CMOS plus stochastic nanomagnets enabling heterogeneous computers for probabilistic inference and learning.

Extending Moore's law by augmenting complementary-metal-oxide semiconductor (CMOS) transistors with emerging nanotechnologies (X) has become increasingly important. One important class of problems involve sampling-based Monte Carlo algorithms used in probabilistic machine learning, optimization, and quantum simulation. Here, we combine stochastic magnetic tunnel junction (sMTJ)-based probabilistic bits (p-bits) with Field Programmable Gate Arrays (FPGA) to create an energy-efficient CMOS + X (X = sMTJ) prototype. This setup shows how asynchronously driven CMOS circuits controlled by sMTJs can perform probabilistic inference and learning by leveraging the algorithmic update-order-invariance of Gibbs sampling. We show how the stochasticity of sMTJs can augment low-quality random number generators (RNG). Detailed transistor-level comparisons reveal that sMTJ-based p-bits can replace up to 10,000 CMOS transistors while dissipating two orders of magnitude less energy. Integrated versions of our approach can advance probabilistic computing involving deep Boltzmann machines and other energy-based learning algorithms with extremely high throughput and energy efficiency.

Targeting multiple disease hallmarks using a synergistic disease-modifying drug combination ameliorates osteoarthritis via inhibition of senescence and inflammation.

AIMS: Osteoarthritis (OA), is a debilitating disease characterized by progressive cartilage degradation, synovial inflammation, and chondrocyte senescence. Various treatment agents independently targeting these hallmarks have been investigated. However, due to the complex multifaceted nature of OA, no disease-modifying osteoarthritis drugs are clinically available. In an attempt to overcome this, we developed a combinatorial approach and demonstrated the efficacy of TsC [Tissue inhibitor of metalloproteinase-3 (TIMP3) + sulfated carboxymethylcellulose (sCMC)] and piperlongumine (PL) combination for the amelioration of OA in a goat ex vivo OA model. MAIN METHODS: The efficacy of the drug combination was evaluated using the goat ex vivo OA explant model and results were validated in clinically relevant human OA cartilage explants. The chondroprotective effects were evaluated in terms of reduced inflammation and cartilage matrix loss, reduction in chondrosenescence, and reduced oxidative stress. KEY FINDINGS: A combination of TsC and PL (TsC-PL) significantly reduced inflammation, cartilage matrix loss, chondrosenescence, and oxidative stress in the goat ex vivo OA model and showed chondroprotective effects. Further, similar chondroprotective effects were observed in human OA cartilage. Additionally, the coefficient of drug interaction analysis indicated that the combination of TsC and PL had a synergistic effect in reducing matrix degrading proteases and inflammation (goat ex vivo OA model) and Reactive oxygen species (ROS) production (human OA cartilage). SIGNIFICANCE: Combinatorial treatment with TsC and PL demonstrated potential disease-modifying effects for the treatment of osteoarthritis via inhibition of inflammation and senescence and supports the usage of treatment strategies targeting multiple pathological factors of OA simultaneously.

Sulfated carboxymethylcellulose mediated enhancement of Timp3 efficacy synergistically attenuates osteoarthritis through inhibition of NFκB and JNK.

Osteoarthritis (OA) is a prevalent degenerative joint condition with no effective disease modifying treatments. In this study, we aimed to address multiple OA hallmarks using a combination of pro-chondrogenic sulfated carboxymethylcellulose (sCMC) and anti-catabolic tissue inhibitor of metalloproteases 3 (Timp3) in relevant disease systems. Firstly, we chemically sulfated carboxymethylcellulose to impart a negative charge and improve the stability of cationic Timp3. The modified sCMC exhibited a molecular weight of 10 kDa and a degree of sulfation of ∼10 %. We further demonstrated that sulfation of CMC confers pro-chondrogenic characteristics. Subsequently, we demonstrated that the combination of sCMC and Timp3 effectively reduced key OA hallmarks, such as matrix degradation, inflammation, and protease expression, in a goat ex vivo OA model compared to individual treatments. We further demonstrated that the anti-OA effect of sCMC and Timp3 is mediated through the suppression of NFκB and JNK activation. To validate the clinical potential and mechanism of action, we conducted experiments on human OA explants. The combination treatment synergistically reduced the expression of MMP13 and NFκB in human OA explants. Overall, sCMC-mediated enhancement of Timp3 efficacy synergistically reduced OA-like traits and demonstrates the potential for OA amelioration.

Ecological health and water quality of village ponds in the subtropics limiting their use for water supply and groundwater recharge.

