Development of Somaliland national harmonised medical curriculum.

BACKGROUND AND OBJECTIVES: The rational for the Somaliland national harmonised curriculum (NHC) was driven by shared concern about the quality of medical education. PROCESS: The Ministry of Education and Science and the Ministry of Health Development produced a Medical Education Policy 2018. Policy objectives included the development of the NHC and accreditation for medical schools that met the standards of the World Federation for Medical Education (WFME). Two bodies were asked to oversee these aims: the National Health Professions' Commission (NHPC) and the National Commission of Higher Education (NCHE). Between 2018 and 2020, a collaborative approach between the Somaliland government, medical school stakeholders, King's Global Health Partnership's (KGHP) volunteers and the Tropical Health Education Trust (THET) team was used to design the 6-years NHC. The NHC structure, content and delivery were grounded by WFME standards, health needs of the local population, student focused and active learning methods, and feasibility of implementation in medical schools. OUTCOMES: The NHC comprises details about the educational outcomes, curriculum model and framework, educational principles, instructional and learning methods, core as well as optional content, and assessment strategy. CONCLUSIONS: The approach used to develop the NHC ensured it is bespoken for Somaliland. Ongoing evaluation of patient and population needs, each medical school's review of programme implementation and outcomes will inform continuous revision and renewal.

The phage-encoded PIT4 protein affects multiple two-component systems of Pseudomonas aeruginosa.

IMPORTANCE: More and more Pseudomonas aeruginosa isolates have become resistant to antibiotics like carbapenem. As a consequence, P. aeruginosa ranks in the top three of pathogens for which the development of novel antibiotics is the most crucial. The pathogen causes both acute and chronic infections, especially in patients who are the most vulnerable. Therefore, efforts are urgently needed to develop alternative therapies. One path explored in this article is the use of bacteriophages and, more specifically, phage-derived proteins. In this study, a phage-derived protein was studied that impacts key virulence factors of the pathogen via interaction with multiple histidine kinases of TCSs. The fundamental insights gained for this protein can therefore serve as inspiration for the development of an anti-virulence compound that targets the bacterial TCS.

Artificial Intelligence Based Approach for Classification of Human Activities Using MEMS Sensors Data.

The integration of Micro Electronic Mechanical Systems (MEMS) sensor technology in smartphones has greatly improved the capability for Human Activity Recognition (HAR). By utilizing Machine Learning (ML) techniques and data from these sensors, various human motion activities can be classified. This study performed experiments and compiled a large dataset of nine daily activities, including Laying Down, Stationary, Walking, Brisk Walking, Running, Stairs-Up, Stairs-Down, Squatting, and Cycling. Several ML models, such as Decision Tree Classifier, Random Forest Classifier, K Neighbors Classifier, Multinomial Logistic Regression, Gaussian Naive Bayes, and Support Vector Machine, were trained on sensor data collected from accelerometer, gyroscope, and magnetometer embedded in smartphones and wearable devices. The highest test accuracy of 95% was achieved using the random forest algorithm. Additionally, a custom-built Bidirectional Long-Short-Term Memory (Bi-LSTM) model, a type of Recurrent Neural Network (RNN), was proposed and yielded an improved test accuracy of 98.1%. This approach differs from traditional algorithmic-based human activity detection used in current wearable technologies, resulting in improved accuracy.

Country readiness and prerequisites for successful design and transition to implementation of essential packages of health services: experience from six countries.

