Loss-free tensile ductility of dual-structure titanium composites via an interdiffusion and self-organization strategy.

The deformation-coordination ability between ductile metal and brittle dispersive ceramic particles is poor, which means that an improvement in strength will inevitably sacrifice ductility in dispersion-strengthened metallic materials. Here, we present an inspired strategy for developing dual-structure-based titanium matrix composites (TMCs) that achieve 12.0% elongation comparable to the matrix Ti6Al4V alloys and enhanced strength compared to homostructure composites. The proposed dual-structure comprises a primary structure, namely, a TiB whisker-rich region engendered fine grain Ti6Al4V matrix with a three-dimensional micropellet architecture (3D-MPA), and an overall structure consisting of evenly distributed 3D-MPA "reinforcements" and a TiBw-lean titanium matrix. The dual structure presents a spatially heterogeneous grain distribution with 5.8 µm fine grains and 42.3 µm coarse grains, which exhibits excellent hetero-deformation-induced (HDI) hardening and achieves a 5.8% ductility. Interestingly, the 3D-MPA "reinforcements" show 11.1% isotropic deformability and 66% dislocation storage, which endows the TMCs with good strength and loss-free ductility. Our enlightening method uses an interdiffusion and self-organization strategy based on powder metallurgy to enable metal matrix composites with the heterostructure of the matrix and the configuration of reinforcement to address the strength-ductility trade-off dilemma.

Ovarian cancer survival in sub-Saharan Africa by human development index and histological subtypes: A population-based registry study.

Ovarian cancer (OC) is the fourth most common cancer of women in sub-Saharan Africa (SSA), although few data have been published on population-level survival. We estimate ovarian cancer survival in SSA by human development index and histological subtype, using data from seven population-based cancer registries in six countries: Kenya (Nairobi and Eldoret), Mauritius, Uganda (Kampala), Cote d'Ivoire (Abidjan), Ethiopia (Addis Ababa) and South Africa (Eastern Cape). A total of 644 cases diagnosed during 2008-2014 were included, with 77% being of epithelial subtypes (range 47% [Abidjan]-80% [Mauritius]). The overall observed survival in the study cohort was 73.4% (95% CI: 69.8, 77.0) at 1 year, 54.4% (95% CI: 50.4, 58.7) at 3 years and 45.0% (95% CI: 41.0, 49.4) at 5 years. Relative survival at Year 1 ranged from 44.4% in Kampala to 86.3% in Mauritius, with a mean for the seven series of 67.4%. Relative survival was highest in Mauritius at 72.2% and lowest in Kampala, Uganda at 19.5%, with a mean of 47.8%. There was no difference in survival by age at diagnosis. Patients from high and medium HDI countries had significantly better survival than those from low HDI countries. Women with cancers of epithelial cell origin had much lower survival compared to women with other histological subtypes (p = .02). Adjusted for the young age of the African patients with ovarian cancer (44% aged <50) survival is much lower than in USA or Europe, and underlines the need for improvements in the access to diagnosis and treatment of OC in SSA.

Unravelling the threads: understanding the interplay of Cultural values, female workforce engagement, human development index and suicide rates.

PURPOSE: Suicide is a major public health problem across the world. Extensive research on the field shows that suicide is affected by several sociological, economic, and cultural risk factors. Over the last century, social changes have driven the reshaping of traditional gender roles, often in an uneven fashion, strongly depending on context. This study proposes updated findings on the impact that changes in traditional gender roles could have on suicide rates METHODS: It will do so by examining the correlation between female labor force participation (FLPR) and sex-specific suicide rates. Moreover, it will examine this association depending on human development (HDI) and Hofstede's individualism index. To do so, data from 2010 to 2019 from 47 countries is collected from the WHO, ILOSTAT and UN agencies' websites. RESULTS: Analysis show a significant interaction between FLPR, HDI and individualism index scores on male suicide rates (p = 0.002). There is a negative association between FLPR and male suicide rates in relatively lower HDI countries, while in very high HDI countries an increase in FLPR is correlated with an increase in male suicide rates. Similar trends but no significant interaction is observed for female suicide rates. CONCLUSION: This study suggests that female participation is beneficial for male population as it reduces male suicide rates. However, this association appears to be context dependent. In countries where institutional adjustment is already established, and human development is very high, other factors might be of interest in examining the trends of suicide rates among men and women.