Ponds are a typical feature of many villages in the subtropics, and have been widely used as important sources of water for agriculture, aquaculture and groundwater recharge, as well as enhancing village resilience to floods and drought. Currently many village ponds are in a very poor state and in dire need of rejuvenation. This paper assesses the current water quality status and ecological health of twelve sub-tropical village ponds, situated in western Uttar Pradesh, India. This assessment is used to evaluate their wastewater treatment needs in relation to potential village uses of the water. Physico-chemical (Secchi depth, Total phosphorus and Total nitrogen) and biological (Phytoplankton chlorophyll-a) indicators highlight hypertrophic conditions in all the ponds. The study indicates that the status of village ponds requires significant investments in wastewater treatment to restore their use for many purposes, including aquaculture, although some may still be acceptable for irrigation purposes, as long as pathogenic bacteria are not abundant. We propose increased implementation of decentralised systems for wastewater treatment, such as septic tanks and constructed wetlands, to reduce the organic and nutrient loads entering village ponds and allow their use for a wider range of purposes.

The durability of long-lasting insecticidal nets distributed to the households between 2009 and 2013 in Nepal.

BACKGROUND: Understanding and improving the durability of long-lasting insecticidal nets (LLINs) in the field are critical for planning future implementation strategies including behavioral change for care and maintenance. LLIN distribution at high coverage is considered to be one of the adjunctive transmission reduction strategies in Nepal's Malaria Strategic Plan 2014-2025. The main objective of this study was to assess the durability through assessment of community usage, physical integrity, residual bio-efficacy, and chemical retention in LLINs: Interceptor®, Yorkool®, and PermaNet ®2.0 which were used in Nepal during 2009 through 2013. METHODS: Assessments were conducted on random samples (n = 440) of LLINs from the eleven districts representing four ecological zones: Terai plain region (Kailali and Kanchanpur districts), outer Terai fluvial ecosystem (Surkhet, Dang, and Rupandhei districts), inner Terai forest ecosystem (Mahhothari, Dhanusa, and Illam districts), and Hills and river valley (Kavrepalanchock and Sindhupalchok districts). For each LLIN, fabric integrity in terms of proportionate hole index (pHI) and residual bio-efficacy were assessed. However, for chemical retention, a representative sample of 44 nets (15 Yorkool®, 10 Permanet®2.0, and 19 Interceptor®) was evaluated. Data were analyzed using descriptive statistics stratified by LLINs brand, districts, and duration of exposure. RESULTS: On average, duration of use of LLINs was shortest for the Yorkool® samples, followed by PermaNet® 2.0 and Interceptor® with median ages of 8.9 (IQR = 0.4), 23.8 (IQR = 3.2), and 50.1 (IQR = 3.2) months, respectively. Over 80% of field distributed Yorkool® and PermaNet® 2.0 nets were in good condition (pHI< 25) compared to Interceptor® (66%). Bio-efficacy analysis showed that average mortality rates of Interceptor and Yorkool were below World Health Organization (WHO) optimal effectiveness of ≥ 80% compared to 2-year-old PermaNet 2.0 which attained 80%. Chemical retention analysis was consistent with bio-efficacy results. CONCLUSION: This study shows that distribution of LLINs is effective for malaria control; however, serviceable life of LLINs should be considered in terms of waning residual bio-efficacy that warrants replacement. As an adjunctive malaria control tool, National Malaria Control Program of Nepal can benefit by renewing the distribution of LLINs in an appropriate time frame in addition to utilizing durable and effective LLINs.

Micro-stratification of malaria risk in Nepal: implications for malaria control and elimination.