This paper reviews the experience of six low-income and lower middle-income countries in setting their own essential packages of health services (EPHS), with the purpose of identifying the key requirements for the successful design and transition to implementation of the packages in the context of accelerating progress towards universal health coverage (UHC). The analysis is based on input from three meetings of a knowledge network established by the Disease Control Priorities 3 Country Translation Project and working groups, supplemented by a survey of participating countries.All countries endorsed the Sustainable Development Goals target 3.8 on UHC for achievement by 2030. The assessment of country experiences found that health system strengthening and mobilising and sustaining health financing are major challenges. EPHS implementation is more likely when health system gaps are addressed and when there are realistic and sustainable financing prospects. However, health system assessments were inadequate and the government planning and finance sectors were not consistently engaged in setting the EPHS in most of the countries studied. There was also a need for greater engagement with community and civil society representatives, academia and the private sector in package design. Leadership and reinforcement of technical and managerial capacity are critical in the transition from EPHS design to sustained implementation, as are strong human resources and country ownership of the process. Political commitment beyond the health sector is key, particularly commitment from parliamentarians and policymakers in the planning and finance sectors. National ownership, institutionalisation of technical and managerial capacity and reinforcing human resources are critical for success.The review concludes that four prerequisites are crucial for a successful EPHS: (1) sustained high-level commitment, (2) sustainable financing, (3) health system readiness, and (4) institutionalisation.

Acrylamide adsorption by Enterococcus durans and Enterococcus faecalis: In vitro optimization, simulated digestive system and binding mechanism.

Acrylamide is an unsaturated amide that forms in heated, starchy food products. This study was conducted to (1) examine the ability of 38 LAB to remove acrylamide; (2) optimize acrylamide removal of selected LAB under various conditions (pH, temperature, time and salt) using the Box-Behnken design (BBD); (3) the behavior of the selected LAB under the simulated gastrointestinal conditions; and (4) investigate the mechanism of adsorption. Out of the 38 LAB, Enterococcus durans and Enterococcus faecalis had the highest results in removing acrylamide, with 33 and 30% removal, respectively. Those two LAB were further examined for their binding abilities under optimized conditions of pH (4.5-6.5), temperature (32°C - 42°C), time (14-22 h), and NaCl (0-3% w/v) using BBD. pH was the main factor influenced the acrylamide removal compared to other factors. E. durans and E. faecalis exhibited acrylamide removal of 44 and 53%, respectively, after the in vitro digestion. Zeta potential results indicated that the changes in the charges were not the main cause of acrylamide removal. Transmission electron microscopes (TEM) results indicated that the cell walls of the bacteria increased when cultured in media supplemented with acrylamide.

Validity of smartphone-based retinal photography (PEEK-retina) compared to the standard ophthalmic fundus camera in diagnosing diabetic retinopathy in Uganda: A cross-sectional study.

INTRODUCTION: Diabetic retinopathy (DR) is one of the major complications of diabetes mellitus and is a significant cause of blindness worldwide. In Uganda, the prevalence of diabetes is approximately 2.7% of the urban population and 1% in rural areas. Many diabetics cannot access an eye exam due to the lack of less costly and user-friendly equipment that primary eye workers can use. Smartphone-based fundus photography allows for a cheap and mobile fundus examination. The study aimed to determine the sensitivity and specificity of the Portable Eye Examination Kit (PEEK) retina compared to a standard ophthalmic fundus camera (Zeiss Visucam 200) for the diagnosis of DR. METHODS: From January-March 2020, 286 people with diabetes (type 1 & 2) patients were seen at Kiruddu National referral hospital diabetes clinic. All participants had funduscopy with PEEK retina and the standard ophthalmic fundus camera following ophthalmic examination and pupillary dilation. The PEEK retina's sensitivity, specificity and reliability were determined using an ophthalmic fundus camera as the gold standard. RESULTS: The participants' mean age was 51 with a standard deviation of ±11years, 213 (74.5%) were females, and the majority (93.4%) had Type 2 diabetes. The overall Sensitivity of PEEK retina for DR was 84% (95% CI 70.9-83.5), while the specificity was 79.9% (95% CI 76-83.5) with a positive predictive value (PPV) of 30.9% (95% CI 23.2-39.4) and a negative predictive value (NPV) of 97.9% (95% CI 95.9-99.1). CONCLUSIONS: PEEK retina has high sensitivity and specificity, making it suitable for screening and diagnostic purposes. Therefore, we recommend the integration of the PEEK retina in the screening and diagnosis of DR in resource-limited settings.