Exploring structure/property relationships to health and environmental hazards of polymeric polyisocyanate prepolymer substances-3. Aquatic exposure and hazard of aliphatic diisocyanate-based prepolymers.

The water extractability and acute aquatic toxicity of seven aliphatic diisocyanate-based prepolymer substances were investigated to determine if lesser reactivity of the aliphatic isocyanate groups, as well as increased ionization potential of the expected (aliphatic amine-terminated) polymeric hydrolysis products, would influence their aquatic behavior compared to that of previously investigated aromatic diisocyanate-based prepolymers. At loading rates of 100 and 1,000 mg/L, only the substances having log Kow ≤9 exhibited more than 1% extractability in water, and a maximum of 66% water extractability was determined for a prepolymer having log Kow = 2.2. For the more hydrophobic prepolymer substances (log Kow values from 18-37), water extractability was negligible. High-resolution mass spectrometric analyses were performed on the water-accommodated fractions (WAF) of the prepolymers, which indicated the occurrence of primary aliphatic amine-terminated polymer species having backbones and functional group equivalent weights aligned to those of the parent prepolymers. Measurements of reduced surface tension and presence of suspended micelles in the WAFs further supported the occurrence of these surface-active cationic polymer species as hydrolysis products of the prepolymers. Despite these characteristics, the water-extractable hydrolysis products were practically non-toxic to Daphnia magna. All of the substances tested exhibited 48-h EL50 values of >1,000 mg/L, with one exception of EL50 = 157 mg/L. The results from this investigation support a grouping of the aliphatic diisocyanate-based prepolymers as a class of water-reactive polymer substances having predictable aquatic exposure and a uniformly low hazard potential, consistent with that previously demonstrated for the aromatic diisocyanate-based prepolymers.

Exploring the effect of human-drone communication modality on safety and balance control in virtual construction environments.

This study examines the impact of Human-Drone Interaction (HDI) modalities on construction workers' safety and balance control within virtual environments. Utilising virtual reality (VR) simulations, the study explored how gesture and speech-based communications influence workers' physical postures and balance, contrasting these modalities with a non-interactive control group. One hundred participants were recruited, and their movements and balance control were tracked using motion sensors while they interacted with virtual drones through either gesture, speech, or without communication. Results showed that interactive modalities significantly improved balance control and reduced the risk of falls, suggesting that advanced HDI can enhance safety on construction sites. However, speech-based interaction increased cognitive workload, highlighting a trade-off between physical safety and mental strain. These findings underscore the potential of integrating intuitive communication methods into construction operations, although further research is needed to optimise these interactions for long-term use and in diverse noise environments.

This study examines the impact of Human-Drone Interaction (HDI) modalities on construction workers' safety and balance control within virtual environments with a human subject experiment. Results showed that interactive modalities significantly improved balance control and reduced the risk of falls.

Breast cancer screening programmes and self-reported mammography use in European countries.

