AGO2 promotes tumor progression in KRAS-driven mouse models of non-small cell lung cancer.

Lung cancer is the deadliest malignancy in the United States. Non-small cell lung cancer (NSCLC) accounts for 85% of cases and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g., KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)-a component of the RNA-induced silencing complex (RISC)-physically interacts with RAS and promotes its downstream signaling. We therefore hypothesized that AGO2 could promote KRASG12D-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of Ago2 knockout in the KPC (LSL-KrasG12D/+;p53f/f;Cre) mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stop-floxed KRASG12D allele and biallelic ablation of p53 Simultaneous biallelic ablation of floxed Ago2 inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the KPHetC model, in which the Clara cell-specific CCSP-driven Cre activates KRASG12D and ablates a single p53 allele. In these mice, Ago2 ablation also reduced tumor size and grade. In both models, Ago2 knockout inhibited ERK phosphorylation (pERK) in tumor cells, indicating impaired KRAS signaling. RNA sequencing (RNA-seq) of KPC nodules and nodule-derived organoids demonstrated impaired canonical KRAS signaling with Ago2 ablation. Strikingly, accumulation of pERK in KPC organoids depended on physical interaction of AGO2 and KRAS. Taken together, our data demonstrate a pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work may have future translational relevance.

Toward global availability of low-cost, patient-specific cranial implants: creation and validation of automated CranialRebuild freeware application.

PURPOSE: Financial restrictions limit the options for hermetically precise, patient-specific cranial implants (PSCIs) after decompressive hemicraniectomy (DHC) in low-income countries. Use of image segmentation, modeling software, and 3D printers has lowered costs associated with PSCIs. However, requirements of time and technical expertise have prevented widespread utilization. Our objective was to create a fully automated software algorithm that is able to generate a virtual model (.STL) of a negative of an implant using CT imaging following DHC. METHODS: A freeware algorithm (CranialRebuild) was constructed with the following capabilities: (1) after the upload of digital imaging and communications in medicine files, the normal side is analyzed in reference to the side of DHC, (2) Boolean subtraction is used to obtain a virtual image of the desired implant, and (3) a two-piece virtual model (.STL) of the PSCI mold is generated. In four cadaveric specimens, a standard DHC was performed. Post-DHC CT imaging was used to obtain a .STL of the negative of the implant, which was then printed using poly-lactic acid (PLA). Methylmethacrylate cement was used to generate a PSCI from the mold. The PSCIs were implanted into the index specimens; cosmesis was subjectively evaluated using a 5-point Likert scale. RESULTS: Two specimens were graded as 4/5, indicating that minor post-processing modification was needed for optimal cosmesis. Two specimens were graded as 3/5, indicating that optimal cosmesis could be obtained following moderate post-processing modification. CONCLUSIONS: CranialRebuild can be used to create hermetically precise PSCIs at a fraction of the price of third-party vendors. Validation of this technology has significant implications for the accessibility of customized cranial implants worldwide.

Multiplexed and Ultralow-Input ChIP-seq Enabled by Tagmentation-Based Indexing and Facile Microfluidics.

Epigenome constitutes an important layer that regulates gene expression and dynamics during development and diseases. Extensive efforts have been made to develop epigenome profiling methods using a low number of cells and with high throughput. Chromatin immunoprecipitation (ChIP) is the most important approach for profiling genome-wide epigenetic changes such as histone modifications. In this report, we demonstrate microfluidic ChIPmentation (mu-CM), a microfluidic technology that enables profiling cell samples that individually do not generate enough ChIP DNA for sequencing library preparation. We used a simple microfluidic device to allow eight samples to be processed simultaneously. The samples were indexed differently using a tagmentation-based approach (ChIPmentation) and then merged for library preparation. A histone modification profile for each individual sample was obtained by demultiplexing the sequencing reads based on the indexes. Our technology allowed profiling 20 cells and is well suited for cell-type-specific studies using low-abundance tissues.

Long-term palliation of a malignant colonic anastomotic stricture using a lumen-apposing metal stent (LAMS).

Malignant recurrent colonic strictures at the anastomotic site are difficult to treat long term with traditional uncovered metal stents due to the location and risk for tumour ingrowth. We present a case with the use of a lumen-apposing metal stent (LAMS) to successfully palliate a high-grade obstruction at an anastomotic site without recurrence of obstructive symptoms for 14 months.