Design of a Microfluidic Photocatalytic Reactor for Removal of Volatile Organic Components: Process Simulation and Techno-Economic Assessment.

This study reports on a gas-phase photocatalytic microreactor (MR) employed for the degradation of 2-propanol in indoor air. A process flow diagram was developed and simulated in Aspen Hysys V10, and a techno-economic assessment was carried out based on the simulated results. An economic evaluation was carried out using a fixed and demand-dependent variable cost model. Decreasing the mass flow rate or the initial concentration of the 2-propanol in indoor air and increasing the diameter or length of the MR resulted in a better air remediation efficacy. Sensitivity analysis for the economics of the manufactured MR showed that the optimal plant production volume is 10,000 units per year. At this volume, the total manufacturing cost was 2.8 M$/y with a production cost of $ 127 per unit and a levelized cost of a MR (LCOM) of about $ 280 per unit. These findings herein can help bolster research into both technical and economic aspects of MR production for the photocatalytic remediation of air. The resulting design could be applied in air conditioner units and other home ventilation units for the removal of harmful volatile organic compounds in the air.

Acrylamide Elimination by Lactic Acid Bacteria: Screening, Optimization, In Vitro Digestion, and Mechanism.

Acrylamide is a toxic compound that is formed in cooked carbohydrate-rich food. Baking, roasting, frying, and grilling are cooking methods that cause its formation in the presence of reducing sugar and asparagine. To prevent acrylamide formation or to remove it after its formation, scientists have been trying to understand acrylamide formation pathways, and methods of prevention and removal. Therefore, this study aimed to: (1) screen newly isolated LAB for acrylamide removal, (2) optimize conditions (pH, temperature, time, salt) of the acrylamide removal for selected LAB isolates using Box-Behnken design (BBD), (3) investigate the acrylamide removal abilities of selected LAB isolates under the in vitro digestion conditions using INFO-GEST2.0 model, and (4) explore the mechanism of the acrylamide removal using scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS), zeta potential, transmission electron microscopy (TEM) measurement, and Fourier transform infrared spectroscopy (FTIR). Forty strains were tested in MRS broth, where Streptococcus lutetiensis and Lactiplantibacillus plantarum had the highest capability of acrylamide removal by 39% and 26%, respectively. To enhance the binding ability, both strains were tested under controlled conditions of pH (4.5, 5.5 and 6.5), temperature (32 °C, 37 °C and 42 °C), time (14, 18 and 22 h), and NaCl (0%, 1.5% and 3% w/v) using Box-Behnken design (BBD). Both strains removed more acrylamide in the range of 35-46% for S. lutetiensis and 45-55% for L. plantarum. After testing the bacterial binding ability, both strains were exposed to a simulated gastrointestinal tract environment, removing more than 30% of acrylamide at the gastric stage and around 40% at the intestinal stage. To understand the mechanism of removal, LAB cells were characterized via scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS) and transmission electron microscopy (TEM) techniques. Cell charges were characterized by zeta potential and functional groups analyzed by Fourier transform infrared spectroscopy (FTIR). Results indicated that increasing cell wall thickness improved acrylamide adsorption capacity. Both FTIR and EDS indicated that functional groups C=O, C-O, and N-H were associated with acrylamide adsorption.

Micronized cellulose from citrus processing waste using water and electricity only.

Along with a water-soluble fraction rich in pectin, the hydrodynamic cavitation of citrus processing waste carried out in water demonstrated directly on semi-industrial scale affords an insoluble fraction consisting of micronized cellulose of low crystallinity ("CytroCell"). Lemon and grapefruit CytroCell respectively consist of 100-500 nm wide cellulose nanorods, and of 500-1000 nm wide ramified microfibrils extending for several µm. These findings establish a technically viable route to low crystallinity micronized cellulose laying in between nano- and microcellulose, using water and electricity only.

