energy environmental Kuznets curve (EEKC) during the 1990-2017 period for 144 countries using models for total energy, renewable energy, and non-renewable energy consumptions. We employ panel mean and quantile regressions, accounting for individual and distributional heterogeneities. It is found that the EEKC sustains among the higher middle-income countries while it cannot be verified at some lower-income quantiles due to the heterogeneous nature of the different groups of countries. The relationship between economic growth, total energy, and non-renewable energy consumption is positive and non-linear. The quantile estimations revealed mixed (positive and non-linear, inverted U-shape, U-shape, and N-shape) EEKC. The maximum and minimum turning values of GDP per capita for total energy consumption (is 43,201.58 and 89,630.49), for renewable energy consumption (53,535.07 and 89,869.41), and for non-renewable energy consumption (42,188.16 and 89,487.71). Urbanization and population growth had positive impacts on energy consumption while these effects become more significant as moving from low to high-income quantiles. The study implies that while the developed nations can adopt energy-efficient policies without compromising on the growth momentum and environment, this might be not recommended for the developing nations and it would be preferable for these countries to "grow first and clean up later." The study indicates the importance of the developed nations to support the developing countries to achieve economic growth along the EEKC by transferring energy-efficient technologies.