Macrophage and neutrophil death programs differentially confer resistance to tuberculosis.

Apoptosis can potently defend against intracellular pathogens by directly killing microbes and eliminating their replicative niche. However, the reported ability of Mycobacterium tuberculosis to restrict apoptotic pathways in macrophages in vitro has led to apoptosis being dismissed as a host-protective process in tuberculosis despite a lack of in vivo evidence. Here we define crucial in vivo functions of the death receptor-mediated and BCL-2-regulated apoptosis pathways in mediating protection against tuberculosis by eliminating distinct populations of infected macrophages and neutrophils and priming T cell responses. We further show that apoptotic pathways can be targeted therapeutically with clinical-stage compounds that antagonize inhibitor of apoptosis (IAP) proteins to promote clearance of M. tuberculosis in mice. These findings reveal that any inhibition of apoptosis by M. tuberculosis is incomplete in vivo, advancing our understanding of host-protective responses to tuberculosis (TB) and revealing host pathways that may be targetable for treatment of disease.

Bump-and-Hole Engineering Identifies Specific Substrates of Glycosyltransferases in Living Cells.

Studying posttranslational modifications classically relies on experimental strategies that oversimplify the complex biosynthetic machineries of living cells. Protein glycosylation contributes to essential biological processes, but correlating glycan structure, underlying protein, and disease-relevant biosynthetic regulation is currently elusive. Here, we engineer living cells to tag glycans with editable chemical functionalities while providing information on biosynthesis, physiological context, and glycan fine structure. We introduce a non-natural substrate biosynthetic pathway and use engineered glycosyltransferases to incorporate chemically tagged sugars into the cell surface glycome of the living cell. We apply the strategy to a particularly redundant yet disease-relevant human glycosyltransferase family, the polypeptide N-acetylgalactosaminyl transferases. This approach bestows a gain-of-chemical-functionality modification on cells, where the products of individual glycosyltransferases can be selectively characterized or manipulated to understand glycan contribution to major physiological processes.

Chronic kidney disease may evoke anxiety by altering CRH expression in the amygdala and tryptophan metabolism in rats.

Chronic kidney disease (CKD) is associated with anxiety; however, its exact mechanism is not well understood. Therefore, the aim of the present study was to assess the effect of moderate CKD on anxiety in rats. 5/6 nephrectomy was performed in male Wistar rats. 7 weeks after, anxiety-like behavior was assessed by elevated plus maze (EPM), open field (OF), and marble burying (MB) tests. At weeks 8 and 9, urinalysis was performed, and blood and amygdala samples were collected, respectively. In the amygdala, the gene expression of Avp and the gene and protein expression of Crh, Crhr1, and Crhr2 were analyzed. Furthermore, the plasma concentration of corticosterone, uremic toxins, and tryptophan metabolites was measured by UHPLC-MS/MS. Laboratory tests confirmed the development of CKD. In the CKD group, the closed arm time increased; the central time and the total number of entries decreased in the EPM. There was a reduction in rearing, central distance and time in the OF, and fewer interactions with marbles were detected during MB. CKD evoked an upregulation of gene expression of Crh, Crhr1, and Crhr2, but not Avp, in the amygdala. However, there was no alteration in protein expression. In the CKD group, plasma concentrations of p-cresyl-sulfate, indoxyl-sulfate, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid, xanthurenic acid, 5-hydroxyindoleacetic acid, picolinic acid, and quinolinic acid increased. However, the levels of tryptophan, tryptamine, 5-hydroxytryptophan, serotonin, and tyrosine decreased. In conclusion, moderate CKD evoked anxiety-like behavior that might be mediated by the accumulation of uremic toxins and metabolites of the kynurenine pathway, but the contribution of the amygdalar CRH system to the development of anxiety seems to be negligible at this stage.

Evaluation of a population-wide, systematic screening initiative for tuberculosis on Daru island, Western Province, Papua New Guinea.