Estimating the proportion of nonsense variants undergoing the newly described phenomenon of manufactured splice rescue.

A recent report described a nonsense variant simultaneously creating a donor splice site, resulting in a truncated but functional protein. To explore the generalizability of this unique mechanism, we annotated >115,000 nonsense variants using SpliceAI. Between 0.61% (donor gain delta score >0.8, for high precision) and 2.57% (>0.2, for high sensitivity) of nonsense variants were predicted to create new donor splice sites at or upstream of the stop codon. These variants were less likely than other nonsense variants in the same genes to be classified as pathogenic/likely pathogenic in ClinVar (p < 0.001). Up to 1 in 175 nonsense variants were predicted to result in small in-frame deletions and loss-of-function evasion through this "manufactured splice rescue" mechanism. We urge caution when interpreting nonsense variants where manufactured splice rescue is a strong possibility and correlation with phenotype is challenging, as will often be the case with secondary findings and newborn genomic screening programs.

National burden of rheumatoid arthritis in Canada, 1990-2019: findings from the Global Burden of Disease Study 2019 - a GBD collaborator-led study.

OBJECTIVE: The objectives of this study were: (1) to describe burden of rheumatoid arthritis (RA) and trends from 1990 to 2019 using the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) data, (2) to describe age and sex differences in RA and (3) to compare Canada's RA burden to that of other countries. METHODS: Disease burden indicators included prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs) and disability-adjusted life-years (DALYs). GBD estimated fatal and non-fatal outcomes using published literature, survey data and health insurance claims. Data were analysed by Bayesian meta-regression, cause of death ensemble model and other statistical methods. DALYs for Canada were compared with DALYs of countries with similarly high Socio-Demographic Index values. RESULTS: In Canada, the RA prevalence rate increased by 27% between 1990 and 2019, mortality rate decreased by 27%, YLL rate decreased by 30%, YLD increased by 27% and DALY rate increased by 13%, all age standardised. The decline in RA mortality and YLL rates was especially pronounced after 2002. The disease burden was higher in females for all indicators, and DALY rates were higher among older age groups, peaking at age 75-79 years. Prevalence and DALYs were higher in Canada compared with global rates. CONCLUSION: Trends in RA burden indicators over time and differences by age and sex have important implications for Canadian policy-makers, researchers and care providers. Early identification and management of RA in women may help reduce the overall burden of RA in Canada.

Evaluating site-of-care-related racial disparities in kidney graft failure using a novel federated learning framework.

OBJECTIVES: Racial disparities in kidney transplant access and posttransplant outcomes exist between non-Hispanic Black (NHB) and non-Hispanic White (NHW) patients in the United States, with the site of care being a key contributor. Using multi-site data to examine the effect of site of care on racial disparities, the key challenge is the dilemma in sharing patient-level data due to regulations for protecting patients' privacy. MATERIALS AND METHODS: We developed a federated learning framework, named dGEM-disparity (decentralized algorithm for Generalized linear mixed Effect Model for disparity quantification). Consisting of 2 modules, dGEM-disparity first provides accurately estimated common effects and calibrated hospital-specific effects by requiring only aggregated data from each center and then adopts a counterfactual modeling approach to assess whether the graft failure rates differ if NHB patients had been admitted at transplant centers in the same distribution as NHW patients were admitted. RESULTS: Utilizing United States Renal Data System data from 39 043 adult patients across 73 transplant centers over 10 years, we found that if NHB patients had followed the distribution of NHW patients in admissions, there would be 38 fewer deaths or graft failures per 10 000 NHB patients (95% CI, 35-40) within 1 year of receiving a kidney transplant on average. DISCUSSION: The proposed framework facilitates efficient collaborations in clinical research networks. Additionally, the framework, by using counterfactual modeling to calculate the event rate, allows us to investigate contributions to racial disparities that may occur at the level of site of care. CONCLUSIONS: Our framework is broadly applicable to other decentralized datasets and disparities research related to differential access to care. Ultimately, our proposed framework will advance equity in human health by identifying and addressing hospital-level racial disparities.

Disseminated fungal infection in a patient receiving zanubrutinib.

