Occurrences, sources and health hazard estimation of potentially toxic elements in the groundwater of Garhwal Himalaya, India.

High concentrations of potentially toxic elements (PTEs) in potable water can cause severe human health disorders. Present study examined the fitness of groundwater for drinking purpose based on the occurrence of nine PTEs in a heavy pilgrim and tourist influx region of the Garhwal Himalaya, India. The concentrations of analyzed PTEs in groundwater were observed in the order of Zn > Mn > As > Al > Cu > Cr > Se > Pb > Cd. Apart from Mn and As, other PTEs were within the corresponding guideline values. Spatial maps were produced to visualize the distribution of the PTEs in the area. Estimated water pollution indices and non-carcinogenic risk indicated that the investigated groundwater is safe for drinking purpose, as the hazard index was < 1 for all the water samples. Assessment of the cancer risk of Cr, As, Cd, and Pb also indicated low health risks associated with groundwater use, as the values were within the acceptable range of ≤ 1 × 10-6 to 1 × 10-4. Multivariate statistical analyses were used to describe the various possible geogenic and anthropogenic sources of the PTEs in the groundwater resources although the contamination levels of the PTEs were found to pose no serious health risk. However, the present study recommends to stop the discharge of untreated wastewater and also to establish cost-effective as well as efficient water treatment facility nearby the study area. Present work's findings are vital as they may protect the health of the massive population from contaminated water consumption. Moreover, it can help the researchers, governing authorities and water supplying agencies to take prompt and appropriate decisions for water security.

A Hospital-Based Case-Control Study on Raised Homocysteine Level in Vitiligo Patients and Its Association With Disease Severity.

Introduction Vitiligo is an acquired pigmentary disorder clinically manifested by circumscribed depigmented macules and often associated with leucotrichia. Not much is known about the biochemical abnormality occurring in vitiligo. Our study aims to determine whether serum homocysteine is raised in vitiligo patients and whether it can be used as a prognostic marker for vitiligo. Material and methods This study is a hospital-based, case-control, analytical study conducted on 70 patients of vitiligo patients. A total of 30 staff of the hospital served as control. Venous blood was withdrawn from the antecubital vein from all study participants using all aseptic precautions. Investigation of blood homocysteine levels was done in all the study participants. Scoring of vitiligo was done based on Vitiligo European Task Force (VETF) criteria which take into account body surface area, stage, and spread. Results Mean serum homocysteine level among vitiligo patients was 14.40± 5.80 micromoles/lit as compared to 10.33± 5.05 micromole/lit in control groups, and this difference was statistically significant (t-value = 3.19and p-value = 0.002). The correlation coefficient was statistically significant (correlation coefficient = 0.25 and p-value = 0.03) in between homocysteine level and stage of the disease. On multiple comparisons difference in serum homocysteine level of progressing category is significantly raised as compared to control, stable, and regressing categories. Conclusion The mean serum homocysteine level among all vitiligo patients was higher as compared to control groups. Moreover, the serum homocysteine level of active cases is significantly higher as compared to control, stable, and regressing categories. Also, serum homocysteine levels showed a positive correlation with the degree of depigmentation, i.e., stage of the disease.

Integrating an algorithmic and health systems thinking approach to improve the uptake of government antenatal nutrition services in Vidisha, Madhya Pradesh (India), 2018 to 2021.