BACKGROUND: A population-wide, systematic screening initiative for tuberculosis (TB) was implemented on Daru island in the Western Province of Papua New Guinea, where TB is known to be highly prevalent. The initiative used a mobile van equipped with a digital X-ray device, computer-aided detection (CAD) software to identify TB-related abnormalities on chest radiographs, and GeneXpert machines for follow-on diagnostic testing. We describe the results of the TB screening initiative, evaluate its population-level impact and examine risk factors associated with TB detection. METHODS: Through a retrospective review of screening data, we assessed the effectiveness of the screening by examining the enrolment coverage and the proportion of people with TB among screened subjects. A cascade analysis was performed to illustrate the flow of participants in the screening algorithm. We conducted univariate and multivariate analyses to identify factors associated with TB. Furthermore, we estimated the number of additional cases detected by the project by examining the trend of routine TB case notifications during the intervention period, compared to the historical baseline cases and trend-adjusted expected cases. RESULTS: Of the island's 18,854 residents, 8,085 (42.9%) were enrolled and 7,970 (98.6%) had chest X-ray interpreted by the CAD4TB software. A total of 1,116 (14.0%) participants were considered to have abnormal CXR. A total of 69 Xpert-positive cases were diagnosed, resulting in a detection rate of 853 per 100 000 population screened. 19.4% of people with TB had resistance to rifampicin. People who were in older age groups (aOR 6.6, 95%CI: 1.5-29.1 for the 45-59 age group), were severely underweight (aOR 2.5, 95%CI:1.0-6.1) or underweight (aOR 2.1, 95%CI: 1.1-3.8), lived in households < 5 people (aOR 3.4, 95%CI:1.8-6.6) and had a past history of TB (aOR 2.1, 95%CI: 1.2-3.6) were more likely to have TB. The number of bacteriologically confirmed TB notified during the intervention period was 79.3% and 90.8% higher than baseline notifications and forecasted notifications, respectively. CONCLUSION: The screening project demonstrated its effectiveness with the high Xpert-positive TB prevalence among the participants and by successfully yielding additional cases of bacteriologically confirmed TB including rifampicin-resistant TB. The results and lessons learnt from the project should inform future TB screening initiatives in Papua New Guinea.

The impact of health insurance on maternal and reproductive health service utilization and financial protection in low- and lower middle-income countries: a systematic review of the evidence.

BACKGROUND: Low- and middle-income countries have committed to achieving universal health coverage (UHC) as a means to enhance access to services and improve financial protection. One of the key health financing reforms to achieve UHC is the introduction or expansion of health insurance to enhance access to basic health services, including maternal and reproductive health care. However, there is a paucity of evidence of the extent to which these reforms have had impact on the main policy objectives of enhancing service utilization and financial protection. The aim of this systematic review is to assess the existing evidence on the causal impact of health insurance on maternal and reproductive health service utilization and financial protection in low- and lower middle-income countries. METHODS: The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search included six databases: Medline, Embase, Web of Science, Cochrane, CINAHL, and Scopus as of 23rd May 2023. The keywords included health insurance, impact, utilisation, financial protection, and maternal and reproductive health. The search was followed by independent title and abstract screening and full text review by two reviewers using the Covidence software. Studies published in English since 2010, which reported on the impact of health insurance on maternal and reproductive health utilisation and or financial protection were included in the review. The ROBINS-I tool was used to assess the quality of the included studies. RESULTS: A total of 17 studies fulfilled the inclusion criteria. The majority of the studies (82.4%, n = 14) were nationally representative. Most studies found that health insurance had a significant positive impact on having at least four antenatal care (ANC) visits, delivery at a health facility and having a delivery assisted by a skilled attendant with average treatment effects ranging from 0.02 to 0.11, 0.03 to 0.34 and 0.03 to 0.23 respectively. There was no evidence that health insurance had increased postnatal care, access to contraception and financial protection for maternal and reproductive health services. Various maternal and reproductive health indicators were reported in studies. ANC had the greatest number of reported indicators (n = 10), followed by financial protection (n = 6), postnatal care (n = 5), and delivery care (n = 4). The overall quality of the evidence was moderate based on the risk of bias assessment. CONCLUSION: The introduction or expansion of various types of health insurance can be a useful intervention to improve ANC (receiving at least four ANC visits) and delivery care (delivery at health facility and delivery assisted by skilled birth attendant) service utilization in low- and lower-middle-income countries. Implementation of health insurance could enable countries' progress towards UHC and reduce maternal mortality. However, more research using rigorous impact evaluation methods is needed to investigate the causal impact of health insurance coverage on postnatal care utilization, contraceptive use and financial protection both in the general population and by socioeconomic status. TRIAL REGISTRATION: This study was registered with Prospero (CRD42021285776).