Updated review on microplastics in water, their occurrence, detection, measurement, environmental pollution, and the need for regulatory standards.

The gravity of the impending threats posed by microplastics (MPs) pollution in the environment cannot be over-emphasized. Several research studies continue to stress how important it is to curb the proliferation of these small plastic particles with different physical and chemical properties, especially in aquatic environments. While several works on how to monitor, detect and remove MPs from the aquatic environment have been published, there is still a lack of explicit regulatory framework for mitigation of MPs globally. A critical review that summarizes recent advances in MPs research and emphasizes the need for regulatory frameworks devoted to MPs is presented in this paper. These frameworks suggested in this paper may be useful for reducing the proliferation of MPs in the environment. Based on all reviewed studies related to MPs research, we discussed the occurrence of MPs by identifying the major types and sources of MPs in water bodies; examined the recent ways of detecting, monitoring, and measuring MPs routinely to minimize projected risks; and proposed recommendations for consensus regulatory actions that will be effective for MPs mitigation.

RRMonitor: A Resource-Aware End-to-End System for Continuous Monitoring of Respiration Rate Using Earbuds.

Respiration rate is considered as a critical vital sign, and daily monitoring of respiration rate could provide helpful information about any acute condition in the human body. While researchers have been exploring mobile devices for respiration rate monitoring, passive and continuous monitoring is still not feasible due to many usability challenges (e.g., active participation) in existing approaches. This paper presents an end-to-end system called RRMonitor that leverages the movement sensors from commodity earbuds to continuously monitor the respiration rate in near real-time. While developing the systems, we extensively explored some key parameters, algorithms, and approaches from existing literature that are better suited for continuous and passive respiration rate monitoring. RRMonitor can passively track the respiration rate with a mean absolute error as low as 1.64 cycles per minute without requiring active participation from the user.

Global research priorities for COVID-19 in maternal, reproductive and child health: results of an international survey

BackgroundThe World Health Organizations "Coordinated Global Research Roadmap: 2019 Novel Coronavirus" outlined the need for research that focuses on the impact of COVID-19 on pregnant women and children. More than one year after the first reported case, significant knowledge gaps remain, highlighting the need for a coordinated approach. To address this need, the Maternal, Newborn and Child Health Working Group (MNCH WG) of the COVID-19 Clinical Research Coalition conducted an international survey to identify global research priorities for COVID-19 in maternal, reproductive and child health. MethodThis project was undertaken using a modified Delphi method. An electronic questionnaire was disseminated to clinicians and researchers in three different languages (English, French and Spanish) via MNCH WG affiliated networks. Respondents were asked to select the five most urgent research priorities among a list of 17 identified by the MNCH WG. Analysis of questionnaire data was undertaken to identify key similarities and differences among respondents according to questionnaire language, location and specialty. Following elimination of the seven lowest ranking priorities, the questionnaire was recirculated to the original pool of respondents. Thematic analysis of final questionnaire data was undertaken by the MNCH WG from which four priority research themes emerged. ResultsQuestionnaire 1 was completed by 225 respondents from 29 countries. Questionnaire 2 was returned by 49 respondents. The four priority research themes were 1) access to healthcare during the COVID-19 pandemic, 2) the direct and 3) indirect effects of COVID-19 on pregnant and breastfeeding women and children and 4) the transmission of COVID-19 and protection from infection. ConclusionThe results of these questionnaires indicated a high level of concordance among continents and specialties regarding priority research themes. This prioritized list of research uncertainties, developed to specifically highlight the most urgent clinical needs as perceived by healthcare professionals and researchers, could help funding organizations and researchers to answer the most pressing questions for clinicians and public health professionals during the pandemic. It is hoped that these identified priority research themes can help focus the discussion regarding the allocation of limited resources to enhance COVID-19 research in MNCH globally.

A review of recent and emerging antimicrobial nanomaterials in wastewater treatment applications.