In 2018, the Government of Madhya Pradesh initiated the feasibility testing of integrating an algorithmic approach (assess, give, counsel, treat) to strengthen antenatal nutrition services in routine government-funded programmes coupled with a health system thinking approach to strengthen the health service delivery platform. Implementation phases included (1) an evidence review and stakeholder consultations (April 2018) and (2) a health systems strengthening preparedness phase (May-December 2018), including pilot testing in Vidisha district (January-December 2019) covering ∼54 100 pregnant women with 237 antenatal contact points through 241 government auxiliary nurse midwives/staff nurses. During 2020-21, feasibility testing was expanded to an additional 7 districts. We used programme registers of the Auxiliary Nurse Midwives Registers (2019-21) and National Family Health Survey data for 2016 and 2021 to show changes in the Vidisha district and 7 expansion districts. We compare the performance of Vidisha district with Ashok Nagar district, where no such intervention occurred. Comparing 2016 and 2021 data, the Vidisha district showed improvements in receipt of antenatal care in the first trimester (29 to 85%) and in four antenatal visits (17 to 54%). Using the difference-in-difference approach, a 42% net increase in first-trimester antenatal check-ups in Vidisha as compared to Ashok Nagar is observed. There was also an improvement in the maternal nutrition budget of the state from USD 8.5 million to USD 17.8 million during this period. The Vidisha initiative offers several lessons in time-effective workflow to deliver all constituents of nutrition services at various antenatal contact points through and via routine government health systems. Continued execution of the algorithm for screening, with longitudinal data on the management of all nutrition risks, will be critical to show its long-term impact on maternal morbidities and birth outcomes.

Public health supply chain for iron and folic acid supplementation in India: Status, bottlenecks and an agenda for corrective action under Anemia Mukt Bharat strategy.

PURPOSE: The IFA supplementation program under the Anemia Mukt Bharat (AMB) program is one of the most ambitious nutrient supplementation programs in India. The delivery of services often suffers due to frequent stock outs and shortages. It is critical to understand the bottleneck in the supply chain adversely affecting the performance and coverage of the program. The paper attempts to identify the bottlenecks of the IFA supply chain in key areas of supply chain i.e., forecasting, procurement, warehousing and inventory management, transportation, distribution, logistic information system and suggests a plan of action aimed at ensuring uninterrupted supplies to the end beneficiaries. DESIGN/METHODOLOGY/APPROACH: The data source for the present paper is the nationwide IFA Supply Chain Assessment (2018-19) conducted across 29 Indian states with a total of 58 districts, 116 blocks, 232 Sub-Centres, 232 Anganwadi centres and 232 schools covered under the assessment as a multi-partner collaborative initiative. Field insights from supply chain strengthening interventions under different public health programs in India and other developing countries were taken to arrive at corrective actions and recommendations. Findings were disseminated to government and an action plan was suggested for connecting service delivery points through an app-based system, developing a micro plan for ensuring fixed distribution schedule, followed by continuous monitoring and review meetings identified for follow up. FINDINGS: The average lead time across states was 35 weeks with top three performing states being Goa, Sikkim, and Telangana. The average per unit cost of procurement was Rs 0.35 for IFA Red, Rs 0.25 for IFA Blue, Rs 0.31 for IFA Pink and Rs 7.30 for IFA syrup. Out of the 704 districts in India, only 213 has IFA Red, only 140 had IFA Blue, 152 had IFA Pink and 163 had IFA Syrup available in four quarters of 2018-19. The key issues identified in the assessment were-a lack of standardized forecasting process, absence of inventory management techniques, no fixed distribution schedule, inadequate availability of transport vehicles and an absence of an integrated MIS. ORIGINALITY/VALUE: The identification of bottlenecks in the IFA supply chain and its impact on the performance of the supply chain would provide policy guidelines for the government as well as development partner agencies to design an effective and efficient supply chain. It would also enable the policy planners to understand the challenges associated with managing different components of a supply chain, their interrelation and impact on the overall performance of the supply chain. The suggested recommendations would equip program managers with the tool to devise and implement field level solutions.

Coverage of iron and folic acid supplementation in India: progress under the Anemia Mukt Bharat strategy 2017-20.

High prevalence of anaemia is a severe public health problem in India. In 2018, India launched the Anemia Mukt Bharat (AMB) strategy that focuses on six beneficiary groups for coverage, six institutional mechanisms for health system strengthening and six programmatic interventions to accelerate reductions in anaemia prevalence. This paper uses the Health Management Information System data (2017-18 to 2019-20) to examine gains in IFA coverage across Indian states. A coverage-based AMB index is computed to review performance across states. After the launch of AMB strategy, the Iron and Folic Acid (IFA) supplementation coverage between 2017-18 and 2019-20 has increased for all beneficiary groups [pregnant women from 78% to 90%; lactating mothers from 34% to 49%; school going adolescent girls (boys) from 23% to 40% (21% to 42%); out-of-school adolescent girls from 6% to 23%; children 5-9 years from 8% to 3% and children 6-59 months from 7% to 15%]. Coverage was relatively low for target groups being served through a multi-departmental convergence mechanism (health and other departments such as education department for schools or women and child development department for Anganwadi centres) than compared to those served by health department alone. However, no major gender disparities are noted in the coverage of IFA supplementation among school-going girls and boys. Bulk of the variations in coverage is attributable to state-specific differences. Training and sensitization workshops for state and district officials are found to be associated with increased coverage across beneficiary groups. The paper argues that despite following international best practices in the field, it is important to harness synergy in programme implementation across line departments to eliminate coverage inefficiencies.