BACKGROUND: A significant reduction in malaria cases over the recent years in Nepal has encouraged the government to adopt a goal of "malaria-free nation by 2025." Nevertheless, to achieve this goal, it is critical to identify the epidemiological burden of malaria by specific regions and areas for an effective targeted intervention. The main objective of this study was to estimate the risk of malaria at Village Development Committee (VDC) level in Nepal based on disease, vector, parasite, and geography. METHODS: In 2012, the micro-stratification of malaria risk was carried out in 75 districts of Nepal. Instruments such as a questionnaire, case record forms, and guidelines for malaria micro-stratification were developed and pre-tested for necessary adaptations. Village Development Committee (VDC)-wise malaria data were analyzed using exploratory statistics and were stratified by geographical variables that contributed to the risk of malaria. To understand the transmission risk at VDC level, overlay analysis was done using ArcGIS 10. To ensure transparent, reproducible, and comprehensible risk assessment, standard scoring method was selected and utilized for data from 2009 to 2011. Thus identified, three major variables (key determinants) were given weights (wt.) accordingly to stratification of the malaria risk (disease burden, "0.3" wt.; ecology/vector transmission, "0.5" wt.; and vulnerability-population movement, "0.2" wt.). Malaria risk in a VDC was determined based on the overall scores and classified into four categories: no risk, low risk, moderate risk, and high risk. RESULTS: Analyzing the overall risk based on scoring of the total VDCs (n = 3976), 54 (1.36%), 201 (5.06%), 999 (25.13%), and 2718 (68.36%) were identified as high-, moderate-, low-, and no-risk categories for malaria, respectively. Based on the population statistics, 3.62%, 9.79%, 34.52%, and 52.05% of the country's total population live in high-risk, moderate-risk, low-risk, and no-risk VDCs for malaria, respectively. Our micro-stratification study estimates are 100,000 population at high risk. Regional distribution showed that the majority of the high-risk VDCs were identified in the Far- and Mid-western regions (19 and 18 VDCs) followed by Central and Western regions (10 and 7 VDCs) with no high-risk VDCs in the Eastern region. Similarly, 77, 59, 27, 24, and 14 VDCs of the Central, Mid-western, Western, Eastern, and Far-western regions, respectively, were found under moderate malaria risk. Of the low-risk VDCs, 353, 215, 191, 148, and 92 were respectively from the Central, Eastern, Western, Far-western, and Mid-western regions. CONCLUSIONS: The current micro-stratification study provides insights on malaria risk up to the VDC level. This will help the malaria elimination program to target interventions at the local level thereby ensuring the best utilization of available resources to substantially narrowed-down target areas. With further updates and refinement, the micro-stratification approach can be employed to identify the risk areas up to smaller units within the VDCs (ward and villages).

Efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Nepal.

BACKGROUND: The national treatment guidelines of Nepal have adopted Artemisinin Combination Therapies (ACTs) for the treatment of uncomplicated falciparum malaria since 2004. Emergence of Artemisinin resistance in the Greater Mekong Sub-region (GMS) and beyond may become a threat for Nepal as well. The main objective of this study was to assess the therapeutic efficacy of antimalarial drug artemether-lumefantrine in uncomplicated P. falciparum infected patients at health centers/hospitals treated over the period of 2 years (2013-2014). METHODS: Giemsa stained thick and thin smears, prepared from uncomplicated falciparum malaria patients who visited the selected sentinel sites in Nepal during 2013 to 2014 and met the inclusion criteria that included parasitemia (1000-10,000 /µL of blood), were evaluated until 28 days after ACTs treatment, following a World Health Organization (WHO) therapeutic efficacy protocol. Based on the re-occurrence of fever and resurge in parasitemia, the study patients were classified as resistant or susceptible. Blood specimens on filter papers were further analyzed by Polymerase Chain Reaction (PCR), specifically for the K13 propeller gene mutation (a recently identified molecular marker for ACT resistance). RESULTS: A total of 56,013 suspected malaria cases were screened for this study. Of which, 120 (0.21%) were infected with falciparum malaria. Out of 120, 28 cases of P. falciparum (28/120; 23.33%) were enrolled in the study, of which 24 cases completed the post-treatment follow up for 28 days. Only one case out of 24 (4%) was identified as a late treatment failure (LTF). K13 mutation, a proxy indicator for ACT resistance in parasites, was not detected on the day 1, which indicates resistance had not yet reached the molecular level. CONCLUSION: Only one case of late treatment failure was identified in this study. ACT combination using artemether-lumefantrine was still effective for the treatment of uncomplicated falciparum malaria in Nepal. A close monitoring and supervision for ACT resistance is essential for future malaria treatment in Nepal.

Glucose-6-phosphate dehydrogenase deficiency in people living in malaria endemic districts of Nepal.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) is a rate limiting enzyme of the pentose phosphate pathway and is closely associated with the haemolytic disorders among patients receiving anti-malarial drugs, such as primaquine. G6PD deficiency (G6PDd) is an impending factor for radical treatment of malaria which affects the clearance of gametocytes from the blood and subsequent delay in the achievement of malaria elimination. The main objective of this study was to assess the prevalence of G6PD deficiency in six malaria endemic districts in Southern Nepal. METHODS: A cross-sectional population based prevalence survey was conducted in six malaria endemic districts of Nepal, during April-Dec 2013. A total of 1341 blood samples were tested for G6PDd using two different rapid diagnostic test kits (Binax-Now® and Care Start™). Equal proportions of participants from each district (n ≥ 200) were enrolled considering ethnic and demographic representation of the population groups. RESULTS: Out of total 1341 blood specimens collected from six districts, the overall prevalence of G6PDd was 97/1341; 7.23% on Binax Now and 81/1341; 6.0% on Care Start test. Higher prevalence was observed in male than females [Binax Now: male 10.2%; 53/521 versus female 5.4%; 44/820 (p = 0.003) and Care Start: male 8.4%; 44/521 versus female 4.5%; 37/820 (p = 0.003)]. G6PDd was higher in ethnic groups Rajbanshi (11.7%; 19/162) and Tharu (5.6%; 56/1005) (p = 0.006), major inhabitant of the endemic districts. Higher prevalence of G6PDd was found in Jhapa (22/224; 9.8%) and Morang districts (18/225; 8%) (p = 0.031). In a multivariate analysis, male were found at more risk for G6PDd than females, on Binax test (aOR = 1.97; CI 1.28-3.03; p = 0.002) and Care Start test (aOR = 1.86; CI 1.16-2.97; p = 0.009). CONCLUSIONS: The higher prevalence of G6PDd in certain ethnic group, gender and geographical region clearly demonstrates clustering of the cases and ascertained the risk groups within the population. This is the first study in Nepal which identified the vulnerable population groups for G6PDd in malaria endemic districts. The finding of this study warrants the need for G6PDd testing in vulnerable population groups in endemic districts, and also facilitates use of primaquine in mass supporting timely progress for malaria elimination.

