Software Tools to Facilitate Community-Based Surveillance: A Scoping Review.

INTRODUCTION: Public health surveillance traditionally occurs at a health facility; however, there is growing concern that this provides only partial and untimely health information. Community-based surveillance (CBS) enables early warning and the mobilization of early intervention and response to disease outbreaks. CBS is a method of surveillance that can monitor a wide range of information directly from community members. CBS can be done using short message service, phone calls, paper forms, or a specialized software tool. No scoping review of the available software tools with the capability for CBS exists in the literature. This review aims to map software tools that can be used for CBS in both community health programs and emergency settings and demonstrate their use cases. METHODS: We conducted a scoping review of academic literature and supplemental resources and conducted qualitative interviews with stakeholders working with digital community health and surveillance tools. RESULTS: All of the tools reviewed have features necessary to support the reporting process of CBS; only 3 (CommCare, Community Health Toolkit, and DHIS2 Tracker) provided all 10 attributes included in the mapping. AVADAR and Nyss were the only tools designed specifically for CBS and for use by volunteers, while the other tools were designed for community health workers and have a broader use case. CONCLUSION: The findings demonstrate that several software tools are available to facilitate public health surveillance at the community level. In the future, emphasis should be put on contextualizing these tools to meet a country's public health needs and promoting institutionalization and ownership by the national health system. There is also an opportunity to explore improvements in event-based surveillance at the community level.

Resveratrol induces major histocompatibility complex class I antigen presentation in a STING-dependent and independent manner in melanoma.

Immune checkpoint inhibitor therapy has drastically improved outcomes in treating cancer, particularly in melanoma. However, half of melanoma patients are resistant to treatment. One mechanism used by tumor cells to evade immune attack is to down-regulate major histocompatibility complex (MHC) class I molecules, which are required for cytotoxic CD8 T-cells to eliminate cancer cells. To increase immunotherapeutic efficacy, it is critical to identify how to restore MHC-I expression on cancer cells so that tumor antigens are presented. We found that resveratrol elevated MHC-I expression, so that tumor antigens are presented to cytotoxic CD8 T-cell killing. Through proteomic interrogation, we identified the STING pathway as a potential mechanism of action. Further studies indicated that resveratrol-mediated regulation of STING induced MHC-I expression potentially through both interferon-independent and dependent pathways. Our results have indicated the potential of STING to induce MHC-I expression independent of interferon signaling, broadening the potential of STING modulation as a tool to improve immune checkpoint blockade.

Increased Response to Immune Checkpoint Inhibitors with Dietary Methionine Restriction in a Colorectal Cancer Model.

Dietary methionine restriction (MR), defined as a reduction of methionine intake by around 80%, has been shown to reproducibly decrease tumor growth and synergize with cancer therapies. In this study, we combined DMR with immune checkpoint inhibitors (ICIs) in a model of colon adenocarcinoma. In vitro, we observed that MR increased the expression of MHC-I and PD-L1 in both mouse and human colorectal cancer cells. We also saw an increase in the gene expression of STING, a known inducer of type I interferon signaling. Inhibition of the cGAS-STING pathway, pharmacologically or with siRNA, blunted the increase in MHC-I and PD-L1 surface and gene expression following MR. This indicated that the cGAS-STING pathway, and interferon in general, played a role in the immune response to MR. We then combined dietary MR with ICIs targeting CTLA-4 and PD-1 in an MC38 colorectal cancer tumor model developed in immunocompetent C57BL/6 mice. The combination treatment was five times more effective at reducing the tumor size than ICIs alone in male mice. We noted sex differences in the response to dietary MR, with males showing a greater response than females. Finally, we observed an increase in membrane staining for the PD-L1 protein in MC38 tumors from animals who were fed an MR diet. MHC-I was highly expressed in all tumors and showed no expression difference when comparing tumors from control and MR-treated mice. These results indicated that MR increased PD-L1 expression both in vitro and in vivo and improved the response to ICIs in mice.

Increased response to immune checkpoint inhibitors with dietary methionine restriction.

Dietary methionine restriction, defined as reduction of methionine intake by around 80%, reproducibly decreases tumor growth and synergizes with cancer therapies. Here, we combined dietary methionine restriction with immune checkpoint inhibitors in a model of colon adenocarcinoma. In vitro , we observed that methionine restriction increased the expression of MHC-I and PD-L1 in both mouse and human colorectal cancer cells. We also saw an increase in the gene expression of STING, a known inducer of type I interferon signaling. Inhibition of the cGAS-STING pathway, pharmacologically or with siRNA, blunted the increase in MHC-I and PD-L1 surface and gene expression following methionine restriction. PD-L1 expression was also This indicated that the cGAS-STING pathway in particular, and interferon in general, is playing a role in the immune response to methionine restriction. We then combined dietary methionine restriction with immune checkpoint inhibitors targeted against CTLA-4 and PD-1 in a MC38 colorectal cancer tumor model in C57BL/6 mice. The combination treatment was five times more effective at reducing tumor size than immune checkpoint inhibition alone in males. We noted sex differences in the response to dietary methionine restriction for the MC38 tumor model in C57BL/6 mice. Finally, we observed an increase in PD-L1 protein expression in MC38 tumors from animals who were fed a methionine-restricted diet. Furthermore, the distribution of CD8 staining changed from mostly peripheric in the controls, to intratumoral in the methionine-restricted tumors. MHC-I, which has a high basal expression in MC38 cells, was highly expressed in all tumors. These results indicate that methionine restriction improves the response to immune checkpoint inhibitors in mice, and that this improvement is associated with the cGAS-STING pathway and interferon signaling.