In this paper, we present a critical review on antimicrobial nanomaterials with demonstrated potential for application as a disinfection technology in wastewater treatment. Studies involving fabrication and testing of antimicrobial nanomaterials for wastewater treatment were gathered, critically reviewed, and analyzed. Our review shows that there are only a few eligible candidate nanoparticles (NPs) (metal and metal oxide) that can adequately serve as an antimicrobial agent. Nanosilver (nAg) was the most studied and moderately understood metal NPs with proven antimicrobial activity followed by ZnO (among antimicrobial metal oxide NPs) which outperformed titania (in the absence of light) in efficacy due to its better solubility in aqueous condition. The direction of future work was found to be in the development of antimicrobial nanocomposites, since they provide more stability for antimicrobial metal and metal oxides NPs in water, thereby increasing their activity. This review will serve as an updated survey, yet touching also the fundamentals of the antimicrobial activity, with vital information for researchers planning to embark on the development of superior antimicrobial nanomaterials for wastewater treatment applications.

Survival analysis of all critically ill patients with COVID-19 admitted to the main hospital in Mogadishu, Somalia, 30 March to 12 June 2020: what interventions are proving effective?

OBJECTIVESTo determine risk factors for death in patients with COVID-19 admitted to the main public sector hospital in Somalia and identify interventions contributing to improved clinical outcome in a low-resource and fragile setting. SETTINGMain public sector tertiary hospital in Mogadishu, Somalia. PARTICIPANTSAll 131 laboratory-confirmed COVID-19 patients admitted to the main public tertiary hospital in Somalia between 30 March and 12 June 2020. MAIN OUTCOME MEASURESWe extracted demographic and clinical data from hospital records of all 131 COVID-19 patients admitted to hospital until their death or recovery. We used Kaplan-Meier statistics to estimate survival probabilities and the log-rank test to assess significant differences in survival between groups. We used the Cox proportional hazard model to estimate likelihood of death and assess the effect of risk factors on survival. RESULTSOf the 131 patients, 52 (40%) died in the hospital and 79 (60%) survived to discharge. The factors independently associated with increased risk of in-hospital death were: age [≥] 60 years - survival probability on day 21 in patients < 60 years was 0.789 (95% confidence interval (CI): 0.658-0.874) compared with 0.339 (95% CI: 0.205-0.478) in patients [≥] 60 years; cardiovascular disease (survival probability 0.478 (95% CI: 0.332-0.610) in patients with cardiovascular disease compared with 0.719 (95% CI: 0.601-0.807) in patients without cardiovascular disease); and non-invasive ventilation on admission - patients who were not ventilated were significantly more likely to survive than those who were (P < 0.001). CONCLUSIONOur study, which includes the largest cohort of COVID-19 patients admitted to a single hospital in a sub-Saharan African country, confirms that underlying conditions and age are associated with increased risk of in-hospital death in patients with COVID-19. Our results show the advantage of medical oxygen over non-invasive ventilation in the treatment of patients with severe COVID-19 symptoms.

Delirium and Post-Discharge Neuropsychological Outcomes in Critically Ill Patients with COVID-19: an Institutional Case Series

ObjectiveTo characterize the clinical course of delirium for COVID-19 patients in the intensive care unit, including post-discharge cognitive outcomes. Patients and MethodsA retrospective chart review was conducted for patients diagnosed with COVID-19 (n=148) admitted to an intensive care unit at Michigan Medicine between March 1, 2020 and May 31, 2020. A validated chart review method was used to identify presence of delirium, and various measures (e.g., Family Confusion Assessment Method, Short Blessed Test, Patient-Health Questionnaire-9) were used to determine neuropsychological outcomes between 1-2 months after hospital discharge. ResultsDelirium was identified in 108/148 (73%) patients in the study cohort, with median (interquartile range) duration lasting 10 (4 - 17) days. In the delirium cohort, 50% (54/108) of patients were African American, and delirious patients were more likely to be female (76/108, 70%) (absolute standardized differences >.30). Sedation regimens, inflammation, deviation from delirium prevention protocols, and hypoxic-ischemic injury were likely contributing factors, and the most common disposition for delirious patients was a skilled care facility (41/108, 38%). Among patients who were delirious during hospitalization, 4/17 (24%) later screened positive for delirium at home based on caretaker assessment, 5/22 (23%) demonstrated signs of questionable cognitive impairment or cognitive impairment consistent with dementia, and 3/25 (12%) screened positive for depression within two months after discharge. ConclusionPatients with COVID-19 commonly experience a prolonged course of delirium in the intensive care unit, likely with multiple contributing factors. Furthermore, neuropsychological impairment may persist after discharge.

