Development and external validation of machine learning algorithms for postnatal gestational age estimation using clinical data and metabolomic markers.

BACKGROUND: Accurate estimates of gestational age (GA) at birth are important for preterm birth surveillance but can be challenging to obtain in low income countries. Our objective was to develop machine learning models to accurately estimate GA shortly after birth using clinical and metabolomic data. METHODS: We derived three GA estimation models using ELASTIC NET multivariable linear regression using metabolomic markers from heel-prick blood samples and clinical data from a retrospective cohort of newborns from Ontario, Canada. We conducted internal model validation in an independent cohort of Ontario newborns, and external validation in heel prick and cord blood sample data collected from newborns from prospective birth cohorts in Lusaka, Zambia and Matlab, Bangladesh. Model performance was measured by comparing model-derived estimates of GA to reference estimates from early pregnancy ultrasound. RESULTS: Samples were collected from 311 newborns from Zambia and 1176 from Bangladesh. The best-performing model accurately estimated GA within about 6 days of ultrasound estimates in both cohorts when applied to heel prick data (MAE 0.79 weeks (95% CI 0.69, 0.90) for Zambia; 0.81 weeks (0.75, 0.86) for Bangladesh), and within about 7 days when applied to cord blood data (1.02 weeks (0.90, 1.15) for Zambia; 0.95 weeks (0.90, 0.99) for Bangladesh). CONCLUSIONS: Algorithms developed in Canada provided accurate estimates of GA when applied to external cohorts from Zambia and Bangladesh. Model performance was superior in heel prick data as compared to cord blood data.

Synthesis, in vitro bioassays, and computational study of heteroaryl nitazoxanide analogs.

Antiprotozoal drug nitazoxanide (NTZ) has shown diverse pharmacological properties and has appeared in several clinical trials. Herein we present the synthesis, characterization, in vitro biological investigation, and in silico study of four hetero aryl amide analogs of NTZ. Among the synthesized molecules, compound 2 and compound 4 exhibited promising antibacterial activity against Escherichia coli (E. coli), superior to that displayed by the parent drug nitazoxanide as revealed from the in vitro antibacterial assay. Compound 2 displayed zone of inhibition of 20 mm, twice as large as the parent drug NTZ (10 mm) in their least concentration (12.5 µg/ml). Compound 1 also showed antibacterial effect similar to that of nitazoxanide. The analogs were also tested for in vitro cytotoxic activity by employing cell counting kit-8 (CCK-8) assay technique in HeLa cell line, and compound 2 was identified as a potential anticancer agent having IC50 value of 172 µg which proves it to be more potent than nitazoxanide (IC50  = 428 µg). Furthermore, the compounds were subjected to molecular docking study against various bacterial and cancer signaling proteins. The in vitro test results corroborated with the in silico docking study as compound 2 and compound 4 had comparatively stronger binding affinity against the proteins and showed a higher docking score than nitazoxanide toward human mitogen-activated protein kinase (MAPK9) and fatty acid biosynthesis enzyme (FabH) of E. coli. Moreover, the docking study demonstrated dihydrofolate reductase (DHFR) and thymidylate synthase (TS) as probable new targets for nitazoxanide and its synthetic analogs. Overall, the study suggests that nitazoxanide and its analogs can be a potential lead compound in the drug development.

Biochemical alterations and liver toxicity analysis with pioglitazone in healthy subjects.

Pioglitazone, a member of the thiazolidinediones, is a potent, highly selective agonist for peroxisome proliferator-activated receptor gamma and is an excellent insulin sensitizer used in treating type 2 diabetes mellitus. The present study investigated the effect of pioglitazone on glucose, total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol and high density lipoprotein (HDL) cholesterol, total proteins, albumin (ALB), alanine transaminase (ALT), and aspartate transaminase (AST) levels in 20 healthy Bengali male volunteers in a randomized, placebo-controlled study. Blood samples were collected before and 0.5-24.0 hours after a single oral dose of a 30 mg pioglitazone tablet. Plasma pioglitazone level was determined using a validated method of reverse-phase binary high-performance liquid chromatography. Blood lipid profile and levels of glucose, ALT, and AST were estimated using enzyme assay kits, plasma protein level was estimated by the biuret method, and plasma ALB level was determined colorimetrically. No significant change in blood glucose, total proteins, total cholesterol, triglyceride, HDL, and LDL levels was observed over the 24-hour assessment period, indicating no plasma biochemical alterations. There were no significant differences between baseline and 24-hour values of ALB, ALT, and AST levels, indicating a lack of liver toxicity. Our results indicate that a single dose of 30 mg of pioglitazone has no hypoglycemic or hypolipidemic effect or liver toxicity within 24 hours of treatment among healthy Bengali males.

A comprehensive situation assessment of injection practices in primary health care hospitals in Bangladesh.