Mammography screening has been shown to be able to reduce breast cancer mortality, leading most European countries to implement mammography-based screening programmes. In our study, we analysed key characteristics of breast cancer screening programmes and mammography use in European countries. Information on screening programmes were obtained from the 2017 European Union (EU) screening report, websites from governments and cancer registries, and through literature search in PubMed (studies published up to 20 June 2022). Data on self-reported mammography use in the past 2 years were obtained from Eurostat and had been derived from the European health interview survey (cross-sectional survey), conducted in the 27 EU countries, Iceland, Norway, Serbia, Turkey and the UK in 2013 to 2015 and 2018 to 2020. Data were analysed for each country according to their human development index (HDI). By 2022, all included countries besides Bulgaria and Greece had introduced an organised mammography-based screening programme; Romania and Turkey had only pilot programmes. Screening programmes differ substantially across countries, particularly in timing of implementation (e.g., in Sweden, the Netherlands before 1990; Belgium, France between 2000 and 2004; Denmark, Germany between 2005 and 2009; Austria, Slovakia after 2010). Self-reported mammography use also differed considerably across countries, and went along with HDI-from <36% in all countries with HDI <0.85 to >70% in most countries with HDI >0.90. The data call for efforts to improve mammography screening use across Europe, particularly in countries with lower development levels where breast cancer mortality rates are also among the highest in the region.

Global epidemiological trends and variations in the burden of gallbladder cancer.

BACKGROUND: Gallbladder cancer (GBC) is a rare but lethal malignancy with a dismal prognosis. The aim of this study is to analyze the burdens and trends of GBC across the world based on geography, socioeconomic development (based on human development index [HDI]), and gender. METHODS: GLOBOCAN 2020 database was used to extract data (2020-2040) relating to the incidence and mortality of GBC across the world. RESULTS: Asia had the highest burden of GBC with India and China contributing to majority of the absolute burden. The burden of GBC by age standardized rate was highest in Latin America (Bolivia and Chile) and Southeast Asia (Bangladesh and Nepal). Medium HDI countries had a higher mortality rate compared to very high HDI countries. Females had a higher predilection for GBC across different regions and socioeconomic groups. GBC burden is expected to significantly increase across the world by 2040 with variable trends across different regions, age groups, and genders. CONCLUSION: The global burden of GBC will significantly increase over the next two decades with marked regional and demographic variations. The results of this study will empower national and global health leaders to develop policies to address the increasing burden of this lethal malignancy.

Global trends in the incidence and mortality of pancreatic cancer based on geographic location, socioeconomic status, and demographic shift.

BACKGROUND: Pancreatic cancer (PC) is a lethal malignancy with a significantly rising rate of incidence and mortality. This study aims to describe the influence of geography, socioeconomic development (based on the Human Development Index [HDI]), gender, and demographic shift on the temporal trends in the global burden of PC. METHODS: Data (2020-2040) relating to the incidence, mortality of PC, and demographic shifts based on continents and HDI areas were extracted from GLOBOCAN 2020. RESULTS: PC was associated with a higher socioeconomic status. Asia contributed to the majority of the burden, led by China. Advanced age (≥65 years) contributed to the majority of the burden in all socioeconomic regions except in Medium HDI and Low HDI countries, where the younger population (<65 years) contributed more. Females contributed to a higher burden in certain countries. Future trends for 2040 showed a >60% increase in the incidence and mortality of PC with an associated demographic shift. CONCLUSION: The global burden of PC is expected to rise significantly over the next few decades regardless of geography, socioeconomic development, age, and gender. Advance knowledge of this data can help to formulate strategies and public health policies to specifically target countries and populations at risk.

Distribution incidence, mortality of tuberculosis and human development index in Iran: estimates from the global burden of disease study 2019.