Pyrolysis of date palm waste to biochar using concentrated solar thermal energy: Economic and sustainability implications.

A system of concentrated solar energy for pyrolysis of date palm waste to biochar is designed and simulated using SuperPro Designer v8.5. Both economic and environmental sustainability implications are evaluated by bench-marking with the conventional process (electric heating-based pyrolysis). Economic analysis shows that this process is more economically viable than the conventional process, with payback time (PBT) of 4 years and 132 days, internal rate of return (IRR) of 14.8%, return on investment (ROI) of 22.9% and gross margin of 35.5%. Environmental impact assessment shows that CO2 emissions from concentrated solar energy-based pyrolysis accounts for only 38% of that of the conventional pyrolysis, indicating that concentrated solar energy pyrolysis is more environmentally friendly. Sensitivity analysis shows that PBT is more sensitive to changes in biochar selling price than changes in the cost of acquiring date palm waste. This process presents sustainable opportunities for biochar production while reducing life cycle emissions and costs.

Vitamin-D2 treatment-associated decrease in 25(OH)D3 level is a reciprocal phenomenon: a randomized controlled trial.

BACKGROUND: Vitamin-D2 (D2) treatment has been associated with a decrease in 25-hydroxy (25(OH)) vitamin-D3 (D3) level, suggesting that D3 treatment would be preferred to raise total 25(OH) vitamin-D (D) level. We postulated that D2 treatment-associated decrease in 25(OH)D3 level is related to the increase in 25(OH)D level rather than being D2-specific, and thus there would be a similar D3 treatment-associated decrease in 25(OH)D2 level. METHODS: Fifty volunteers were block-randomized to 50,000 IU D2 or placebo orally once (study-1) and fifty volunteers received 50,000 IU D2 orally once and 4 days later block-randomized to 50,000 IU D3 or placebo orally once (study-2). Interventions were concealed from volunteers and research coordinators and blindly-administered. Serum 25(OH)D2 and 25(OH)D3 levels were blindly-determined at baseline and days 14, 28, 42, and 56, post-randomization by high performance liquid chromatography assay. Results of 97 participants were analyzed. Primary outcome measure was day-28 D2-associated change in 25(OH)D3 level in study-1 and D3-associated change in 25(OH)D2 level in study-2, adjusted for baseline levels. RESULTS: Mean (95% confidence interval) difference between the active and placebo arms in the decrease in day-28 25(OH)D3 (study-1) and 25(OH)D2 (study-2) levels was 13.2 (9.7 to 16.6) and 9.8 (5.2 to 14.4) nmol/L, respectively. Corresponding differences at day-56 were 10.8 (6.8 to 14.8) and 1.7 (- 7.6 to 11.1) nmol/L, respectively. The difference between the placebo and active arms in area-under-the-curve at day-28 (AUC28) and day-56 (AUC56) were 262.3 (197.8 to 326.7) and 605.1 (446.3 to 784.0) for 25(OH)D3 (study-1) and 282.2 (111.2 to 453.3) and 431.2 (179.3 to 683.2) nmol.d/L for 25(OH)D2 (study-2), respectively. There were significant correlations between day-28 changes in 25(OH)D2 and 25(OH)D3 levels in study-1 (rho = - 0.79, p < 0.001) and study-2 (rho = - 0.36, p = 0.01), and between day-28 changes in 25(OH)D2 level and baseline 25(OH)D level in study-2 (rho = - 0.42, p = 0.003). CONCLUSIONS: Compared to placebo, D3 treatment is associated with a decrease in 25(OH)D2 level similar in magnitude to D2-treatment associated decrease in 25(OH)D3 level; however, the D3-placebo difference in 25(OH)D2 level is shorter-lasting. Changes in 25(OH)D2 and 25(OH)D3 levels are correlated with each other and with baseline 25 (OH) D levels, suggesting a common regulatory mechanism. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT03035084 (registered January 27, 2017).

