Use of Artificial Intelligence-Based Strategies for Assessing Suicidal Behavior and Mental Illness: A Literature Review.

Mental illness leading to suicide attempts is prevalent in a large portion of the population especially in low and middle-income nations. There remains a significant social stigma associated with mental illness that can lead to stigmatization of patients. Hence, patients are reluctant to communicate their problems to health care providers. Physicians have difficulty in timely identification of patients at risk for suicide. Novel and rigorously designed strategies are needed to determine the population at risk for suicide. This would be the first step in overcoming the multitude of barriers in the management of mental illness. Clinical tools and the use of electronic medical records (EMR) are time intensive. Recently, several artificial intelligence (AI)-based predictive technologies have gained momentum. The aim of this review is to summarize the recent advances in this landscape.

Accelerating Harmonization in Digital Health.

Digital tools play an important role in supporting front-line health workers who deliver primary care. This paper explores the current state of efforts undertaken to move away from single-purpose applications of digital health towards integrated systems and solutions that align with national strategies. Through examples from health information systems, data and health worker training, this paper demonstrates how governments and stakeholders are working to integrate digital health services. We emphasize three factors as crucial for this integration: development and implementation of national digital health strategies; technical interoperability and collaborative approaches to ensure that digital health has an impact on the primary care level. Consolidation of technologies will enable an integrated, scaleable approach to the use of digital health to support health workers. PURPOSE: As this edition explores a paradigm shift towards harmonization in primary healthcare systems, this paper explores complementary efforts undertaken to move away from single-purpose applications of digital health towards integrated systems and solutions that align with national strategies. It describes a paradigm shift towards integrated and interoperable systems that respond to health workers' needs in training, data and health information; and calls for the consolidation and integration of digital health tools and approaches across health areas, functions and levels of the health system. It then considers the critical factors that must be in place to support this paradigm shift. This paper aims not only to describe steps taken to move from fractured pilots to effective systems, but to propose a new perspective focused on consolidation and collaboration guided by national digital health strategies.

The Effect of Acetyl Salicylic Acid Induced Nitric Oxide Synthesis in the Normalization of Hypertension through the Stimulation of Renal Cortexin Synthesis and by the Inhibition of Dermcidin Isoform 2, A Hypertensive Protein Production.

Currently, there is no specific medication for essential hypertension (EH), a major form of the condition, in man. As acetyl salicylic acid (aspirin) is reported to stimulate the synthesis of renal (r)-cortexin, an anti-essential hypertensive protein, and, as aspirin is reported to inhibit dermcidin isoform 2 (dermcidin), a causative protein for EH, the role of aspirin in the control of EH in man was studied. Oral administration of 150 mg aspirin/70 kg body weight in subjects with EH was found to reduce both the elevated systolic and diastolic blood pressures to normal levels within 3 h due to the normalization of dermcidin level in these subjects. The plasma cortexin level at day 0, 1, 30 and 90 were 0.5 pmol/ml, 155.5 pmol/ml, 160.2 pmol/ml, 190.5 pmol/ml respectively with increased NO synthesis (r=+0.994). In vitro studies demonstrated that the incubation of the goat kidney cortex cells with aspirin stimulated (r)-cortexin synthesis due to NO synthesis. It could be suggested that the use of aspirin might control EH in man.

MGMT gene silencing by promoter hypermethylation in gastric cancer in a high incidence area.

PURPOSE: Inactivation of tumor suppressor and DNA repair genes by promoter hypermethylation does commonly occur in human cancers. O(6)-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that removes methyl groups as well as larger adducts at the O(6) position of guanine. In the absence of MGMT activity, O(6)-methylguanine mispairs with thymine during DNA replication, resulting in G:C to A:T transitions. Promoter hypermethylation of the MGMT gene has been observed in various cancers, including gastric cancer. Here, we aimed at assessing the promoter hypermethylation, mutation and expression status of the MGMT gene in patients from a geographic region with a high incidence of gastric cancer (Kashmir, North India) and to investigate their association with various clinicopathological characteristics. METHODS: In this study 82 gastric cancer samples and adjacent normal tissues were included. Mutations in the MGMT gene were detected by single stranded conformational polymorphism (SSCP) analysis and direct sequencing. Methylation-specific polymerase chain reaction (MS-PCR) and Western blot analyses were performed to detect promoter hypermethylation and concomitant (loss of) expression of the MGMT gene. RESULTS: Promoter hypermethylation of the MGMT gene was found in 52.44% (43 of 82) of the tumor samples and loss of MGMT protein expression was detected in 45.12% (37 of 82) of the tumor samples. Hypermethylation and loss of expression were significantly associated with higher tumor grades (moderately/poorly differentiated) (P < 0.05) and higher tumor stages (III/IV) (P < 0.05). In addition, MGMT hypermethylation and loss of expression were found to be significantly associated with high salt tea consumption (P < 0.05). CONCLUSIONS: Our results indicate that MGMT promoter hypermethylation and concomitant loss of MGMT protein expression may play an important role in the development of gastric cancer in the Kashmiri population. High salt tea consumption may be a risk factor.