We report a case of fatal disseminated aspergillosis in the setting of administration of zanubrutinib, a second-generation Bruton's tyrosine kinase inhibitor thought to have a lower rate of immunosuppression-related side effects.

Adding caplacizumab to standard of care in thrombotic thrombocytopenic purpura: a systematic review and meta-analysis.

Immune thrombotic thrombocytopenic purpura (iTTP) is an acquired, fatal microangiopathy if untreated. Randomized controlled trials (RCTs) demonstrated faster time to response with addition of caplacizumab to standard of care (SOC). However, concerns about RCT selection bias and the high cost of caplacizumab warrant examination of all evidence, including real-world observational studies. In this systematic review and meta-analysis, we searched for comparative studies evaluating SOC with or without caplacizumab for the treatment of iTTP. We assessed risk of bias using the Cochrane risk-of-bias-2 tool (RCTs) and the Newcastle-Ottawa Scale (observational studies). The primary efficacy and safety outcomes were all-cause mortality and treatment-emergent bleeding, respectively. Secondary outcomes included exacerbation and relapse, refractory iTTP, and time to response. We included 2 high-quality RCTs and 3 observational studies at high risk of bias comprising 632 total participants. Compared with SOC, caplacizumab was associated with a nonsignificant reduction in the relative risk [RR] of death in RCTs (RR, 0.21; 95% confidence interval [CI], 0.05-1.74) and observational studies (RR, 0.62; 95% CI, 0.07-4.41). Compared with SOC, caplacizumab was associated with an increased bleeding risk in RCTs (RR, 1.37; 95% CI, 1.06-1.77). In observational studies, bleeding risk was not significantly increased (RR, 7.10; 95% CI, 0.90-56.14). Addition of caplacizumab was associated with a significant reduction in refractory iTTP and exacerbation risks and shortened response time but increased relapse risk. Frontline addition of caplacizumab does not significantly reduce all-cause mortality compared with SOC alone, although it reduces refractory disease risk, shortens time to response, and improves exacerbation rates at the expense of increased relapse and bleeding risk.

Best practice guidance for antibiotic audit and feedback interventions in primary care: a modified Delphi study from the Joint Programming Initiative on Antimicrobial resistance: Primary Care Antibiotic Audit and Feedback Network (JPIAMR-PAAN).

BACKGROUND: Primary care is a critical partner for antimicrobial stewardship efforts given its high human antibiotic usage. Peer comparison audit and feedback (A&F) is often used to reduce inappropriate antibiotic prescribing. The design and implementation of A&F may impact its effectiveness. There are no best practice guidelines for peer comparison A&F in antibiotic prescribing in primary care. OBJECTIVE: To develop best practice guidelines for peer comparison A&F for antibiotic prescribing in primary care in high income countries by leveraging international expertise via the Joint Programming Initiative on Antimicrobial Resistance-Primary Care Antibiotic Audit and Feedback Network. METHODS: We used a modified Delphi process to achieve convergence of expert opinions on best practice statements for peer comparison A&F based on existing evidence and theory. Three rounds were performed, each with online surveys and virtual meetings to enable discussion and rating of each best practice statement. A five-point Likert scale was used to rate consensus with a median threshold score of 4 to indicate a consensus statement. RESULTS: The final set of guidelines include 13 best practice statements in four categories: general considerations (n = 3), selecting feedback recipients (n = 1), data and indicator selection (n = 4), and feedback delivery (n = 5). CONCLUSION: We report an expert-derived best practice recommendations for designing and evaluating peer comparison A&F for antibiotic prescribing in primary care. These 13 statements can be used by A&F designers to optimize the impact of their quality improvement interventions, and improve antibiotic prescribing in primary care.

Regional and national antimicrobial stewardship activities: a survey from the Joint Programming Initiative on Antimicrobial Resistance-Primary Care Antibiotic Audit and Feedback Network (JPIAMR-PAAN).