Does the placebo effect modulate drug bioavailability? Randomized cross-over studies of three drugs.

BACKGROUND: Medication effect is the sum of its drug, placebo, and drug*placebo interaction effects. It is conceivable that the interaction effect involves modulating drug bioavailability; it was previously observed that being aware of caffeine ingestion may prolong caffeine plasma half-life. This study was set to evaluate such concept using different drugs. METHODS: Balanced single-dose, two-period, two-group, cross-over design was used to compare the pharmacokinetics of oral cephalexin, ibuprofen, and paracetamol, each described by its name (overt) or as placebo (covert). Volunteers and study coordinators were deceived as to study aim. Drug concentrations were determined blindly by in-house, high performance liquid chromatography assays. Terminal-elimination half-life (t½) (primary outcome), maximum concentration (Cmax), Cmax first time (Tmax), terminal-elimination-rate constant (λ), area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or to Tmax of overt drug (AUCOverttmax), and Cmax/AUCI were calculated blindly using standard non-compartmental method. Covert-vs-overt effect on drug pharmacokinetics was evaluated by analysis-of-variance (ANOVA, primary analysis), 90% confidence interval (CI) using the 80.00-125.00% bioequivalence range, and percentage of individual pharmacokinetic covert/overt ratios that are outside the +25% range. RESULTS: Fifty, 30, and 50 healthy volunteers (18%, 10%, and 6% females, mean (SD) age 30.8 (6.2), 31.4 (6.6), and 31.2 (5.4) years) participated in 3 studies on cephalexin, ibuprofen, and paracetamol, respectively. Withdrawal rate was 4%, 0%, and 4%, respectively. Eighteen blood samples were obtained over 6, 10, and 14 h in each study period of the three drugs, respectively. ANOVA showed no significant difference in any pharmacokinetic parameter for any of the drugs. The 90% CIs for AUCT, AUCI, Cmax, AUCOverttmax, and Cmax/AUCI were within the bioequivalence range, except for ibuprofen Cmax (76.66-98.99), ibuprofen Cmax/AUCI (77.19-98.39), and ibuprofen (45.32-91.62) and paracetamol (51.45-98.96) AUCOverttmax. Out of the 126 individual covert/overt ratios, 2.0-16.7% were outside the +25% range for AUCT, 2.0-4.2% for AUCI, 25.0-44.9% for Cmax, 67.3-76.7% for AUCOverttmax, and 45.8-71.4% for Tmax. CONCLUSIONS: This study couldn't confirm that awareness of drug ingestion modulates its bioavailability. However, it demonstrates the trivial effect of blinding in bioequivalence studies and the extent of bio-variability that would be expected when comparing a drug product to itself. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01501747 (registered Dec 26, 2011).

Differential effects of vitamin D2 and D3 supplements on 25-hydroxyvitamin D level are dose, sex, and time dependent: a randomized controlled trial.