An Updated Nerve Sparing Surgical Technique for Addressing Morton's Neuroma.

Morton's neuroma is a common painful pathology that occurs in the plantar forefoot. Many treatment options exist and surgical management is used after conservative treatment options fail. While within the literature, there is a high success rate with primary neurectomy procedures, the risk of recurrence of symptoms or "stump neuromas" remains difficult to treat and can lead to debilitating pain. This article expands on a previously published article to discuss an update on a nerve sparing, microneurosurgical, procedure for the management of Morton's neuromas.

A hospital-based cross-sectional study on suicidal poisoning in Western Uttar Pradesh.

BACKGROUND AND AIMS: Poisoning is most common method of committing suicide in India. Objectives of this study to assess prevalence of suicidal poisoning among all poisoning cases, its socio-demographic profile and its reasons in all admitted cases of suicidal poisoning in hospital. METHODS: A cross-sectional study was conducted on cases of poisoning of any age group admitted in the Chhatrapati Shivaji Subharti Hospital, Meerut. Poisoning cases with history or evidence of suicide were further interviewed. A semi-structured interview schedule in Hindi was used to collect data. Microsoft Excel 365 and R software version 3.6.0 were used for data entry and analysis respectively. RESULTS: Among total 135 poisoning cases admitted in hospital, 126 provided consent and included in the study. Prevalence of suicidal poisoning was 77.7% (98). Most common age group involved was 11-20 years (36.7%) and 21-30 years (35.7%) and most of the participants were males (59.2%). Most suicidal poisoning cases took Aluminum Phosphide (31.6%), followed by Organophosphates (20.4%) as poison. Most frequent reasons for suicide as described by participants were 'Family quarrel or family unhappiness' (29.6%), 'failure in examination or interview or business' (23.5%), 'ill treatment by spouse or in laws' (16.3%) and 'unemployment' (9.2%). CONCLUSION: Our study shows that consuming Agriculture poisons (Aluminum Phosphide and Organophosphates) are most common (52%) poisons consumed by suicidal poisoning cases. Agriculture poisons (Aluminum Phosphide and Organophosphates) are easily available in markets in India. There should be some restriction on their purchase to reduce suicidal incidences.

Design and optimization of (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones as potent PLK4 inhibitors with oral antitumor efficacy.

Previous efforts from our laboratory demonstrated that (E)-3-((3-(E)-vinylaryl)-1H-indazol-6-yl)methylene)-indolin-2-ones are potent PLK4 inhibitors with in vivo anticancer efficacy upon IP dosing. As part of a continued effort to develop selective and orally efficacious inhibitors, we examined variations on this theme wherein 'directly-linked' aromatics, pendant from the indazole core, replace the arylvinyl moiety. Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones. The latter compounds are potent and selective inhibitors of PLK4 with oral exposure in rodents and in vivo anticancer activity. Compound 13b, in particular, has a bioavailability of 22% and achieved a 96% tumor growth inhibition in an MDA-MB-468 xenograft study.

Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent.

This work describes a scaffold hopping exercise that begins with known imidazo[1,2-a]pyrazines, briefly explores pyrazolo[1,5-a][1,3,5]triazines, and ultimately yields pyrazolo[1,5-a]pyrimidines as a novel class of potent TTK inhibitors. An X-ray structure of a representative compound is consistent with 1(1)/2 type inhibition and provides structural insight to aid subsequent optimization of in vitro activity and physicochemical and pharmacokinetic properties. Incorporation of polar moieties in the hydrophobic and solvent accessible regions modulates physicochemical properties while maintaining potency. Compounds with enhanced oral exposure were identified for xenograft studies. The work culminates in the identification of a potent (TTK K i = 0.1 nM), highly selective, orally bioavailable anticancer agent (CFI-402257) for IND enabling studies.