The Use of Patient Reported Outcome Measures (PROMs) 6 Months Post-Stroke and Their Association with the National Institute of Health Stroke Scale (NIHSS) on Admission to Hospital.

Patient Reported Outcome Measures (PROMs) assess clinical outcomes from the perspective of the patient. The stroke community recommended fifteen questions for use in stroke survivors, based on the established PROMIS10 with five additional stroke-specific questions. This study aimed to determine its association with the National Institute of Health Stroke Scale (NIHSS) on admission. PROM responses were taken from an existing randomised control trial and, using secondary analysis, the total score was calculated out of 100. The association between PROMs and NIHSS was estimated. Using a multivariable regression, an adjusted mean difference (aMD) in PROM total score for the baseline clinical characteristics was calculated. 343 participants (16.3%) completed the PROM; mean age 71.7 (30-94) years; 133 women (38.8%). There was a strong association between increasing NIHSS Scores on admission to hospital and worsening PROM scores at 6 months (p = 0.002). There was consistency between the NIHSS and modified Rankin score with the stroke-specific domain and total PROM scores. When adjusted, women had lower (worse) total PROM scores, with aMD = -3.85 (95% CI -6.30--1.41; p = 0.002) and so did haemorrhagic strokes, with a reduction of 3.88 (95% CI -0.61-7.37; p = 0.097). This study contributes to the evaluation process of this stroke-specific PROM and emphasises that stroke severity on admission correlates with poorer patient outcomes 6 months following a stroke, especially in women and those suffering haemorrhagic stroke.

Differences in cell death in methionine versus cysteine depletion.

Restriction of the sulfur amino acids methionine and cysteine has recently been proposed as potential adjuvant therapy in cancer. While cysteine depletion has been associated with ferroptotic cell death, methionine depletion has not. We hypothesized that comparing the response of melanoma cell lines to depletion of the amino acids methionine and cysteine would give us insight into the critical role in cancer of these two closely related amino acids. We analyzed the response to three conditions: methionine depletion, methionine replacement with homocysteine, and cysteine depletion. In cancer cells, the transcription factor ATF4 was induced by all three tested conditions. The replacement of methionine with homocysteine produced a strong ferroptotic gene signature. We also detected an activation of the NRF2 antioxidant pathway by both methionine and cysteine depletion. Total glutathione levels were decreased by 42% in melanoma cells grown without methionine, and by 95% in cells grown without cysteine. Lipid peroxidation was increased in cells grown without cysteine, but not in cells grown without methionine. Despite the large degree of overlap in gene expression between methionine and cysteine depletion, methionine depletion and replacement of methionine with homocysteine was associated with apoptosis while cysteine depletion was associated with ferroptosis. Glutamine depletion produced comparable gene expression patterns and was associated with a 28% decrease in glutathione. Apoptosis was detected in these cells. In this experiment, a strong ATF4-driven ferroptotic gene signature was insufficient to induce ferroptosis without a concomitant profound decrease in glutathione levels.

Sex-Specific Effects of Dietary Methionine Restriction on the Intestinal Microbiome.

Dietary methionine restriction is associated with improved health outcomes and an increase in lifespan in animal models. We have previously shown that an increase in dietary methionine induces alteration in the intestinal microbiome. The composition of the intestinal microbiota is a determinant of health and we, therefore, hypothesized that dietary methionine restriction would also induce changes in the murine microbiome. After one month on a methionine-restricted diet, five-month-old male and female C57BL/6 mice had decreased levels of serum methionine, without changes in body weight. We identified a decrease in the hepatic methylation status of animals fed a methionine-restricted diet compared to controls. This decrease was not associated with changes in DNA or protein methylation in the liver. In males, we saw an increase in families Bacteroidaceae and Verrucoccaceae (mostly A. mucinophila) and a decrease in Rumminococcaceae in animals fed a methionine-restricted diet compared to controls. In females, Bacteroidales family S24-7 was increased two-fold, while families Bacteroidaceae, Verrucoccaceae, Rumminococcaceae, and Rikenellaceae were decreased compared to controls. In summary, feeding a methionine-restricted diet for one month was associated with significant and sex-specific changes in the intestinal microbiome.

Uncertainty, fear and whistling happy tunes.

Uncertainty in medical practice is ineradicable, despite great scientific advances over the last century. Uncertainty provokes fear, not just in patients but also in doctors. Patients cope with theirfear by seeking the advice and reassurance of doctors; doctors, on the other hand, cope by denial and self-deception. But today, in this scientific, truth-seeking age doctors are encouraged to share their uncertainty with patients in order to 'empower' patients and improve doctor-patient relations. While in theory doctors might agree with this approach, in practice they continue to deny it and instead whistle happy tunes--deceiving both themselves and their patients. A disclosure of uncertainty requires an acknowledgement of uncertainty and, in practice, the ability of doctors to acknowledge and to tolerate uncertainty is limited. Whenever I feel afraid, I hold my head erect. And whistle a happy tune, So no one will suspect I'm afraid. While shivering in my shoes, I strike a careless pose. And whistle a happy tune, And no one ever knows. I'm afraid. The result of this deception, Is very strange to tell. For when I fool the people I fear, I fool myself as well!