Measuring the Burden of Infodemics: Summary of the Methods and Results of the Fifth WHO Infodemic Management Conference.

Background: An infodemic is excess information, including false or misleading information, that spreads in digital and physical environments during a public health emergency. The COVID-19 pandemic has been accompanied by an unprecedented global infodemic that has led to confusion about the benefits of medical and public health interventions, with substantial impact on risk-taking and health-seeking behaviors, eroding trust in health authorities and compromising the effectiveness of public health responses and policies. Standardized measures are needed to quantify the harmful impacts of the infodemic in a systematic and methodologically robust manner, as well as harmonizing highly divergent approaches currently explored for this purpose. This can serve as a foundation for a systematic, evidence-based approach to monitoring, identifying, and mitigating future infodemic harms in emergency preparedness and prevention. Objective: In this paper, we summarize the Fifth World Health Organization (WHO) Infodemic Management Conference structure, proceedings, outcomes, and proposed actions seeking to identify the interdisciplinary approaches and frameworks needed to enable the measurement of the burden of infodemics. Methods: An iterative human-centered design (HCD) approach and concept mapping were used to facilitate focused discussions and allow for the generation of actionable outcomes and recommendations. The discussions included 86 participants representing diverse scientific disciplines and health authorities from 28 countries across all WHO regions, along with observers from civil society and global public health-implementing partners. A thematic map capturing the concepts matching the key contributing factors to the public health burden of infodemics was used throughout the conference to frame and contextualize discussions. Five key areas for immediate action were identified. Results: The 5 key areas for the development of metrics to assess the burden of infodemics and associated interventions included (1) developing standardized definitions and ensuring the adoption thereof; (2) improving the map of concepts influencing the burden of infodemics; (3) conducting a review of evidence, tools, and data sources; (4) setting up a technical working group; and (5) addressing immediate priorities for postpandemic recovery and resilience building. The summary report consolidated group input toward a common vocabulary with standardized terms, concepts, study designs, measures, and tools to estimate the burden of infodemics and the effectiveness of infodemic management interventions. Conclusions: Standardizing measurement is the basis for documenting the burden of infodemics on health systems and population health during emergencies. Investment is needed into the development of practical, affordable, evidence-based, and systematic methods that are legally and ethically balanced for monitoring infodemics; generating diagnostics, infodemic insights, and recommendations; and developing interventions, action-oriented guidance, policies, support options, mechanisms, and tools for infodemic managers and emergency program managers.

Transiently silent acquired antimicrobial resistance: an emerging challenge in susceptibility testing.

Acquisition and expression of antimicrobial resistance (AMR) mechanisms in bacteria are often associated with a fitness cost. Thus, evolutionary adaptation and fitness cost compensation may support the advance of subpopulations with a silent resistance phenotype when the antibiotic selection pressure is absent. However, reports are emerging on the transient nature of silent acquired AMR, describing genetic alterations that can change the expression of these determinants to a clinically relevant level of resistance, and the association with breakthrough infections causing treatment failures. This phenomenon of transiently silent acquired AMR (tsaAMR) is likely to increase, considering the overall expansion of acquired AMR in bacterial pathogens. Moreover, the augmented use of genotypic methods in combination with conventional phenotypic antimicrobial susceptibility testing (AST) will increasingly enable the detection of genotype and phenotype discrepancy. This review defines tsaAMR as acquired antimicrobial resistance genes with a corresponding phenotype within the wild-type distribution or below the clinical breakpoint for susceptibility for which genetic alterations can mediate expression to a clinically relevant level of resistance. References to in vivo resistance development and therapeutic failures caused by selected resistant subpopulations of tsaAMR in Gram-positive and Gram-negative pathogens are given. We also describe the underlying molecular mechanisms, including alterations in the expression, reading frame or copy number of AMR determinants, and discuss the clinical relevance concerning challenges for conventional AST.