Efficacy of a high-intensity home stretching device and traditional physical therapy in non-operative management of adhesive capsulitis - a prospective, randomized control trial.

BACKGROUND: Historically, in-person physical therapy serves as a foundational component of nonoperative treatment of adhesive capsulitis (AC). This study compares the effectiveness of an at-home high-intensity stretch (HIS) device to traditional physical therapy (PT) and to PT in combination with the HIS device. We hypothesize that the HIS device will be as effective as PT alone or as combination therapy in the first-line treatment of AC and use of the HIS device will exhibit improvement at higher rate. METHODS: Thirty-four patients with idiopathic adhesive capsulitis and a minimum of 12 months follow-up were included in this study. Patients were randomized into one of the three groups: HIS device, PT alone, or HIS device + PT. Passive range of motion (ROM), American Shoulder and Elbow Surgeons (ASES), and Simple Shoulder Test (SST) scores were measured. Additionally, patient satisfaction, compliance and complications were recorded. Paired t-test, ANOVA and Chi-squared tests were used in analysis. RESULTS: Final ROM in all planes improved for all groups compared to baseline (p < 0.001), with only HIS device group able to restore > 95% of contralateral ROM in all planes at final follow-up. Patients with PT alone were on average slowest to improve ROM from baseline, at 3 months, 6 months, and 1 year in all planes except internal rotation. ASES and SST scores improved for all groups when compared to baseline (p < 0.001). Use of HIS-device resulted in greater improvement in SST and ASES Total scores compared to PT alone (p = 0.045, and p = 0.048, respectively). CONCLUSIONS: Use of an at-home high-intensity stretching device for conservative treatment of idiopathic adhesive capsulitis improves outcomes in ROM and in ASES and SST scores both when used as an adjunct to physical therapy and when used alone. TRIAL REGISTRATION: The study protocol was registered at www. CLINICALTRIALS: gov (20/05/2022, NCT05384093).

Revision reverse shoulder arthroplasty for the management of baseplate failure: an analysis of 676 revision reverse shoulder arthroplasty procedures.

BACKGROUND: Baseplate failure in reverse shoulder arthroplasty (RSA) is a rare but potentially catastrophic complication owing to poor patient outcomes and significant glenoid bone loss. The purpose of this study was to report on the prevalence, causes, and outcomes of revision RSA (rRSA) for baseplate failure or loosening. METHODS: A retrospective review of our institutional database was performed to identify all patients treated for a failed RSA from 2006 to 2021 who required revision to another RSA (rRSA) performed by a single surgeon. A total of 676 failed RSA procedures were identified, and further analysis identified 46 patients (6.8%) who underwent rRSA for baseplate failure with a confirmed loose baseplate at the time of rRSA. The primary outcome was repeated failure of the reimplanted baseplate following rRSA. The mode of failure associated with baseplate failure was stratified into 1 of 3 groups: aseptic, septic, or traumatic. Twenty-four patients underwent primary revision, and 22 had undergone >1 previous arthroplasty prior to undergoing re-revision. Five patients underwent previous rRSA for baseplate failure performed by an outside surgeon. The criteria for secondary outcome analysis of final American Shoulder and Elbow Surgeons score, Simple Shoulder Test score, and range of motion were met by 32 patients and 23 patients at 1- and 2-year follow-up, respectively. RESULTS: Three patients (6.5%) had repeated baseplate failure requiring re-revision; 2 had baseplate failure at <1 year with associated periprosthetic infections and underwent conversion to hemiarthroplasty. The third patient experienced traumatic failure at 10 years and underwent successful rRSA. The mean American Shoulder and Elbow Surgeons scores at 1 and 2 years were 62.3 and 61.7, respectively. There was no significant difference in outcomes based on mode of baseplate failure (P = .232) or total arthroplasty burden (P = .305) at 1 year. There were 13 total complications in 11 patients, 5 of which required reoperation for reasons other than baseplate failure. CONCLUSION: In this study, rRSA for baseplate failure constituted 6.8% of all revisions performed over a period of 15 years. Re-revision for recurrent baseplate failure was required in 3 of 46 patients (6.5%). Complications and reoperation rates were higher than those for primary RSA but outcomes were comparable for revision of failed anatomic shoulder arthroplasty.