BACKGROUND: Understanding injection practices is crucial for evidence-based development of intervention initiatives. This study explored the extent of injection use and injection safety practices in primary care hospitals in Bangladesh. METHODS: The study employed both quantitative and qualitative research methods. The methods used were--a retrospective audit of prescriptions (n = 4320), focus group discussions (six with 43 participants), in-depth interviews (n = 38) with a range service providers, and systematic observation of the activities of injection providers (n = 120), waste handlers (n = 48) and hospital facilities (n = 24). Quantitative and qualitative data were assessed with statistical and thematic analysis, respectively, and then combined. RESULTS: As many as 78% of our study sample (n = 4230) received an injection. The most commonly prescribed injections (n = 3354) including antibiotics (78.3%), IV fluids (38.6%), analgesics/pain killers (29.4%), vitamins (26.7%), and anti-histamines (18.5%). Further, 43.7% (n = 1145) of the prescribed antibiotics (n = 2626) were given to treat diarrhea and 42.3% (n = 600) of IV fluids (n = 1295) were used to manage general weakness conditions. Nearly one-third (29.8%; n = 36/120) of injection providers reported needle-stick injuries in the last 6 months with highest incidences in Rajshahi division followed by Dhaka division. Disposal of injection needles, syringes and other materials was not done properly in 83.5% (n = 20/24) of the facilities. Health providers' safety concerns were not addressed properly; only 23% (n = 28/120) of the health providers and 4.2% (n = 2/48) of the waste handlers were fully immunized against Hepatitis B virus. Moreover, 73% (n = 87/120) of the injection providers and 90% (n = 43/48) of the waste handlers were not trained in injection safety practices and infection prevention. Qualitative data further confirmed that both providers and patients preferred injections, believing that they provide quick relief. The doctors' perceived injection use as their prescribing norm that enabled them to prove their professional credibility and to remain popular in a competitive health care market. Additionally, persistent pressure from hospital administration to use up injections before their expiry dates also influenced doctors to prescribe injections regardless of actual indications. CONCLUSIONS: As far as the patients and providers' safety is concerned, this study demonstrated a need for further research exploring the dynamics of injection use and safety in Bangladesh. In a context where a high level of injection use and unsafe practices were reported, immediate prevention initiatives need to be operated through continued intervention efforts and health providers' training in primary care hospitals in Bangladesh.

Emergence of Multidrug Resistant Extended-Spectrum ß-Lactamase Producing Eshcherichia coli Associated With Urinary Tract Infections in Bangladesh.

The incidence of infections due to extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli has been increased dramatically in recent years. Treatment is difficult because of frequent multidrug resistance. To identify the sensitivity of commonly used antibiotics, 36 ESBL producing E. coli strains were isolated from young adult female patients in a govt. medical college hospital in Bangladesh. The samples were studied for antimicrobial sensitivity against nine (9) commonly used antibiotics namely ampicillin (amp), trimethoprim-sulfomethoxazole (tms), tetracycline (tet), ciprofloxacin (cip), mecillinum (mel), ceftriaxone (cef), nalidixic acid (nal), Azithromycin (azm) and Chloramphenicol (chl) and the MIC values were determined by agar dilution method. Overall, 72% of the strains were multidrug resistant (MDR) i.e. resistant to two or more drugs. Among 36 strains, 14 isolates were initially found to be resistant against third generation cephalosporin, ceftriaxone. Those were subjected to the test for production of ESBL (Extended Spectrum ß-Lactamase) and 7 showed positive results.

Total synthesis and analgesic activity of 6-fluoroindan-1-acetic acid and its 3-oxo derivative.

6-Fluoro-3-oxo-indan-1-acetic acid (5) and 6-fluoroindan-1-acetic acid (6) were conveniently synthesised from 3-fluorobenzaldehyde in four and five steps, respectively. The structures of these new compounds and two other intermediates, 3-fluorobenzylidine-bis-acetoacetate (2) and 3-fluoro-beta-phenyl glutaric acid (3) were elucidated by spectroscopic means, notably, HRMS, 1D and 2D NMR. The analgesic activity of compounds 5 and 6 were assessed by the acetic acid induced writhing in Swiss albino mice.

Effect of aqueous extracts of black and green teas in arsenic-induced toxicity in rabbits.