Background: Antibiotic overuse and misuse in primary care are common, highlighting the importance of antimicrobial stewardship (AMS) efforts in this setting. Audit and feedback (A&F) interventions can improve professional practice and performance in some settings. Objectives and methods: To leverage the expertise from international members of the Joint Programming Initiative on Antimicrobial Resistance - Primary care Antibiotic Audit and feedback Network (JPIAMR-PAAN). Network members all have experience of designing and delivering A&F interventions to reduce inappropriate antibiotic prescribing in primary care settings. We aim to introduce the network and explore ongoing A&F activities in member regions. An online survey was administered to all network members to collect regional information. Results: Fifteen respondents from 11 countries provided information on A&F activities in their country, and national/regional antibiotic stewardship programmes or policies. Most countries use electronic medical records as the primary data source, antibiotic appropriateness as the main outcome of feedback, and target GPs as the prescribers of interest. Funding sources varied across countries, which could influence the frequency and quality of A&F interventions. Nine out of 11 countries reported having a national antibiotic stewardship programme or policy, which aim to provide systematic support to ongoing AMS efforts and aid sustainability. Conclusions: The survey identified gaps and opportunities for AMS efforts that include A&F across member countries in Europe, Canada and Australia. JPIAMR-PAAN will continue to leverage its members to produce best practice resources and toolkits for antibiotic A&F interventions in primary care settings and identify research priorities.

Challenges in the development of digital public health interventions and mapped solutions: Findings from a scoping review.

Background: "Digital public health" has emerged from an interest in integrating digital technologies into public health. However, significant challenges which limit the scale and extent of this digital integration in various public health domains have been described. We summarized the literature about these challenges and identified strategies to overcome them. Methods: We adopted Arksey and O'Malley's framework (2005) integrating adaptations by Levac et al. (2010). OVID Medline, Embase, Google Scholar, and 14 government and intergovernmental agency websites were searched using terms related to "digital" and "public health." We included conceptual and explicit descriptions of digital technologies in public health published in English between 2000 and June 2020. We excluded primary research articles about digital health interventions. Data were extracted using a codebook created using the European Public Health Association's conceptual framework for digital public health. Results and analysis: Overall, 163 publications were included from 6953 retrieved articles with the majority (64%, n = 105) published between 2015 and June 2020. Nontechnical challenges to digital integration in public health concerned ethics, policy and governance, health equity, resource gaps, and quality of evidence. Technical challenges included fragmented and unsustainable systems, lack of clear standards, unreliability of available data, infrastructure gaps, and workforce capacity gaps. Identified strategies included securing political commitment, intersectoral collaboration, economic investments, standardized ethical, legal, and regulatory frameworks, adaptive research and evaluation, health workforce capacity building, and transparent communication and public engagement. Conclusion: Developing and implementing digital public health interventions requires efforts that leverage identified strategies to overcome diverse challenges encountered in integrating digital technologies in public health.

A new strategy to reconcile amyloid cross-seeding and amyloid prevention in a binary system of α-synuclein fragmental peptide and hIAPP.

Amyloid cross-seeding and amyloid inhibition are two different research subjects being studied separately for different pathological purposes, in which amyloid cross-seeding targets to study the co-aggregation of different amyloid proteins and potential molecular links between different neurodegenerative diseases, while amyloid inhibition aims to design different molecules for preventing amyloid aggregation. While both amyloid cross-seeding and amyloid inhibition are critical for better understanding the pathological causes of different neurodegenerative diseases including Parkinson disease (PD) and Type 2 diabetes (T2D), less efforts have been made to reconcile the two phenomena. Herein, we proposed a new preventive strategy to demonstrate (a) the cross-seeding of octapeptide TKEQVTNV from α-synuclein (associated with PD) with hIAPP (associated with T2D) and (b) the cross-seeding-promoted hIAPP fibrillization and cross-seeding-reduced hIAPP toxicity. Collective results confirmed that TKEQVTNV can indeed cross-seed with hIAPP monomers and oligomers, not protofibrils, to form ß-structure-rich fibrils and to accelerate hIAPP fibrillization. Moreover, such cross-seeding-induced promotion effect by TKEQVTNV also rescued the pancreatic cells from hIAPP-induced cytotoxicity by increasing cell viability and reducing cell apoptosis simultaneously. This work provides a new angle to discover amyloid fragments and use them as amyloid modulators (inhibitors or promotors) to interfere with amyloid aggregation of other amyloid proteins, as well as sequence/structure basis to explore the amyloid cross-seeding between different amyloid proteins that may help explain a potential molecular talk between different neurodegenerative diseases.