Neutralization by insulin of the hypertensive effect of dermcidin isoform 2: an environmentally induced diabetogenic and hypertensive protein.

The effect of dermcidin isoform 2 (dermcidin), an environmentally induced stress protein, was investigated on the genesis of diabetes mellitus and hypertension, the two major atherosclerotic risk factors. The role of dermcidin as an atherosclerotic risk factor related to the impaired systemic insulin level was investigated. Dermcidin was prepared by electrophoresis using plasma from the subjects with acute ischemic heart disease. Injection of 0.2 µM dermcidin in mice increased the blood glucose level from 98 ± 2.45 mg/dL to 350 ± 10.2 mg/dL which was normalized by the oral administration of acetyl salicylic acid (aspirin) after 24 h. Hypertensive subjects with systolic and diastolic blood pressure of 165 mm and 95 mm of Hg, respectively, had plasma dermcidin level of 95 nM. Ingestion of acetyl salicylic acid (aspirin) (150 mg/70 kg body weight) decreased the systolic and diastolic pressures to 125 mm and 80 mm of Hg, respectively, with decrease of dermcidin level to 15 nM. Incubation of kidney cortex cells with 0.2 µM dermcidin-inhibited synthesis of (r)-cortexin, an antihypertensive protein, and the basal (r)-cortexin level was reduced from 33 nM to 15 nM. Addition of 25 µunits of insulin/mL was found to reverse the inhibition of cortexin synthesis. The effect of dermcidin as a diabetogenic and a hypertensive agent could be controlled either by aspirin or by insulin.

Lack of mutational events of RAS genes in sporadic thyroid cancer but high risk associated with HRAS T81C single nucleotide polymorphism (case-control study).

High incidence of thyroid cancer worldwide indicates the importance of studying genetic alterations that lead to its carcinogenesis. Specific acquired RAS mutations have been found to predominate in different cancers, and HRAS T81C polymorphism has been determined to contribute the risk of various cancers, including thyroid cancer. We screened the exons 1 and 2 of RAS genes (HRAS, KRAS, and NRAS) in 60 consecutive thyroid tissue (tumor and adjacent normal) samples, and a case-control study was also conducted for HRAS T81C polymorphism in HRAS codon 27 using the polymerase chain reaction-restriction fragment length polymorphism to test the genotype distribution of 140 thyroid cancer patients in comparison with 170 cancer-free controls from a Kashmiri population. No mutation was found in any of the thyroid tumor tissue samples, but we frequently detected polymorphism at nucleotide 81 (T > C) in exon 1 of HRAS gene. In HRAS T81C SNP, frequencies of TT, TC, and CC genotypes among cases were 41.4, 38.6, and 20.0 %, while in controls genotype frequencies were 84.1, 11.7, and 4.2 %, respectively. A significant difference was observed in variant allele frequencies (TC + CC) between the cases and controls (58.6 vs. 16 %) with odds ratio = 7.4; confidence interval (CI) = 4.3-12.7 (P < 0.05). Interestingly, combined TC and CC genotype abundantly presented in follicular thyroid tumor (P < 0.05). Moreover, a significant association of the variant allele (TC + CC) was found with nonsmokers (P < 0.05). This study shows that although thyroid cancer is highly prevalent in this region, the mutational events for RAS genes do not seem to be involved. Contrary to this HRAS T81C SNP of HRAS gene moderately increases thyroid cancer risk with rare allele as a predictive marker for follicular tumors.

HRAS T81C polymorphism modulates risk of urinary bladder cancer and predicts advanced tumors in ethnic Kashmiri population.

OBJECTIVE: Specific acquired HRAS mutations have been found to predominate in bladder cancer, and HRAS T81C polymorphism has been determined to contribute the risk of various cancers, including bladder cancer. MATERIALS AND METHODS: We screened the exon 1and 2 of HRAS and frequently detected polymorphism at nucleotide 81T to C (exon 1). A case-control study was conducted using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to test the genotype distribution of 140 bladder cancer patients in comparison with 160 cancer-free controls from a Kashmiri population. RESULTS: In HRAS T81C SNP, frequencies of TT, TC, and CC genotypes among controls were 84.4%, 15.6%, and 0.0%, while in cases allele frequencies were 64.3%, 30%, and 5.7%, respectively. A significant differences was observed between the control and cases with odds ratio (OR) = 3.0 and 95% confidence interval (CI) = 1.74-5.20 (P = 0.000). Interestingly, combined TC and CC genotype abundantly presented in high grade (OR = 5.4 and 95% CI = 2.8-10.2; P < 0.00) and in advanced tumors (OR = 3.3, 95% CI = 1.71-6.30; P < 0.05). A significant association of the variant allele (TC+CC) was found with male subjects (≥50) and ever smokers (P = 0.001). CONCLUSION: It is evident from our study that HRAS T81C SNP moderately increases bladder cancer risk, and rare allele is a predictive marker of advanced bladder tumors.