Do preoperative scapular fractures affect long-term outcomes after reverse shoulder arthroplasty?

BACKGROUND: Postoperative scapular stress fractures (SSFs) are a formidable problem after reverse shoulder arthroplasty (RSA). Less is known about patients who have these fractures preoperatively. The primary aim of this study was to examine postoperative satisfaction in patients undergoing primary RSA who have preoperative SSF and compared to a matched cohort without preoperative fracture. The secondary aim was to examine the differences in patient-reported outcomes between and within study cohorts. METHODS: A retrospective chart review of primary RSAs performed by a single surgeon from 2000 to 2020 was conducted. Patients diagnosed with cuff tear arthropathy (CTA), massive cuff tear (MCT), or rheumatoid arthritis (RA) were included. Five hundred twenty-five shoulders met inclusion criteria. Fractures identified on preoperative computed tomography scans were divided into 3 groups: (1) os acromiale, (2) multifragments (MFs), and (3) Levy types. Seventy-two shoulders had an occurrence of SSF. The remaining 453 shoulders were separated into a nonfractured cohort. American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) and visual analog scale (VAS) scores were compared pre- and postoperatively in the total fracture group and the nonfractured group cohort. The multifragment subgroup was also compared to the pooled Os/Levy subgroup. RESULTS: The total incidence of SSF in all shoulders was 13.7%. There was a difference in satisfaction scores at all time points between the nonfracture (7.9 ± 2.8) and total fracture group (5.4 ± 3.6, P < .001, at last visit). There was also a greater ASES total score in the nonfractured group vs the total fracture group at the final visit (69.4 ± 23.4 and 62.1 ± 24.2; P = .02). The MF group had worse ASES functional or VAS functional scores than the Os/Levy group at all time points: at 1 year, ASES function: MF 24.2 ± 14.5 and Os/Levy 30.7 ± 14.2 (P = .045); at 2 years, ASES function: MF 21.4 ± 14.4 and Os/Levy 35.5 ± 10.6 (P < .001); and at last follow-up, VAS function: MF 4.8 ± 2.8 and Os/Levy 6.4 ± 3.2 (P = .023). DISCUSSION: Scapular fractures were proportionally most common in patients diagnosed with CTA (16.3%) compared with a 9.2% and 8.6% incidence in patients diagnosed with MCT and RA, respectively. Patients with preoperative SSF still see an improvement in ASES scores after RSA but do have lower satisfaction scores compared with the nonfractured cohort. The multifragment fracture group has lower functional and satisfaction scores at all postoperative time points compared with both the nonfracture and the Os/Levy fracture group.

Factors affecting risk of recurrence with periprosthetic infection in shoulder arthroplasty.