Budesonide with Low-Dose 6-Mercaptopurine as a Possible New Treatment for IgG4-Related Sclerosing Cholangitis and Systemic IgG4-Related Disease: A Case Report.

BACKGROUND Systemic IgG4-related disease is a rare disease that can affect the hepatobiliary system and may lead to tissue fibrosis and organ failure. Diagnostic criteria for IgG4-related disease are well established, and systemic glucocorticoids are recommended for initiation of treatment. Besides the beneficial properties of glucocorticoids, the long-term treatment with systemic steroids carries the risk of toxicity, especially in elderly patients, in whom IgG4-related disease is more common. Furthermore, disease relapses may occur during the tapering of steroids. Overall, the optimal treatment approach for maintenance therapy has not been clarified yet and is an area of current clinical research. CASE REPORT We present a patient with IgG4-related sclerosing cholangitis and histologically confirmed systemic (multi-organ) IgG4-related disease who was at increased risk of disease recurrence. The effects of immunosuppressants (prednisolone, 6-mercaptopurine, budesonide) on clinical symptoms, laboratory parameters (AST, ALT, AP, γGT, bilirubin), and imaging examinations (magnetic resonance cholangiography) were documented over 56 months. Control of IgG4-related sclerosing cholangitis was achieved - without systemic prednisolone - with the locally acting glucocorticoid budesonide in combination with low-dose 6-mercaptopurine. During treatment with 6-mercaptopurine, transient hepatotoxicity occurred, which was reversed by intermittent pausing and subsequent dose reduction. In addition, gangrenous cholecystitis occurred as a complication of immunosuppression and was treated by emergency cholecystectomy. CONCLUSIONS Budesonide could be a new treatment modality for IgG4-related sclerosing cholangitis. Systemic manifestations of immunoglobulin G4-related disease can be controlled with low-dose 6-mercaptopurine. Gangrenous cholecystitis may occur as a complication of immunosuppressive treatment.

enAsCas12a Enables CRISPR-Directed Evolution to Screen for Functional Drug Resistance Mutations in Sequences Inaccessible to SpCas9.

While drug resistance mutations provide the gold standard proof for drug target engagement, target deconvolution of inhibitors identified from a phenotypic screen remains challenging. Genetic screening for functional in-frame drug resistance mutations by tiling CRISPR-Cas nucleases across protein coding sequences is a method for identifying a drug's target and binding site. However, the applicability of this approach is constrained by the availability of nuclease target sites across genetic regions that mediate drug resistance upon mutation. In this study, we show that an enhanced AsCas12a variant (enAsCas12a), which harbors an expanded targeting range, facilitates screening for drug resistance mutations with increased activity and resolution in regions that are not accessible to other CRISPR nucleases, including the prototypical SpCas9. Utilizing enAsCas12a, we uncover new drug resistance mutations against inhibitors of NAMPT and KIF11. These findings demonstrate that enAsCas12a is a promising new addition to the CRISPR screening toolbox and allows targeting sites not readily accessible to SpCas9.

Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way?

BACKGROUND: Immune checkpoint inhibitors (ICI) improve survival but cause immune-related adverse events (irAE). We sought to determine if CTCAE classification, IBD biomarkers/endoscopic/histological scores correlate with irAE colitis outcomes. METHODS: A dual-centre retrospective study was performed on patients receiving ICI for melanoma, NSCLC or urothelial cancer from 2012 to 2018. Demographics, clinical data, endoscopies (reanalysed using Mayo/Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores), histology (scored with Nancy Index) and treatment outcomes were analysed. RESULTS: In all, 1074 patients were analysed. Twelve percent (134) developed irAE colitis. Median patient age was 66, 59% were male. CTCAE diarrhoea grade does not correlate with steroid/ infliximab use. G3/4 colitis patients are more likely to need infliximab (p < 0.0001) but colitis grade does not correlate with steroid duration. CRP, albumin and haemoglobin do not correlate with severity. The UCEIS (p = 0.008) and Mayo (p = 0.016) scores correlate with severity/infliximab requirement. Patients with higher Nancy indices (3/4) are more likely to require infliximab (p = 0.03). CONCLUSIONS: CTCAE assessment does not accurately reflect colitis severity and our data do not support its use in isolation, as this may negatively impact timely management. Our data support utilising endoscopic scoring for patients with >grade 1 CTCAE disease, and demonstrate the potential prognostic utility of objective histologic scoring.