The XRCC1 Arg399Gln gene polymorphism and risk of colorectal cancer: a study in Kashmir.

BACKGROUND: The DNA repair gene XRCC1 Arg399Gln gene polymorphism has been found to be implicated in the development of various cancers, including colorectal cancer (CRC), in different populations. We aimed to determine any association of this polymorphism with the risk of CRC in Kashmir. MATERIALS AND METHODS: A total of 120 confirmed cases of CRC and 146 healthy cancer free controls from the Kashmiri population were included in this study. Genotyping was carried out by the polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Genotype frequencies of XRCC1 Arg399Gln observed in controls were 34.2%, 42.5% and 23.3% for GG (Arg/Arg), GA (Arg/Gln), AA( Gln/Gln), respectively, and 28.3%, 66.7% and 5% in cases, with an odds ratio (OR)=5.7 and 95% confidence interval (CI) =2.3-14.1 (p=0.0001). No significant association of Arg399Gln SNP with any clinicopathological parameters of CRC was found. CONCLUSIONS: We found the protective role of 399Gln allele against risk to the development of CRC. The XRCC1 heterozygote status appears to be a strong risk factor for CRC development in the Kashmiri population.

Impact of codon 72 Arg > Pro single nucleotide polymorphism in TP53 gene in the risk of kangri cancer: a case control study in Kashmir.

Kangri cancer found only in Kashmir (north India) is a unique thermally induced squamous cell carcinoma of the skin that develops because of chronic and persistent irritation due to the use of a kangri (a brazier) by the Kashmiri people to combat the chilling cold temperature during winter. Being unique to this region, the molecular etiology of the invasive kangri cancer is not known fully. The TP53 gene, codon 72 polymorphism (Arg72Pro), has been found to be associated with cancer susceptibility but has not been investigated in kangri cancer risk. A case control study was conducted to find the genotype distribution of TP53 Arg72Pro SNP and to elucidate the possible role of this SNP as risk factor in kangri cancer development. Using the polymerase chain reaction-restriction fragment length polymorphism approach, we tested the genotype distribution of 106 kangri cancer patients in comparison with 200 cancer-free controls from the same geographical region. A significant difference was observed between the control and kangri cancer patients with odds ratio = 2.02 and 95% confidence interval = 1.2-3.3 (p = 0.01). Interestingly, the proline form was abundantly observed in advanced-grade tumors (p < 0.05). We also found a significant association of the variant allele (GC + CC) with male subjects and patients >45 years of age (p < 0.05). Thus, it is evident from our study that Arg72Pro SNP is implicated in kangri cancer and that the rare, proline-related allele is connected with higher susceptibility to kangri cancer.

Novelty of Axin 2 and lack of Axin 1 gene mutation in colorectal cancer: a study in Kashmiri population.

Colorectal cancer is (CRC) one of the leading causes of mortality and morbidity. Various genetic factors have been reported to be involved in the development of colorectal cancers including Axin gene. Axin, a major scaffold protein, plays an important role in various bio signaling pathways. We aim to study mutational pattern of Axin gene in colorectal cancer patients of Kashmiri population. The paired tumor and adjacent normal tissue specimens of 50 consecutive patients with CRC were used in our study. The DNA preparations were evaluated for the occurrence of Axin 1 and Axin 2 gene mutations by direct DNA sequencing. We analyzed exon 1a, 1b, 1c, 2, 4, 6, and 10 of Axin 1 and exon 7 of Axin 2. In this study, we found a novel mutation of G>T (GCT>TCT) transversion in exon 7 of Axin 2 gene at codon G695T (p.alanine > serine) at a frequency of 6% (3/50). In the same exon of Axin 2 gene a single nucleotide polymorphism (SNP) was detected in codon L688L (CCT>CTT) at a frequency of 36% (18/50). In exon 1c of Axin 1 a SNP was detected at codon D726D (GAT>GAC) at a frequency of 62.5% (31/50). Both the SNPs were synonymous hence do not lead to change of amino acid. Although Axin 1 and Axin 2 gene mutations have been found to be involved in the development of colorectal cancers, it seems to be a relatively rare event in Kashmiri population. However, an interesting finding of this study is the novelty of Axin 2 gene mutations which may be a predisposing factor in ethnic Kashmiri population to CRC.