Arsenic causes oxidative stress in the body. Its administration (3 mg/kg/day) for 14 days in rabbits resulted in a significant reduction of whole blood glutathione (GSH), and elevation of thiobarbituric acid reactive substances (TBARS) and the index of nitrite/nitrate (NOx) levels. These are the markers of oxidative stress. Both black tea (BT) and green tea (GT) (Camellia sinensis), when administered to the arsenic-treated rabbits for 14 days, caused a significant elevation of the depleted GSH level to 53.12% and 57.47%, respectively. On the contrary, in the placebo group the level was 26.59%. The BT and GT reduced the elevated TBARS level to 43.27% and 62.28%, respectively, whereas the corresponding level in the placebo groups was 21.24%. The NOx levels were also reduced to 63.62%, 67.67% and 58.94% in BT, GT and the placebo groups, respectively. When arsenic and black tea were given concurrently to another group the results were even more pronounced. The polyphenol components of black and green tea were 27.69% and 29.71% of the dry weight of the total extracts, respectively. These results indicated that arsenic-induced toxicities in rabbits were significantly reversed by the black and green tea polyphenols. The greater activity of green tea than that of black tea correlates with the slightly higher content of polyphenols in green tea.

Antibacterial activity of two limonoids from Swietenia mahagoni against multiple-drug-resistant (MDR) bacterial strains.

Solvent partitioning followed by column chromatography of the MeOH extract of the seeds of Swietenia mahagoni afforded two limonoids, swietenolide (1) and 2-hydroxy-3-O-tigloylswietenolide (2). The compounds were identified by spectroscopic means. The antibacterial activity of these compounds was assessed against eight multiple-drug-resistant bacterial strains (clinical isolates) by the conventional disc diffusion method. While both compounds were active against all test organisms, compound 2 displayed overall more potent activity than compound 1.

Pachypodol, a flavonol from the leaves of Calycopteris floribunda, inhibits the growth of CaCo 2 colon cancer cell line in vitro.

Calycopteris floribunda Lam., commonly known as 'goichia lata or goache lata', is a large climbing woody shrub from Bangladesh, and well distributed in a number of other south-east Asian countries. Traditionally, C. floribunda has been used in colic, as an antihelminthic, astringent and carminative, and for the treatment of diarrhoea, dysentery, jaundice and malaria in many countries including Bangladesh. Pachypodol (5,4'-dihydroxy-3,7,3'-trimethoxyflavone) has been isolated from the leaves of C. floribunda by repeated column chromatography on silica gel, and the structure confirmed by spectroscopic means. While the general toxicity of pachypodol was determined by the brine shrimp lethality assay, the cytotoxic potential of this flavonoid has been evaluated by the Promega's CellTiter 96 Non-Radioactive Cell Proliferation Assay using the CaCo-2 colon cancer cell line (IC(50) = 185.6 microM). A summary of the biological activities of pachypodol reported to date is also presented.

Effect of standard treatment guidelines with or without prescription audit on prescribing for acute respiratory tract infection (ARI) and diarrhoea in some thana health complexes (THCs) of Bangladesh.

Inappropriate prescribing for ARI and diarrhoea is a serious health problem in many developing countries including Bangladesh. A baseline retrospective prescribing survey for ARI and diarrhoea have been conducted in randomly selected 60 thana health complexes (THCs) of Dhaka division of Bangladesh. In the 38 of 60 THCs, the prescribers did not comply with the standard treatment guidelines (STG) for ARI. They are marked as 'unsatisfactory performers'. In these THCs unnecessary antibiotics were prescribed in more than 50% of the encounters. The study further revealed that in 26 THCs, comprising 41.6% of the 38 THCs, the situation was even worse regarding the indiscriminate use of antibiotics. In these THCs antibiotics were prescribed in > or =72% of the encounters. For diarrhoea, only in 8.3% of the THCs antibiotics were prescribed in > or =50% of the encounters. Encouragingly, most of the prescribers prescribed ORS. So the diarrhoea cases were dropped from the intervention. The 24 out of 26 worse performing THCs for ARI management, were grouped into three groups: Group-I (implementing STG+ Audit), Group-II (STG) and Group-III (no intervention, control). The prescribers of the THCs belonging to Group-I and Group-II received STG+Audit and STG only respectively as intervention(s). On the contrary, the prescribers of the THCs of Group-III (control) did not receive any intervention. It was observed that after the implementation of interventions the use of the unnecessary antibiotics to treat ARI was significantly reduced (p<0.01) compared to pre-intervention period in Group-I (STG+Audit). In this group highly significant (p<0.000) reduction in antibiotics use was achieved in 6 out of 8 THCs. The average reduction in antibiotic use in terms of encounters was 23.7 and 15.2% in the Group-I and Group-II respectively owing to the intervention(s). Significant reduction in antibiotic use in terms of THCs was 3 (out of 8 THCs) and 2 (out of 8 THCs) belonging to the Group-II and Group-III respectively. When compensated for the change in the control group, the reduction of antibiotic use in terms of encounters was 15.2 and 6.9% in the THCs of the Group-I and Group-II respectively due to introduction of the interventions. The study concludes that STG supported by prescription audit are highly effective interventions to change the prescribing behaviour of the prescribers for ARI in the THCs.

Water and electrolyte salvage in an animal model of dehydration and malnutrition.