Meniscus Root Repair vs Meniscectomy or Nonoperative Management to Prevent Knee Osteoarthritis After Medial Meniscus Root Tears: Clinical and Economic Effectiveness.

BACKGROUND: Medial meniscus root tears are a common knee injury and can lead to accelerated osteoarthritis, which might ultimately result in a total knee replacement. PURPOSE: To compare meniscus repair, meniscectomy, and nonoperative treatment approaches among middle-aged patients in terms of osteoarthritis development, total knee replacement rates (clinical effectiveness), and cost-effectiveness. STUDY DESIGN: Meta-analysis and cost-effectiveness analysis. METHODS: A systematic literature search was conducted. Progression to osteoarthritis was pooled and meta-analyzed. A Markov model projected strategy-specific costs and disutilities in a cohort of 55-year-old patients presenting with a meniscus root tear without osteoarthritis at baseline. Failure rates of repair and meniscectomy procedures and disutilities associated with osteoarthritis, total knee replacement, and revision total knee replacement were accounted for. Utilities, costs, and event rates were based on literature and public databases. Analyses considered a time frame between 5 years and lifetime and explored the effects of parameter uncertainty. RESULTS: Over 10 years, meniscus repair, meniscectomy, and nonoperative treatment led to 53.0%, 99.3%, and 95.1% rates of osteoarthritis and 33.5%, 51.5%, and 45.5% rates of total knee replacement, respectively. Meta-analysis confirmed lower osteoarthritis and total knee replacement rates for meniscus repair versus meniscectomy and nonoperative treatment. Discounted 10-year costs were $22,590 for meniscus repair, as opposed to $31,528 and $25,006 for meniscectomy and nonoperative treatment, respectively; projected quality-adjusted life years were 6.892, 6.533, and 6.693, respectively, yielding meniscus repair to be an economically dominant strategy. Repair was either cost-effective or dominant when compared with meniscectomy and nonoperative treatment across a broad range of assumptions starting from 5 years after surgery. CONCLUSION: Repair of medial meniscus root tears, as compared with total meniscectomy and nonsurgical treatment, leads to less osteoarthritis and is a cost-saving intervention. While small confirmatory randomized clinical head-to-head trials are warranted, the presented evidence seems to point relatively clearly toward adopting meniscus repair as the preferred initial intervention for medial meniscus root tears.

Mobile health messaging service and helpdesk for South African mothers (MomConnect): history, successes and challenges.

MomConnect is a flagship programme of the South African National Department of Health that has reached over 1.5 million pregnant women. Using mobile technology, MomConnect provides pregnant and postpartum women with twice-weekly health information text messages as well as access to a helpdesk for patient queries and feedback. In just 3 years, MomConnect has been taken to scale to reach over 95% of public health facilities and has reached 63% of all pregnant women attending their first antenatal appointment. The helpdesk has received over 300 000 queries at an average of 250 per day from 6% of MomConnect users. The service is entirely free to its users. The rapid deployment of MomConnect has been facilitated by strong government leadership, and an ecosystem of mobile health implementers who had experience of much of the content and technology required. An early decision to design MomConnect for universal coverage has required the use of text-based technologies (short messaging service and Unstructured Supplementary Service Data) that are accessible via even the most basic mobile phones, but cumbersome to use and costly at scale. Unlike previous mobile messaging services in South Africa, MomConnect collects the user's identification number and facility code during registration, enabling future linkages with other health and population databases and geolocated feedback. MomConnect has catalysed additional efforts to strengthen South Africa's digital health architecture. The rapid growth in smartphone penetration presents new opportunities to reduce costs, increase real-time data collection and expand the reach and scope of MomConnect to serve health workers and other patient groups.