Primary Dural Repair via an Endoscopic Endonasal Corridor: Preliminary Development of a 3D-Printed Model for Training.

Objectives Endonasal suturing is an investigational method for dural repair that has been reported to decrease the incidence of cerebrospinal fluid fistula. This method requires handling of single-shaft instrumentation in the narrow endonasal corridor. In this study, we designed a low-cost, surgical model using three-dimensional (3D) printing technology to simulate dural repair through the endonasal corridor and subsequently assess the utility of the model for surgical training. Methods Using an Ultimaker 2+ printer, a 3D-printed replica of the cranial base and nasal cavity was fitted with tissue allograft to recapitulate the dural layer. Residents, fellows, and attending surgeons were asked to place two sutures using a 0-degree endoscope and single-shaft needle driver. Task completion time was recorded. Participants were asked to fill out a Likert scale questionnaire after the experiment. Results Twenty-six participants were separated into groups based on their prior endoscope experience: novice, intermediate, and expert. Twenty-one (95.5%) residents and fellows rated the model as "excellent" or "good" in enhancing their technical skills with endoscopic instrumentation. Three of four (75%) of attendings felt that the model was "excellent" or "good" in usefulness for training in dural suturing. Novice participants required an average of 11 minutes for task completion, as compared with 8.7 minutes for intermediates and 5.7 minutes for experts. Conclusion The proposed model appears to be highly effective in enhancing the endoscopic skills and recapitulating the task of dural repair. Such a low-cost model may be especially important in enhancing endoscopic facility in countries/regions with limited access to cadaveric specimens.

The Impact of C1 Anterior Arch Preservation on Spine Stability After Odontoidectomy: Systematic Review and Meta-Analysis.

BACKGROUND: Odontoidectomy for symptomatic irreducible ventral brainstem compression at the craniovertebral junction may result in spine instability requiring subsequent instrumentation. There is no consensus on the importance of C1 anterior arch preservation in prevention of iatrogenic instability. We conducted a systematic review of the impact of C1 anterior arch preservation on postodontoidectomy spine stability. METHODS: PubMed, Embase, Scopus, Web of Science, and Cochrane were searched following the PRISMA guidelines to include studies of patients undergoing odontoidectomy. Random-effect model meta-analyses were performed to compare spine stability between C1 anterior arch preservation versus removal and posttreatment outcomes between transoral approaches (TOAs) versus endoscopic endonasal approaches (EEAs). RESULTS: We included 27 studies comprising 462 patients. The most common lesions were basilar invagination (73.3%) and degenerative arthritis (12.6%). Symptoms included myelopathy (72%) and neck pain (43.9%). Odontoidectomy was performed through TOA (56.1%) and EEA corridors (34.4%). The C1 anterior arch was preserved in 16.7% of cases. Postodontoidectomy stabilization was performed in 83.3% patients. Median follow-up was 27 months (range, 0.1-145). Rates of spine instability were significantly lower (P = 0.004) when the C1 anterior arch was preserved. Postoperative clinical improvement and pooled complications were reported in 78.8% and 12.6% of patients, respectively, with no significant differences between TOA and EEA (P = 0.892; P = 0.346). Patients undergoing EEA had significantly higher rates of intraoperative cerebrospinal fluid leaks (P = 0.002). CONCLUSIONS: Odontoidectomy is safe and effective for treating craniovertebral junction lesions. Preservation of the C1 anterior arch seems to improve maintenance of spine stability. TOA and EEA show comparable outcomes and complication rates.

Interactive effect of cigarette smoke extract and world trade center dust particles on airway cell cytotoxicity.