BACKGROUND: Tuberculosis is one of the most serious challenges facing the global healthcare system. This study aims to investigate the incidence and mortality of tuberculosis in Iran from 2010 to 2019 as well as its relationship with the human development index (HDI). METHODS: The present study is an ecological study aiming at investigating the incidence and mortality of tuberculosis in Iran during the years 2010 to 2019. The related data were extracted from the Global Burden of Disease (GBD) website. The spatial pattern attributed to tuberculosis in the provinces of Iran was analyzed using ArcGIS software. In this study, the two-variable correlation method was used to analyze the data extracted to study the correlation between Tuberculosis and HDI. RESULT: Based on the results recorded in GBD, the incidence of tuberculosis in 2010, that is, 14.61 (12.72, 16.74), declined compared to 2019, namely 12.29 (10.71, 14.09). The age-standardized mortality rate which was 1.63 (1.52, 1.73) in 2010, has decreased compared to 2019: 1.17 (1.07, 1.32). The incidence and mortality rates of tuberculosis in Iran in all age groups have decreased in 2019 compared to 2010. The highest incidence and mortality among tuberculosis patients were recorded in Sistan and Baluchistan and Golestan provinces. The results indicated that there was a negative and significant correlation between the mortality rate of tuberculosis and the human development index in 2010 (r = -0.509, P-value = 0.003) and 2019 (r = -0.36, P-value = 0.001); however, this correlation between incidence and human development index was not significant (p > 0.05). CONCLUSION: Since mortality is mostly observed in areas with low HDI, health system policymakers must pay more attention to these areas in order to improve care and perform screenings to diagnose and treat patients thus reducing the mortality rate of tuberculosis and preventing an increase in its incidence in Iran.

Environmental quality and its impact on total fertility rate: an econometric analysis from a new perspective.

BACKGROUND: Environmental quality significantly affects various aspects of human existence. This study employs ecological footprint as a proxy to assess the impact of environmental quality on the TFR, measured as births per woman. This study investigates the extent to which ecological footprint indicators impact on the TFR in across 31 countries between from 1990 to 2017. METHODS: We gathered data on ecological footprints, specifically carbon, agricultural land, grazing land, forest products, and fisheries, from the Global Footprint Network. Information on the TFR, Human Development Index (HDI), and per capita Gross National Income (GNI) were sourced from the World Bank and the United Nations. We applied static panel and quantile regression models to scrutinize the connection between the ecological footprint and TFR, showing how the former influences the latter. RESULTS: The outcomes reveal that, in both fixed and random effects models, factors including HDI, carbon, and fishing grounds exert a negative influence on TFR, all at a significance level of p < 0.01. Conversely, cropland and forest product footprints exhibited a favorable impact on the TFR (p < 0.01). Furthermore, GNI per capita positively affected the TFR in both models, with a p-value of 0.01. Quantiles regression analysis demonstrated that HDI and carbon footprint had a negative impact on TFR across all quantiles. This statistical significance is maintained for all quantiles, although it is only significant for the carbon footprint up to the 60th quantile, at p < 0.01. CONCLUSIONS: This study establishes a negative correlation between specific ecological footprint indicators, such as carbon and fishing grounds, and TFR. Conversely, there was a positive correlation between the footprint of forest products and the TFR. The primary conclusion drawn is that there is heterogeneity in the results regarding the relationship between ecological footprint and TFR. Moreover, the ecological footprint indicators considered in this study did not uniformly influence TFR. Each ecological footprint indicator exhibited distinct effects on the TFR, displaying either positive or negative correlation coefficients. Future research endeavors may delve into how ecological footprints impact other population dynamics, such as mortality and migration.

The geographic diversity of authorship in leading general surgery journals; A study of 24,332 authors.

BACKGROUND: Research guides evidence-based general surgery practice, advocacy, policy and resource allocation, but is seemingly lacking representation from those countries with greatest disease burden and mortality. Accordingly, we conducted a geographic study of publications in the most impactful general surgery journals worldwide. METHODS: The six general surgery journals with the highest 2020 impact factors were selected. Only journals specific to general surgery were included. For all original articles over the past five years, the affiliated country and city were extracted for the first, second and last author. Number of publications were adjusted per capita, and compared to Human Development Index (HDI) using logistic regression. RESULTS: 8274 original articles were published in the top six ranked general surgery journals over 2016-2020, with 24,332 affiliated authors. Authors were most commonly associated with the US (27.88%), Japan (9.09%) and China (8.46%), or per capita, The Netherlands, Sweden and Singapore. There is a linear association between publishing in a top six journal and HDI of country of affiliation. Just four publications were from medium or low HDI countries over the period. CONCLUSION: Authorship in leading general surgery journals is predominantly from wealthy, Western countries. Authorship is associated with affiliation with a high HDI country, with few authors from medium or low HDI countries. There is a lack of representation in literature from Africa, Russia, and parts of Southeast Asia, and thus a lack of locally relevant evidence to guide surgical practice in these areas of high disease burden and low life expectancy.