Unpacking the performance of a mobile health information messaging program for mothers (MomConnect) in South Africa: evidence on program reach and messaging exposure.

Despite calls to address broader evidence gaps in linking digital technologies to outcome and impact level health indicators, limited attention has been paid to measuring processes pertaining to the performance of programs. In this paper, we assess the program reach and message exposure of a mobile health information messaging program for mothers (MomConnect) in South Africa. In this descriptive study, we draw from system generated data to measure exposure to the program through registration attempts and conversions, message delivery, opt-outs and drop-outs. Using a logit model, we additionally explore determinants for early registration, opt-outs and drop-outs. From August 2014 to April 2017, 1 159 431 women were registered to MomConnect; corresponding to half of women attending antenatal care 1 (ANC1) and nearly 60% of those attending ANC1 estimated to own a mobile phone. In 2016, 26% of registrations started to get women onto MomConnect did not succeed. If registration attempts were converted to successful registrations, coverage of ANC1 attendees would have been 74% in 2016 and 86% in 2017. When considered as percentage of ANC1 attendees with access to a mobile phone, addressing conversion challenges bring registration coverage to an estimated 83%-89% in 2016 and 97%-100% in 2017. Among women registered, nearly 80% of expected short messaging service messages were received. While registration coverage and message delivery success rates exceed those observed for mobile messaging programs elsewhere, study findings highlight opportunities for program improvement and reinforce the need for rigorous and continuous monitoring of delivery systems.

Long-Term Morphological and Microarchitectural Stability of Tissue-Engineered, Patient-Specific Auricles In Vivo.

Current techniques for autologous auricular reconstruction produce substandard ear morphologies with high levels of donor-site morbidity, whereas alloplastic implants demonstrate poor biocompatibility. Tissue engineering, in combination with noninvasive digital photogrammetry and computer-assisted design/computer-aided manufacturing technology, offers an alternative method of auricular reconstruction. Using this method, patient-specific ears composed of collagen scaffolds and auricular chondrocytes have generated auricular cartilage with great fidelity following 3 months of subcutaneous implantation, however, this short time frame may not portend long-term tissue stability. We hypothesized that constructs developed using this technique would undergo continued auricular cartilage maturation without degradation during long-term (6 month) implantation. Full-sized, juvenile human ear constructs were injection molded from high-density collagen hydrogels encapsulating juvenile bovine auricular chondrocytes and implanted subcutaneously on the backs of nude rats for 6 months. Upon explantation, constructs retained overall patient morphology and displayed no evidence of tissue necrosis. Limited contraction occurred in vivo, however, no significant change in size was observed beyond 1 month. Constructs at 6 months showed distinct auricular cartilage microstructure, featuring a self-assembled perichondrial layer, a proteoglycan-rich bulk, and rounded cellular lacunae. Verhoeff's staining also revealed a developing elastin network comparable to native tissue. Biochemical measurements for DNA, glycosaminoglycan, and hydroxyproline content and mechanical properties of aggregate modulus and hydraulic permeability showed engineered tissue to be similar to native cartilage at 6 months. Patient-specific auricular constructs demonstrated long-term stability and increased cartilage tissue development during extended implantation, and offer a potential tissue-engineered solution for the future of auricular reconstructions.

Effect of Ankle Positioning During Hamstring Stretches for Improving Straight Leg Hip Flexion Motion.