The Discovery of Orally Bioavailable Tyrosine Threonine Kinase (TTK) Inhibitors: 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides as Anticancer Agents.

The acetamido and carboxamido substituted 3-(1H-indazol-3-yl)benzenesulfonamides are potent TTK inhibitors. However, they display modest ability to attenuate cancer cell growth; their physicochemical properties, and attendant pharmacokinetic parameters, are not drug-like. By eliminating the polar 3-sulfonamide group and grafting a heterocycle at the 4 position of the phenyl ring, potent inhibitors with oral exposure were obtained. An X-ray cocrystal structure and a refined binding model allowed for a structure guided approach. Systematic optimization resulted in novel TTK inhibitors, namely 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides. Compounds incorporating the 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl bicyclic system were potent (TTK IC50 < 10 nM, HCT116 GI50 < 0.1 µM), displayed low off-target activity (>500×), and microsomal stability (T(1/2) > 30 min). A subset was tested in rodent PK and mouse xenograft models of human cancer. Compound 75 (CFI-401870) recapitulated the phenotype of TTK RNAi, demonstrated in vivo tumor growth inhibition upon oral dosing, and was selected for preclinical evaluation.

The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S).2-(3-((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl). 1H.indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (CFI-400945) as a potent, orally active antitumor agent.

Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (E)-3-((1Hindazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones, e.g., 3. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double SN2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., 44. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound 48 (designated CFI-400945) as a novel clinical candidate for cancer therapy.

The discovery of Polo-like kinase 4 inhibitors: design and optimization of spiro[cyclopropane-1,3'[3H]indol]-2'(1'H).ones as orally bioavailable antitumor agents.

Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and is linked with a predisposition to tumorigenesis. Previous efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which are superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones reported herein. Optimization of this new cyclopropane-linked series was based on a computational model of a PLK4 X-ray structure and SAR attained from the analogous alkenelinked series. The racemic cyclopropane-linked compounds showed PLK4 affinity and antiproliferative activity comparable to their alkene-linked congeners with improved hysicochemical, ADME, and pharmacokinetic properties. Positive xenograft results from the MDA-MB-468 human breast cancer xenograft model for compound 18 support the investigation of PLK4 inhibitors as anticancer therapeutics. A PLK4 X-ray co-structure with racemate 18 revealed preferential binding of the 1R,2S enantiomer to the PLK4 kinase domain.

Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides.

TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI-400936). This potent inhibitor of TTK (IC50=3.6nM) demonstrated good activity in cell based assay and selectivity against a panel of human kinases. A co-complex TTK X-ray crystal structure and results of a xenograft study with TTK inhibitors from this class are described.

Optimizing managed care peer reviews: turning a "Doc to Doc" talk into better advocacy for psychiatric inpatients.

Clinicians often resent behavioral health managed care peer reviews. However, such reviews need not be onerous. This Open Forum, written by managed care physician reviewers, attempts to help attending psychiatrists, specifically those on inpatient units, achieve more satisfying outcomes for patients by adhering to a few basic principles. Beyond the level-of-care guidelines, attending psychiatrists are advised to focus on immediate acuity, along with specific life events that may have immediate impact on the patient's well-being. A clear diagnosis, relevant treatment plan, salient updates, and strategies for preventing readmission can justify additional treatment time. By contrast, "time-based treatments," dispositional issues, or a patient's lack of acceptance or effective use of treatment are harder to justify.

Intravitreal bevacizumab for treatment of proliferative and nonproliferative type 2 idiopathic macular telangiectasia.