Socioeconomic indices guided linear mixed-effects and meta-regression modelling of the temporal, global and regional prevalence of Helicobacter pylori in environmental waters: A class I carcinogen.

Environmental waters (EW) substantially lend to the transmission of Helicobacter pylori (Hp). But the increase in Hp infections and antimicrobial resistance is often attributed to socioeconomic status. The connection between socioeconomic status and Hp prevalence in EW is however yet to be investigated. This study aimed to assess the impacts of socioeconomic indices (SI: continent, world bank region (WBR), world bank income (WBI), WHO region, Socio-demographic Index (SDI quintile), Sustainable Development Index (SuDI), and Human Development Index (HDI)) on the prevalence of Hp in EW. Hp-EW data were fitted to a generalized linear mixed-effects model and SI-guided meta-regression models with a 1000-resampling test. The worldwide prevalence of Hp in EW was 21.76% [95% confidence interval [CI]: 10.29-40.29], which declined significantly from 59.52% [43.28-74.37] in 1990-99 to 19.36% [3.99-58.09] in 2010-19 and with increasing trend in 2020-22 (33.33%, 22.66-45.43). Hp prevalence in EW was highest in North America (45.12%, 17.07-76.66), then Europe (22.38%, 5.96-56.74), South America (22.09%, 13.76-33.49), Asia (2.98%, 0.02-85.17), and Africa (2.56%, 0.00-99.99). It was negligibly different among sampling settings, WBI, and WHO regions demonstrating highest prevalence in rural location [42.62%, 3.07-94.56], HIEs [32.82%, 13.19-61.10], and AMR [39.43%, 19.92-63.01], respectively. However, HDI, sample size, and microbiological method robustly predict Hp prevalence in EW justifying 26.08%, 21.15%, and 16.44% of the true difference, respectively. In conclusion, Hp is highly prevalence in EW across regional/socioeconomic strata and thus challenged the uses of socioeconomic status as surrogate for hygienic/sanitary practices in estimating Hp infection prevalence.

Distribution of nursing workforce in the world using Gini coefficient.

INTRODUCTION: Unequal Access to human resources for health, reduces access to healthcare services, worsens the quality of services and reduces health outcomes. This study aims to investigate the distribution of the nursing workforce around the world. METHODS: This is a descriptive-analytical study, which was conducted in 2021. The number of nurses and world populations was gathered from World Health Organization (WHO) and The United Nations (UN) databases. The UN has divided world countries based on the Human Development Index (HDI) into four categories of very high, high, medium and low HDI. To investigate the distribution of the nurses around the world, we used the nurse population ratio (per 10,000 population), Gini coefficient, Lorenz curve and Pareto curve. FINDINGS: On average, there were 38.6 nurses for every 10,000 people in the world. Nations with the very high HDI, had the highest nurse/population ratio (95/10,000), while the low HDI nations had the lowest nurse/population ratio (7/10,000). Most nurses around the world were females (76.91%) who were in the age group of 35-44 (29.1%). The Gini coefficient of nations in the each four HDI categories varied from 0.217 to 0.283. The Gini coefficient of the nations between the four HDI categories was 0.467, and the Gini coefficient of the whole world was 0.667. CONCLUSION: There were inequalities between countries all over the world. Policymakers should focus on the equitable distribution of the nursing workforce across all local, national and regional levels.