OBJECTIVE: To compare the effects of stretching the hamstrings with the ankle in either a plantar-flexed (PF) or dorsiflexed (DF) position for improving straight leg hip flexion range of motion (ROM) over a 4-week period. DESIGN: Randomized, single-blinded, pretest, posttest design. SETTING: Athletic training facility. PARTICIPANTS: Each limb of 34 asymptomatic individuals (15 males, 19 females) was randomly assigned to one of the 3 groups. Twenty-four limbs received hamstring stretches with the ankle in DF, 24 limbs received hamstring stretches with the ankle in PF, and 20 limbs received no stretch (control). INDEPENDENT VARIABLES: Ankle position (PF, DF) during hamstring stretching. MAIN OUTCOME MEASURES: We measured pretest and posttest passive straight leg hip flexion ROM with the test ankle in a neutral position. For the intervention groups, the test limb was passively stretched with the ankle held in end range DF or PF for their respective group. Each stretch was held for 30 seconds for a total of 3 applications. Two treatment sessions were completed per week for a total of 4 weeks. The control limbs received no stretching during the 4-week period. We conducted 1-way analyses of covariance to determine significant changes in ROM between groups (P < 0.05). RESULTS: There was no significant difference between treatment groups (P = 0.90), but a significant difference was found for both the PF (P = 0.04) and DF (P = 0.01) groups when compared with the control group. CONCLUSIONS: Our findings indicate that both stretching the hamstrings in either PF or DF improve straight leg hip ROM compared with a control group. CLINICAL RELEVANCE: The results of this study should be considered by clinicians when determining the optimal stretching techniques aimed at increasing hamstring length.

Is providing elective ventilation in the best interests of potential donors?

In this paper, we examine the lawfulness of a proposal to provide elective ventilation to incompetent patients who are potential organ donors. Under the current legal framework, this depends on whether the best interests test could be satisfied. It might be argued that, because the Mental Capacity Act 2005 (UK) (and the common law) makes it clear that the best interests test is not confined to the patient's clinical interests, but extends to include the individual's own values, wishes and beliefs, the proposal will be in the patient's best interests. We reject this claim. We argue that, as things currently stand, the proposal could not lawfully be justified as a blanket proposition by reference to the best interests test. Accordingly, a modification of the law would be necessary to render the proposal lawful. We conclude with a suggestion about how that could be achieved.

Investigation into the use of short message services to expand uptake of human immunodeficiency virus testing, and whether content and dosage have impact.

OBJECTIVE: South Africa has one of the highest human immunodeficiency virus (HIV) prevalence rates in the world, but despite the well-established benefits of HIV counseling and testing (HCT), there is low uptake of HCT. The study aimed to investigate the effectiveness of using short message services (SMSs) to encourage HCT while interrogating the impact of altering SMS content and dosage (the number of SMSs). MATERIALS AND METHODS: About 2,533 participants were recruited via an SMS sent to 24,000 mobiles randomly sampled from a pre-existing database. Recruits were randomly allocated to four intervention groups that received 3 or 10 informational (INFO) or motivational (MOTI) SMSs, and a control group. After the intervention, participants were prompted to go for HCT, and postintervention assessment was done after 3 weeks. RESULTS: In comparison with the control, receipt of 10 MOTI messages had the most impact on uptake of HCT with a 1.7-fold increased odds of testing (confidence interval 95%; p=0.0036). The lack of efficacy of three SMSs indicates a threshold effect, that is, a minimum number of MOTI SMSs is required. INFO SMSs, whether 3 or 10 were sent, did not have a statistically significant effect. The cost can be calculated for the marginal effect of the SMSs, that is, the cost to get people to test over and above those who were likely to test without the intervention. Use of 10 MOTI SMSs yielded a cost-per-tester of $2.41. CONCLUSIONS: While there are methodological issues apparent in our study, the results demonstrate the potential of SMSs to influence the uptake of HCT, the importance of appropriate content, and the need to determine a threshold for SMS-based interventions. These results indicate a potential for SMSs to be used more generally for interventions encouraging people to take health-related actions, and the need for further research in this field. The reasonable cost-per-tester is promising for the scale-up of such an intervention.