PURPOSE: To determine the effect of treatment with intravitreal bevacizumab on retinal thickness and visual acuity in the nonproliferative and proliferative forms of Type 2 idiopathic macular telangiectasia. METHODS: Retrospective chart review of clinic patients treated with bevacizumab for macular telangiectasia Type 2. Treatment was performed until no further changes were seen after repeated bevacizumab injections. All patients had Snellen visual acuity testing, fundus fluorescein angiography, and measurement of central macular thickness by optical coherence tomography at baseline. Visual acuity and central macular thickness were recorded at follow-up visits. RESULTS: Fourteen eyes of 10 patients were included. In 5 eyes with nonproliferative macular telangiectasia Type 2, average follow-up was 17 months (± 7 months), and no eye demonstrated improvement in visual acuity or decrease in central macular thickness at final follow-up compared with baseline. In 9 eyes with proliferative disease, follow-up averaged 17 months (± 9 months). At 6 weeks, central macular thickness decreased 63 µm (± 58 µm), and acuity improved 1.7 lines (± 2 lines). At final follow-up, central macular thickness decreased 48 µm (± 89 µm) and acuity improved 1.1 lines (± 3 lines). Subretinal neovascularization resolved in eight of nine eyes with proliferative disease after treatment. CONCLUSION: Bevacizumab did not improve acuity or reduce retinal thickness in nonproliferative macular telangiectasia Type 2 at final follow-up. In proliferative macular telangiectasia Type 2, bevacizumab caused involution of neovascularization and improved visual acuity.

Mini-subvastus approach for total knee arthroplasty in obese patients.

BACKGROUND: Mini-subvastus approach for Total Knee Arthropalsty allows a faster recovery. It is traditionally not utilized for obese patients because of difficulty in exposure of the knee and eversion of the patella. We hypothesized that obesity should not really cause a problem for patients undergoing a TKA with the mini-subvastus approach as the anatomy of the quadriceps in the obese and the nonobese patient population is the same. We present an analysis of the use of mini-subvastus approach in obese patients. MATERIALS AND METHODS: 97 obese patients (109 knees) 81 females + 16 males with mean age 64 years underwent total knee arthroplasty (TKA) by mini-subvastus approach between January 2006 to July 2007. 16 patients (18 kness) were morbidly obese. All patients were prospectively evaluated by pre- and postoperative Knee Society and function score. The average follow-up was 18 months (range from 1 to 3 years) with minimum 1 year follow-up. RESULTS: The approach provided adequate exposure in all knees, with an average surgical time of 90 minutes. The patella could be everted easily after the tibial and femoral cuts. The average Knee Society score improved from 42 to 89 and the function score from 48 to 65. The complications included medial collateral ligament injury (one case) and patellar tendon avulsion (one case). CONCLUSION: Our results compare favorably with other reported series in obese patients. The mini-subvastus approach can be considered in obese patients.

Comparative study of plateletpheresis using Baxter CS 3000 plus and Haemonetics MCS 3P.

Platelet concentrates made from cell separators are used more frequently due to less donor exposure and leucodepletion. This retrospective study was done to compare plateletpheresis done on two cell separators: Baxter CS 3000 plus and Haemonetics MCS 3p. Plateletpheresis procedures, done from January 1997 to April 2002, were included in the study. One hundred and seven procedures were done on Haemonetics MCS 3p using SDP protocol, 49 procedures were done on Haemonetics MCS 3p using PLP protocol, and 107 were done on Baxter CS 3000 plus. Pre-procedure donor's platelet count and haemoglobin were comparable in all the groups. Platelet yield was comparable in PLP (6.44 x 10(11) platelets) and SDP (5.27 x 10(11)) protocols, but significantly less in Baxter (4.05 x 10(11) platelets, P < 0.001 for PLP and P < 0.05 for SDP). Efficiency of platelet removal was statistically significantly different in all the groups (P < 0.0001), however it was more in PLP (PLP-55.02%, SDP-47.38%, Baxter 38.98%). A significant number of products (19.51%) of Baxter failed to comply platelet count of product < or = 2,435 x 10(9)/l compared to 5.13% in PLP and 1.23% in SDP group; 36.96% of units from PLP and 28% from SDP qualified for split products compared to 1.18% of Baxter. PLP protocol of Haemonetics MCS 3p gives better platelet yield compared to Baxter CS 3000 plus and SDP protocol of Haemonetics MCS 3p.