LMK235, a small molecule inhibitor of HDAC4/5, protects dopaminergic neurons against neurotoxin- and α-synuclein-induced degeneration in cellular models of Parkinson's disease.

Epigenetic modifications in neurodegenerative disease are under investigation for their roles in disease progression. Alterations in acetylation rates of certain Parkinson's disease (PD)-linked genes have been associated with the pathological progression of this disorder. In light of this, and given the lack of disease-modifying therapies for PD, HDAC inhibitors (HDIs) are under consideration as potential pharmacological agents. The neuroprotective effects of pan-HDACs and some class-specific inhibitors have been tested in in vivo and in vitro models of PD, with varying outcomes. Here we used gene co-expression analysis to identify HDACs that are associated with human dopaminergic (DA) neuron development. We identified HDAC3, HDAC5, HDAC6 and HDAC9 as being highly correlated with the DA markers, SLC6A3 and NR4A2. RT-qPCR revealed that mRNA expression of these HDACs exhibited similar temporal profiles during embryonic mouse midbrain DA (mDA) neuron development. We tested the neuroprotective potential of a number of class-specific small molecule HDIs on human SH-SY5Y cells, using neurite growth as a phenotypic readout of neurotrophic action. Neither the class I-specific HDIs, RGFP109 and RGFP966, nor the HDAC6 inhibitor ACY1215, had significant effects on neurite outgrowth. However, the class IIa HDI, LMK235 (a HDAC4/5 inhibitor), significantly increased histone acetylation and neurite outgrowth. We found that LMK235 increased BMP-Smad-dependent transcription in SH-SY5Y cells and that this was required for its neurite growth-promoting effects on SH-SY5Y cells and on DA neurons in primary cultures of embryonic day (E) 14 rat ventral mesencephalon (VM). These effects were also seen in SH-SY5Y cells transfected with HDAC5 siRNA. Furthermore, LMK235 treatment exerted neuroprotective effects against degeneration induced by the DA neurotoxin 1-methyl-4-phenylpyridinium (MPP+), in both SH-SY5Y cells and cultured DA neurons. Treatment with LMK235 was also neuroprotective against axonal degeneration induced by overexpression of wild-type (WT) or A53T mutant α-synuclein in both SH-SY5Y cells and primary cultures of DA neurons. In summary, these data show the neuroprotective potential of the class IIa HDI, LMK235, in cell models of relevance to PD.

Antagonistic Pharmacological Interaction between Sirtuin Inhibitor Cambinol and Paclitaxel in Triple-Negative Breast Cancer Cell Lines: An Isobolographic Analysis.

Breast cancer (BC) is a heterogeneous disease with different intrinsic subtypes. The most aggressive subtype of BC-triple-negative breast cancer (TNBC) is characterized by high heterogeneity and metastasis rate, poor prognosis and lack of therapeutic targets due to the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Targeted therapies have been approved for many other cancers and even other subtypes of BC, but treatment options for TNBC are still mainly limited to chemotherapy. Therefore, new, more effective treatment regimens are needed. Combined chemotherapy with two or more active agents is considered a promising anti-neoplasm tool in order to achieve better therapeutic response and reduce therapy-related adverse effects. The study demonstrated an antagonistic effect commonly used in TNBC therapy cytostatic drug-paclitaxel (PAX) and sirtuin inhibitor: cambinol (CAM) in BT-549, MDA-MB-468 and HCC1937 TNBC cell lines. The type of pharmacological interaction was determined by a precise and rigorous pharmacodynamic method-isobolographic analysis. The cytotoxic and anti-proliferative effects of CAM used alone or combined with PAX were determined utilizing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-bromo-2'-deoxyuridine (BrdU) assays, respectively. Induction of apoptosis in TNBC cell lines after PAX and CAM treatment applied individually or in combination was determined by flow cytometry (FACS) as a number of cells with active caspase-3. It has been observed that both agents used separately inhibit cell proliferation and induce apoptosis; however, applying them in combination ameliorated antiproliferative and pro-apoptotic effects in all analyzed TNBC cell lines. Our results demonstrate that CAM and PAX used in combination act antagonistically, limiting anti-cancer efficacy and showing the importance of preclinical testing.