Rescue workers and residents exposed to the environment surrounding the collapse of the World Trade Center (WTC) on September 11, 2001, have suffered a disproportionate incidence of chronic lung disease attributed to the inhalation of airborne dust. To date, the pathophysiology of this lung disease is poorly understood. The aim of this study was to examine whether airborne dust contaminants recovered from the surrounding area 24-48 h after the collapse of the WTC demonstrate direct cytotoxicity to two airway cell types that were most directly exposed to inhaled dust, airway epithelial and smooth muscle cells. It was also of interest to determine whether the presence of these dusts could modulate the effects of cigarette smoke on these cell types in that some of the individuals who responded to the collapse site were also smokers. Human cultured airway epithelial (BEAS-2B) cells were exposed to 10% cigarette smoke extract (CSE), WTC dust particles (10-53 µm; 0.01-0.5 µg/µl), or a combination of the two for 2-24 h. Cell viability was measured by determining mitochondrial integrity (MTT assays) and apoptosis (poly-ADP-ribose polymerase [PARP] immunoblotting). Conditioned cell culture media recovered from the CSE- and/or WTC dust-exposed BEAS-2B cells were then applied to cultured human airway smooth muscle cells that were subsequently assayed for mitochondrial integrity and their ability to synthesize cyclic AMP (a regulator of airway smooth muscle constriction). BEAS-2B cells underwent necrotic cell death following exposure to WTC dust or CSE for 2-24 h without evidence of apoptosis. Smooth muscle cells demonstrated cellular toxicity and enhanced cyclic AMP synthesis following exposure to conditioned media from WTC- or CSE-exposed epithelial cells. These acute toxicity assays of WTC dust and CSE offer insights into lung cell toxicity that may contribute to the pathophysiology of chronic lung disease in workers and residents exposed to WTC dust. These studies clearly showed that WTC dust (at least the supercoarse particle fraction) or CSE alone exerted direct adverse effects on airway epithelial and smooth muscle cells, and altered the signaling properties of airway smooth muscle cells. In addition the combination of CSE and WTC exerted an interactive effect on cell toxicity. It remains to be determined whether these initial cell death events might account, in part, for the chronic lung effects associated with WTC dust exposure among First Responders and others.

Defining the Scope of Digital Public Health and Its Implications for Policy, Practice, and Research: Protocol for a Scoping Review.

BACKGROUND: There has been rapid development and application of digital technologies in public health domains, which are considered to have the potential to transform public health. However, this growing interest in digital technologies in public health has not been accompanied by a clarity of scope to guide policy, practice, and research in this rapidly emergent field. OBJECTIVE: This scoping review seeks to determine the scope of digital health as described by public health researchers and practitioners and to consolidate a conceptual framework of digital public health. METHODS: The review follows Arksey and O'Malley's framework for conducting scoping reviews with improvements as suggested by Levac et al. The search strategy will be applied to Embase, Medline, and Google Scholar. A grey literature search will be conducted on intergovernmental agency websites and country-specific websites. Titles and abstracts will be reviewed by independent reviewers, while full-text reviews will be conducted by 2 reviewers to determine eligibility based on prespecified inclusion and exclusion criteria. The data will be coded in an iterative approach using the best-fit framework analysis methodology. RESULTS: This research project received funding from the British Columbia Centre for Disease Control Foundation for Population and Public Health on January 1, 2020. The initial search was conducted on June 1, 2020 and returned 6953 articles in total. After deduplication, 4523 abstracts were reviewed, and 227 articles have been included in the review. Ethical approval is not required for this review as it uses publicly available data. CONCLUSIONS: We anticipate that the findings of the scoping review will contribute relevant evidence to health policy makers and public health practitioners involved in planning, funding, and delivering health services that leverage digital technologies. Results of the review will be strategically disseminated through publications in scientific journals, conferences, and engagement with relevant stakeholders. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/27686.

Defining Digital Public Health and the Role of Digitization, Digitalization, and Digital Transformation: Scoping Review.

BACKGROUND: The recent proliferation and application of digital technologies in public health has spurred interest in digital public health. However, as yet, there appears to be a lack of conceptual clarity and consensus on its definition. OBJECTIVE: In this scoping review, we seek to assess formal and informal definitions of digital public health in the literature and to understand how these definitions have been conceptualized in relation to digitization, digitalization, and digital transformation. METHODS: We conducted a scoping literature search in Ovid MEDLINE, Embase, Google Scholar, and 14 government and intergovernmental agency websites encompassing 6 geographic regions. Among a total of 409 full articles identified, we reviewed 11 publications that either formally defined digital public health or informally described the integration of digital technologies into public health in relation to digitization, digitalization, and digital transformation, and we conducted a thematic analysis of the identified definitions. RESULTS: Two explicit definitions of digital public health were identified, each with divergent meanings. The first definition suggested digital public health was a reimagination of public health using new ways of working, blending established public health wisdom with new digital concepts and tools. The second definition highlighted digital public health as an asset to achieve existing public health goals. In relation to public health, digitization was used to refer to the technical process of converting analog records to digital data, digitalization referred to the integration of digital technologies into public health operations, and digital transformation was used to describe a cultural shift that pervasively integrates digital technologies and reorganizes services on the basis of the health needs of the public. CONCLUSIONS: The definition of digital public health remains contested in the literature. Public health researchers and practitioners need to clarify these conceptual definitions to harness opportunities to integrate digital technologies into public health in a way that maximizes their potential to improve public health outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/preprints.27686.