BACKGROUND AND AIM: Recently, a new oral rehydration solution (ORS) called Resomal has been designed specifically for children with severe malnutrition. The aim of this study was to assess the effect of malnutrition on renal and intestinal responses to dehydration, and to compare intestinal water and electrolyte absorption from Resomal and from the standard World Health Organization-Oral Rehydration Solution (WHO-ORS). METHOD: Malnutrition was achieved in a rabbit model by feeding the animals daily for 30 days with half the amount of food that a well-nourished group of control animals had consumed on the previous day. Dehydration was achieved by water deprivation for 46 hours in both control and malnourished rabbits. At 46 hours, dehydration was assessed by changes in body weight, urinary volume and osmolarity, and blood urea nitrogen concentration. At that time active colonic and jejunal mucosal electrolyte transport in Ussing chambers was also measured. Small intestinal absorption of water, sodium, and potassium was measured in vivo during intestinal perfusion of the two ORSs and in vitro by measurement of mucosal electrogenic glucose-stimulated sodium absorption across intestinal patches. RESULTS: Compared to controls (C), well-nourished but dehydrated (C+D) animals lost 12% of their body weight, with an 87% reduction in urine volume, a 110% increase in urine osmolality, and a 94% increase in blood urea nitrogen. In the colon of C+D animals, short-circuit current (Isc) and net sodium transepithelial flux (JNa+ net) were increased. Almost identical results were obtained in malnourished and dehydrated (M+D) animals. In the jejunum, net in vivo absorption of water (JWater), sodium (JNa+), and potassium (JK+) were increased during standard ORS infusion in both dehydrated groups. During Resomal infusion, water absorption was the same as seen with WHO-ORS, but sodium absorption was reduced, and potassium absorption was increased in both well-nourished and malnourished dehydrated animals. In vitro, compared to controls, the glucose-stimulated short-circuit current (DeltaIsc), JNa+ net and G were increased in both dehydrated groups. CONCLUSION: During experimental dehydration, the kidney and large intestine salvage water and electrolytes, thus reducing the consequences of dehydration. These findings indicate that jejunal water absorption from Resomal and WHO-ORS is increased during dehydration, but Resomal allows for less sodium and more potassium to be absorbed, both in well-nourished and malnourished dehydrated rabbits.

Antioxidants in detoxification of arsenic-induced oxidative injury in rabbits: preliminary results.

To assess the oxidative injuries caused by arsenic toxicity in rabbits and evaluate the detoxifying effects of exogenous antioxidants, we administered arsenic trioxide (3-5 mg/kg/day) in rabbits through a feeding tube for seven days. These rabbits were then treated with a recipe of vitamins, zinc, selenium (VZS) or a plant polyphenol or a placebo for the next seven days. Blood samples were collected from ear vein for spectrophotometric assay of reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS), and nitrite/nitrate (NOx; index of nitric oxide formation) before arsenic administration, seven days after arsenic administration, and seven days after antioxidant treatment. The total arsenic concentrations in hair and spot urine samples of rabbits before arsenic administration were 0.6 +/- 0.21 microg/g and 34.0 +/- 5.9 microg/L, respectively. Administration of arsenic trioxide significantly increased arsenic concentrations in hair and in urine to 2.8 +/- 0.40 microg/g (p<0.001) and 7372 +/- 1392.0 microg/L (p<0.001), respectively. Arsenic administration to rabbits significantly reduced GSH concentration (post-arsenic, 17.5 +/- 0.81 mg/dL vs. pre-arsenic, 32.0 +/- 0.76 mg/dL, p<0.001), increased TBARS concentration (post-arsenic, 8 +/- 1.1 microM vs. pre-arsenic, 5 +/- 0.7 microM, p<0.05), and NOx concentration (post-arsenic, 465 +/- 38.5 microM vs. pre-arsenic, 320 +/- 24.7 microM, p<0.001) as compared to the pre-arsenic levels. There was a negative correlation between TBARS and GSH concentrations (r=-0.464, p<0.01) and between NOx and GSH concentrations (r=-0.381, p<0.05) of intoxicated rabbits. The recovery of the depleted GSH was significantly greater in the polyphenols (77.0 +/- 12.0%) or VZS (67.0 +/- 17.0%) treatment groups compared with the placebo group (36.0 +/- 7.0%). The decrease in NOx level of arsenic-treated rabbits was significantly greater in polyphenols treatment group than the placebo group (60.0 +/- 9.0% vs. 17.0 +/- 6.0%, p<0.001). These results indicate that arsenic induces toxicity in rabbits associated with an increase in lipid peroxidation. Arsenic toxicity increases nitric oxide production in the body. Exogenous antioxidants such as polyphenols and recipe of vitamins, zinc, and selenium are useful for arsenic detoxification.