A fair and progressive carbon price for a sustainable economy.

The principle of "common but differentiated responsibility", as a key concept of the United Nations Framework Convention on Climate Change (UNFCCC), acknowledges the conditions for a generally acceptable and differentiated pricing mechanism on carbon emissions. With reference to this principle, carbon price determination has become a necessary instrument for sustainable policies. Considering the development gaps and the historical responsibility of the OECD's countries, a single carbon price would raise a major issue of equity between "developed" and "developing" countries. Although from a climate perspective each molecule of CO2 produces the same level of damage despite the nature or the location of the activity generating the emissions, all CO2 emissions are not on an equal footing. Indeed, some are necessary to improve the lives of people in "developing" countries when others can be considered not indispensable, especially beyond a certain level of development. In this policy paper, we explain how the price of carbon should be fixed according to a reference price depending on the Human Development Index (HDI) and CO2 emissions per capita. The HDI criterion enables to integrate progressivity into taxation while distinguishing what is essential from what is not. By taking a reference price based on the HDI, countries with low HDIs should pay a lower carbon price. However, with same HDI levels, countries with higher CO2 emissions should pay a penalty on the reference price. Our policy paper analyses the benefits of a differentiated and progressive carbon pricing mechanism to facilitate intergovernmental cooperation for a more sustainable economy.

Effects of aerobic exercise and progressive muscle relaxation on migraine.

OBJECTIVE: To determine the effect of aerobic exercises and progressive muscle relaxation in migraine patients. METHODS: The quasi-experimental study was conducted at the Sheikh Khalifa Bin Zayed Al Nayhan Hospital / Combined Military Hospital, Muzaffarabad, Azad Jammu and Kashmir, from February to July 2017, and comprised migraine patients of either gender aged 20-50 years. They were divided into experimental and control group. Experimental group A received supervised exercises protocol, including aerobic exercise (stationary bicycle) 30min with 10min warm-up and 5min cool-down followed by progressive muscle relaxation for 15min 3 times a week for 6 weeks along with prophylactic medicine. The control group received prophylactic medicines flunarazine 5mg twice daily, inderal 10mg thrice daily and nortriptyline 25mg at night. Patients were assessed using Numeric Pain Rating Scale, Migraine Disability Assessment Scale, Headache Disability Index, Headache Impact test-6 and the Central Sensitisation Inventory at baseline, midline and at the completion of intervention. Data was analysed using SPSS 21. RESULTS: Of the 28 patients, there were 14(50%) in each of the two groups. Overall, there were 24(85.7%) females and 4(14.3%) males with a mean age of 29.7±10 years. There were significant improvements in all parameters in both the groups, but group A had significantly better outcome post-intervention (p<0.05). CONCLUSIONS: Prophylactic medicine, aerobic exercises and progressive muscle relaxation, when used together, were found to be effective means of intervention for migraine.

The African natural product knipholone anthrone and its analogue anthralin (dithranol) enhance HIV-1 latency reversal.

A sterilizing or functional cure for HIV is currently precluded by resting CD4+ T cells that harbor latent but replication-competent provirus. The "shock-and-kill" pharmacological ap-proach aims to reactivate provirus expression in the presence of antiretroviral therapy and target virus-expressing cells for elimination. However, no latency reversal agent (LRA) to date effectively clears viral reservoirs in humans, suggesting a need for new LRAs and LRA combinations. Here, we screened 216 compounds from the pan-African Natural Product Library and identified knipholone anthrone (KA) and its basic building block anthralin (dithranol) as novel LRAs that reverse viral latency at low micromolar concentrations in multiple cell lines. Neither agent's activity depends on protein kinase C; nor do they inhibit class I/II histone deacetylases. However, they are differentially modulated by oxidative stress and metal ions and induce distinct patterns of global gene expression from established LRAs. When applied in combination, both KA and anthralin synergize with LRAs representing multiple functional classes. Finally, KA induces both HIV RNA and protein in primary cells from HIV-infected donors. Taken together, we describe two novel LRAs that enhance the activities of multiple "shock-and-kill" agents, which in turn may inform ongoing LRA combination therapy efforts.