Association of bladder cancer risk with an NAD(P)H:quinone oxidoreductase polymorphism in an ethnic Kashmiri population.

NQO1 gene polymorphism at nucleotide 609 (Pro187Ser) results in a lowering of NQO1 detoxifying activity and is associated with susceptibility to various cancers. The NQO1 genotypes were identified by RFLP in 104 bladder cancer cases and 120 control subjects in an ethnic Kashmiri population. The frequency of the variant NQO1 alleles (CT/TT) was 23.3% for controls and 32.2% for cases (P < 0.05). Overall, the variant alleles were associated with a higher risk of bladder cancer in cases than in the control group (OR = 1.90; 95% CI 1.17-3.04; P < 0.01). In addition, the variant allele genotypes (CT/TT) were associated with a risk of bladder cancer that was more than threefold higher in smokers (OR = 3.47; 95% CI 1.84-6.3; P < 0.001). Results of this study strongly suggest that the variant allele of NQO1 (Pro187Ser) may affect individual susceptibility to bladder cancer, particularly among smokers, in this ethnic Kashmiri population.

Role of TP53 Arg72Pro polymorphism in urinary bladder cancer predisposition and predictive impact of proline related genotype in advanced tumors in an ethnic Kashmiri population.

Among various polymorphic variants of TP53 gene, codon 72 polymorphism (Arg72Pro) has been found to be associated with cancer susceptibility, but only few studies have investigated their effect on bladder cancer risk. A case-control study was conducted and we observed the genotype distribution of TP53 Arg72Pro SNP, to elucidate the possible role of this SNP as risk factor in urinary bladder cancer (UBC) development and to examine its correlation with the clinicopathologic variables of UBC cases. Using the polymerase chain reaction-restriction fragment length polymorphism approach, we tested the genotype distribution of 108 bladder cancer patients in comparison with 138 cancer-free controls from the same geographical region. We observed significant differences between the control and bladder cancer patients with odds ratio = 2.9 and 95% confidence interval = 1.5-4.5 (P = 0.00001). Interestingly, the proline form was abundantly observed in advanced tumors (P < 0.05). We also found a significant association of the variant allele (GC+CC) with male subjects and ever smokers (P = 0.001). Thus, it is evident from our study that Arg72Pro SNP is implicated in bladder cancer, and that the rare, proline-related allele is connected with higher susceptibility to bladder cancer.

Screening of N-ras gene mutations in urothelial cell carcinomas of the urinary bladder in the Kashmiri population.

BACKGROUND AND AIMS: The objective of this study was to assess the frequency of specific-point mutations in N-ras of the RAS gene family in a group of Kashmiri patients with bladder cancer and to observe any association with clinicopathological parameters. METHODS: Paired tumor and normal tissue specimens of 55 consecutive patients with urothelial cell carcinoma were screened and DNA was extracted for detection of N-ras activating mutations in exons 1 and 2. In addition, blood was also collected from all the cases to rule out any germ line mutation. RESULTS: Specific point mutations of activated N-ras were detected in 9% (5 of 55) of the bladder cancer patients, all being missense. The base substitutions identified included three transversions (two G toT and one A to T) and two transitions ( A-G). Sixty % of the mutations were detected in codon 61 and 40% in codon 12. No significant correlations were found between the mutations and clinical features. CONCLUSION: Although N-ras gene mutation might be one of the mechanisms underlying oncogenesis of urothelial cancer, it seems to be a relatively rare event in Kasmiris, pointing to involvement of different etiological factors in the induction of bladder tumor in this population.

Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses.

The program death 1 (PD-1) receptor and its ligands, PD-1 ligand (PD-L)1 and PD-L2, define a novel regulatory pathway with potential inhibitory effects on T, B, and monocyte responses. In the present study, we show that human CD4(+) T cells express PD-1, PD-L1, and PD-L2 upon activation, and Abs to the receptor can be agonists or antagonists of the pathway. Under optimal conditions of stimulation, ICOS but not CD28 costimulation can be prevented by PD-1 engagement. IL-2 levels induced by costimulation are critical in determining the outcome of the PD-1 engagement. Thus, low to marginal IL-2 levels produced upon ICOS costimulation account for the greater sensitivity of this pathway to PD-1-mediated inhibition. Interestingly, exogenous IL-2, IL-7, and IL-15 but not IL-4 and IL-21 can rescue PD-1 inhibition, suggesting that among these cytokines only those that activate STAT5 can rescue PD-1 inhibition. As STAT5 has been implicated in the maintenance of IL-2Ralpha expression, these results suggest that IL-7 and IL-15 restore proliferation under conditions of PD-1 engagement by enhancing high-affinity IL-2R expression and hence, IL-2 responsiveness.