BACKGROUND: Vitamin D (D) supplements are indispensable for its world-wide deficiency. Controversy continues on ergocalciferol (D2) and cholecalciferol (D3) relative potency as well as on dosing-schedule and sex role in raising 25-hydroxy D (25(OH)D) level, the best indicator of D status. METHODS: We randomized 279 adults to daily D2, D3, D2/D3, or placebo; 2-weekly D2 or D3; or 4-weekly D2 or D3 (250,000 IU over/140 days). Randomization sequence, stratified by body-mass-index (BMI) and sex, was concealed from study coordinators and participants who were then blinded to capsules' content. D2, D3, 25(OH)D2, and 25(OH)D3 Serum levels were determined blindly on days 0,1,2,3,4,7,14, and 2-weekly thereafter by high performance liquid chromatography assay. The results of 269 participants were available for analysis. Primary endpoint was area-under-the-curve (AUC) of 25(OH)D (25(OH)D2 + 25(OH)D3) adjusted for sex, BMI, and baseline 25(OH)D level. RESULTS: Mean(SD) age was 33.0(8.5) year, 41% were males, and 85% completed follow-up. Baseline 25(OH)D level was 39.8(11.9) and increased by 3.3(11.6) and 28.6(16.3) nmol/L, in the placebo and active-treatment groups, respectively. AUC from day 0 to 140 (AUC140) of 25(OH)D was 40% (D3 daily) to 55% (D3 2-weekly) higher with active-treatment than placebo (p < 0.001). 25(OH)D2 AUC140 was higher in daily than 2-weekly (17%, p = 0.006) and 4-weekly (20%, p = 0.001) D2-treated groups. 25(OH)D3 AUC140 was lower in daily than 2-weekly (11%, p = 0.002) and 4-weekly D3-treated groups (10%, p = 0.008). In D2-treated groups, there was 16.4 nmol/L decrease in 25(OH)D3 level that correlated (p < 0.001) with 25(OH)D2 level increase (r = 0.48) and baseline 25(OH)D level (r = 0.58), in one participant with measurable baseline 25(OH)D2 level, D3 caused a similar decrease in 25(OH)D2 level, while in the D2/D3-treated group, 25(OH)D3 level didn't increase. Incremental AUC from day 0 to 7 (AUC7) of D3 and 25(OH)D3 in D3-treated groups were 118-243% higher and 31-39% lower, respectively, than incremental AUC7 of D2 and 25(OH)D2 in D2-treated groups. Incremental AUC7 of D3 and 25(OH)D3 in D3-treated groups and D2 and 25(OH)D2 in D2-treated groups were higher in females than males (55, 13, 64, and 28%, respectively). Baseline 25(OH)D level predicted response to D2 and D3 (p < 0.001), whereas, BMI was significant predictor only for early response to D2. CONCLUSIONS: Effects of D2 and D3 supplements on 25 (OH)D level may be dosing-schedule and sex-dependent. D2-associated reduction in 25(OH)D3 level may be related to total 25(OH)D level rather than being D2-specific. D2 may be 25-hydroxylated faster than D3. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT01170494 (registered July 25, 2010).

Ran GTPase promotes cancer progression via Met recepto-rmediated downstream signaling.

It has been shown previously that cancer cells with an activated oncogenic pathway, including Met activation, require Ran for growth and survival.Here, we show that knockdown of Ran leads to a reduction of Met receptor expression in several breast and lung cancer cell lines. This, in turn suppressed HGF expression and the Met-mediated activation of the Akt pathway, as well as cell adhesion, migration, and invasion. In a cell line model where Met amplification has previously been shown to contribute to gefitinib resistance, Ran knockdown sensitized cells to gefitinib-mediated inhibition of Akt and ERK1/2 phosphorylation and consequently reduced cell proliferation. We further demonstrate that Met reduction-mediated by knockdown of Ran, occurs at the post-transcriptional level, probably via a matrix metalloproteinase. Moreover, the level of immunoreactive Ran and Met are positively associated in human breast cancer specimens, suggesting that a high level of Ran may be a pre-requisite for Met overexpression. Interestingly, a high level of immunoreactive Ran dictates the prognostic significance of Met, indicating that the co-overexpression of Met and Ran may be associated with cancer progression and could be used in combination as a prognostic indicator.