Correction of Niemann-Pick type C1 trafficking and activity with the histone deacetylase inhibitor valproic acid.

Niemann-Pick type C (NPC) disease is primarily caused by mutations in the NPC1 gene and is characterized by the accumulation of unesterified cholesterol and lipids in the late endosomal (LE) and lysosomal (Ly) compartments. The most prevalent disease-linked mutation is the I1061T variant of NPC1, which exhibits defective folding and trafficking from the endoplasmic reticulum to the LE/Ly compartments. We now show that the FDA-approved histone deacetylase inhibitor (HDACi) valproic acid (VPA) corrects the folding and trafficking defect associated with I1061T-NPC1 leading to restoration of cholesterol homeostasis, an effect that is largely driven by a reduction in HDAC7 expression. The VPA-mediated trafficking correction is in part associated with an increase in the acetylation of lysine residues in the cysteine-rich domain of NPC1. The HDACi-mediated correction is synergistically improved by combining it with the FDA-approved anti-malarial, chloroquine, a known lysosomotropic compound, which improved the stability of the LE/Ly-localized fraction of the I1061T variant. We posit that combining the activity of VPA, to modulate epigenetically the cellular acetylome, with chloroquine, to alter the lysosomal environment to favor stability of the trafficked I1061T variant protein can have a significant therapeutic benefit in patients carrying at least one copy of the I1061T variant of NPC1, the most common disease-associated mutation leading to NPC disease. Given its ability to cross the blood-brain barrier, we posit VPA provides a potential mechanism to improve the response to 2-hydroxypropyl-ß-cyclodextrin, by restoring a functional NPC1 to the cholesterol managing compartment as an adjunct therapy.

Cost per DALY averted in low, middle- and high-income countries: evidence from the global burden of disease study to estimate the cost-effectiveness thresholds.

BACKGROUND: Determining the cost-effectiveness thresholds for healthcare interventions has been a severe challenge for policymakers, especially in low- and middle-income countries. This study aimed to estimate the cost per disability-adjusted life-year (DALY) averted for countries with different levels of Human Development Index (HDI) and Gross Domestic Product (GDP). METHODS: The data about DALYs, per capita health expenditure (HE), HDI, and GDP per capita were extracted for 176 countries during the years 2000 to 2016. Then we examined the trends on these variables. Panel regression analysis was performed to explore the correlation between DALY and HE per capita. The results of the regression models were used to calculate the cost per DALY averted for each country. RESULTS: Age-standardized rate (ASR) DALY (DALY per 100,000 population) had a nonlinear inverse correlation with HE per capita and a linear inverse correlation with HDI. One percent increase in HE per capita was associated with an average of 0.28, 0.24, 0.18, and 0.27% decrease on the ASR DALY in low HDI, medium HDI, high HDI, and very high HDI countries, respectively. The estimated cost per DALY averted was $998, $6522, $23,782, and $69,499 in low HDI, medium HDI, high HDI, and very high HDI countries. On average, the cost per DALY averted was 0.34 times the GDP per capita in low HDI countries. While in medium HDI, high HDI, and very high HDI countries, it was 0.67, 1.22, and 1.46 times the GDP per capita, respectively. CONCLUSIONS: This study suggests that the cost-effectiveness thresholds might be less than a GDP per capita in low and medium HDI countries and between one and two GDP per capita in high and very high HDI countries.