On the imperative of thinking through the ethical, health equity, and social justice possibilities and limits of digital technologies in public health.

The COVID-19 pandemic has demonstrated both the positive and negative use, usefulness, and impact of digital technologies in public health. Digitalization can help advance and sustain the core functions of public health, including health promotion and prevention, epidemiological surveillance, and response to emergent health issues. Digital technologies are thus-in some areas of public discourse-presented as being both necessary and inevitable requirements to address routine and emergency public health issues. However, the circumstances, ways, and extent to which they apply remain a subject of critical reflection and empirical investigation. In this commentary, we argue that we must think through the use of digital technologies in public health and that their usefulness must be assessed in relation to their short- and long-term ethical, health equity, and social justice implications. Neither a sense of digital technological optimism and determinism nor the demands of addressing pressing public health issues should override critical assessment before development and implementation. The urgency of addressing public health emergencies such as the ongoing COVID-19 pandemic requires prompt and effective action, including action facilitated by digital technologies. Nevertheless, a sense of urgency cannot be an excuse or a substitute for a critical assessment of the tools employed.

RéSUMé: La pandémie de COVID-19 a montré les aspects positifs et négatifs de l'utilisation, de l'utilité et de l'impact des technologies numériques en santé publique. La numérisation peut contribuer à promouvoir et à soutenir les fonctions de base de la santé publique, dont la promotion de la santé, la prévention, la surveillance épidémiologique et la riposte aux nouvelles crises sanitaires. Les technologies numériques sont donc­dans certaines parties du discours public­présentées comme étant à la fois nécessaires et inévitables pour résoudre les problèmes de santé publique ordinaires ou urgents. Par contre, les circonstances, les moyens et la mesure dans laquelle elles s'appliquent font encore l'objet d'une réflexion critique et d'une investigation empirique. Dans ce commentaire, nous faisons valoir qu'il faut bien réfléchir à l'utilisation des technologies numériques en santé publique, et que leur utilité doit être analysée par rapport à leurs conséquences à court et à long terme sur l'éthique, l'équité en santé et la justice sociale. Ni les sentiments d'optimisme et de déterminisme à l'égard des technologies numériques, ni la nécessité de résoudre les problèmes de santé publique pressants ne devraient prendre le dessus sur l'analyse critique avant leur développement et leur mise en œuvre. L'urgence de résoudre des crises sanitaires comme la pandémie actuelle de COVID-19 nécessite une action rapide et efficace, et cette action peut être facilitée par les technologies numériques. Néanmoins, le sentiment d'urgence ne doit pas être une excuse et ne peut pas remplacer une analyse critique des outils employés.

Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer.

Multi-tyrosine kinase inhibitors (MTKIs) have thus far had limited success in the treatment of castration-resistant prostate cancer (CRPC). Here, we report a phase I-cleared orally bioavailable MTKI, ESK981, with a novel autophagy inhibitory property that decreased tumor growth in diverse preclinical models of CRPC. The anti-tumor activity of ESK981 was maximized in immunocompetent tumor environments where it upregulated CXCL10 expression through the interferon gamma pathway and promoted functional T cell infiltration, which resulted in enhanced therapeutic response to immune checkpoint blockade. Mechanistically, we identify the lipid kinase PIKfyve as the direct target of ESK981. PIKfyve-knockdown recapitulated ESK981's anti-tumor activity and enhanced the therapeutic benefit of immune checkpoint blockade. Our study reveals that targeting PIKfyve via ESK981 turns tumors from cold into hot through inhibition of autophagy, which may prime the tumor immune microenvironment in advanced prostate cancer patients and be an effective treatment strategy alone or in combination with immunotherapies.