Epidemiology of HIV, programmatic progress and gaps in last 10 years in Nepal.

BACKGROUND AND OBJECTIVES: Nepal has made progress with the control of HIV infection in recent years. There have been changes in epidemiology, programme interventions in different population groups, and changes in policies over the last 10 years, particularly in diagnosis and treatment. Therefore, this review was conducted to identify the effectiveness of different interventions/policies in different sub-populations at risk, targeted towards epidemiology and treatment outcomes for those with HIV infection in Nepal. METHODS: This review was prepared based on a review of published and unpublished documents from the Nepalese HIV infection control programme, published articles in different journals, different survey reports including integrated bio-behavioural surveillance (IBBS) survey reports. RESULTS: The prevalence of HIV infection among adults in 2014 was 0.20% with a progressive decreasing trend from 2005. The prevalence of HIV infection among injecting drug users (51.7% in 2005 and 6.4% in 2015 in Kathmandu valley) was relatively high in all years as compared to other risk groups. HIV infection prevalence among women attending antenatal clinics was higher in the year 2006 (0.25%) but there was a decreasing trend in the following years to 2015, when prevalence was 0.077%. Although different interventions were conducted to cover key populations at risk, the coverage in some risk population was very low. HIV testing status among the general population was very low (7.5% among males and 2.9% among females) in 2011. Only one-third of HIV-infected individuals were on ART in 2015, although this proportion has increased since 2005. The share of domestic budget among the total expenditure on HIV control program is below 15%. CONCLUSIONS: There is the need for implementation of control programmes more efficiently and effectively with expanding geographical and population coverage. Surveillance systems should be strengthened to get up-to-date information for evidence-based planning and developing strategies. The domestic budget for HIV control programme should be increased to improve their sustainability.

Estimates of the years-of-life-lost due to the top nine causes of death in rural areas of major states in India in 1995.

BACKGROUND: Years-of-life-lost (YLL) contribute nearly two-thirds of the disability-adjusted life-years (DALYs) worldwide and are especially Important for India where infant and child mortality is still high. These were estimated for India under the Global Burden of Disease study for the year 1990. No estimates are available for the different states of India. We aimed to prepare state-wise estimates of YLL for different causes of death in rural areas and to determine the causes responsible for a higher burden in different states. METHOD: Percentage deaths of the top 9 causes reported in the Registrar-General's Survey of Causes of Deaths (Rural)--1995 in 13 major states of India and different age groups was applied to the expected number of total deaths. The life lost according to the standard life-table was age-weighted and discounted using the methodology of the Global Burden of Disease 1990 study. The causes of death were based on lay reporting which otherwise seem reliable. RESULTS: The all-cause YLL in rural India in 1995 were 207 per 1,000 population. The minimum was 74 in Kerala and maximum 276 in Madhya Pradesh. Pneumonia was the top cause responsible for 15 YLL. The inter-state variation was high as Tamil Nadu had only 1.6 and Uttar Pradesh 30.5 YLL from this cause. Cancers were a uniform burden across the states. Heart attack, and bronchitis and asthma cut across the more and less developed states. Suicides were a heavy burden in Andhra Pradesh and vehicular accidents in Haryana and Rajasthan. Bihar, Gujarat, Madhya Pradesh, Orissa, Rajasthan and Uttar Pradesh had communicable and nutritional conditions as predominant causes while Kerala and Punjab had non-communicable diseases as the predominant cause of YLL due to premature mortality. CONCLUSION: These results provide a new perspective about the causes of death that need more attention in rural areas of different states of India. These will also help prioritize areas which require more inputs at the state-level and hence will be useful for health policymakers.