BACKGROUND: The goal of treating periprosthetic infection, besides its eradication, is to avoid recurrence. The purpose of this study was to evaluate the impact of increasing Infection Severity (IS) score (based on the 2018 International Consensus Meeting on Orthopedic Infections statement), single-stage revision, and pathogenicity of the infective organism on the risk of infection recurrence. METHODS: A database of 790 revisions performed by a single surgeon from 2004-2020 was reviewed for patients with minimum 2-year follow-up and ≥1 positive culture finding and/or pathology result from the revision surgical procedure. In total, 157 cases performed in 144 patients met the inclusion criteria. These cases were then categorized by infection probability (IS score) according to the 2018 consensus statement. Of 157 cases, 46 (29%) were classified as definitely or probably infected; 25 (16%), possibly infected; and 86 (55%), unlikely to be infected. Additionally, patients were grouped by single-stage surgery and pathogenicity of the infective organism. RESULTS: A recurrence in this study was classified as the growth of the same organism in any patient requiring revision surgery. The 86 cases in the group with unlikely infection showed a recurrence rate of 2.3%. The 25 cases in the group with possible infection showed a recurrence rate of 12%. The 46 cases in the group with definite or probable infection showed a recurrence rate of 17.4%. Patients in the definite/probable infection group had a higher rate of recurrence than those in the groups with possible infection and unlikely infection (P = .009). The IS score was higher in the recurrence group than the non-recurrence group (7.5 ± 4.3 vs. 3.9 ± 3.4, P < .001). Overall, patients who underwent 1-stage revision had a 5.0% recurrence rate, but among the 34 patients with an infection classification of definite or probable who underwent 1-stage revision, the recurrence rate was 5.9%. Cases of highly virulent methicillin-resistant Staphylococcus aureus also showed a recurrence rate of 30.8% compared with 4.0% and 5.9% for Cutibacterium acnes and coagulase-negative staphylococci, respectively (P = .005). CONCLUSION: Recurrent infection after treatment of a periprosthetic infection is associated with increasing severity scores, as defined in the 2018 consensus statement, and more aggressive microorganisms. However, a single-stage surgical procedure, even in patients with higher IS scores, did not impart a significantly increased risk of recurrence.

A Restricted Functional Balancing Technique for Total Knee Arthroplasty With a Varus Deformity: Does a Medial Soft-Tissue Release Result in a Worse Outcome?

BACKGROUND: A functional alignment technique for total knee arthroplasty (TKA) utilizes implant position modifications to balance the soft tissues. There is concern that, in some cases, extreme coronal and tibial component alignment could facilitate early implant failure. To be cautious, a restricted functional alignment may be used. The purpose of our study was to evaluate the results of TKA in patients who have varus deformities using a restricted functional alignment technique. We hypothesized that adding a medial soft-tissue release within restricted boundaries would not result in inferior outcomes. METHODS: A retrospective review was performed on robotic arm-assisted TKA patients with varus deformities utilizing a functional balancing strategy with a three-degree varus coronal limb and tibial component alignment restriction. Outcome scores of those patients still requiring a medial-soft tissue release were compared to those without for inferior outcomes. RESULTS: A total of 202 of 259 (78.0%) knees were able to be balanced without any medial soft-tissue release with an average final hip-knee-ankle alignment of 1.9° varus. The remaining 57 knees required a medial soft-tissue release. They had an average final hip-knee-ankle of 2.8° varus and an average medial proximal tibial angle of 2.5° varus. Comparing the cohorts without and with a release, at final follow-up averaging two years, there was not a statistically significant difference in Knee Society-Knee Score (97.7 and 98.4, P = .525), Functional Score (86.7 and 88.7, P = .514), Forgotten Joint Score (59.8 and 66.6, P = .136), and Knee Injury Osteoarthritis Outcome Survey for Joint Replacement Junior Score (79.5 and 84.8, P = .066). CONCLUSIONS: Utilizing a restrictive functional balancing strategy for TKA minimizes the need for soft-tissue releases and provides for excellent overall outcomes. An additional medial soft-tissue release can still be utilized without an inferior average two-year outcome.

Atrial fibrillation inpatient management patterns and clinical outcomes during the conflict in Syria: An observational cohort study.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia worldwide. However, there is no data on AF inpatient management strategies and clinical outcomes in Syria. OBJECTIVES: The study aims were to review the inpatient management of patients with AF and assess cardiovascular (CV) mortality in a tertiary cardiology centre in Latakia, Syria. METHODS: A single-centre retrospective observational cohort study was conducted at Tishreen's University Hospital, Latakia, Syria, from June 2021 to June 2023. Patients ≥16 years of age presenting and being treated for AF as the primary diagnosis with or without a thromboembolic event were included. Medical records were examined for patients' demographics, laboratory results, treatment plans and inpatient details. Studied outcomes include inpatient all-cause and CV mortality, ischemic and bleeding events, and conversion to sinus rhythm (SR). RESULTS: The study included 596 patients. The median age was 58, and 61% were males. 121 patients (20.3%) were known to have AF. A rhythm control strategy was pursued in 39% of patients. Ischemic and bleeding events occurred in 62 (11%) and 12 (2%), respectively. CV and all-cause mortality occurred in 28 (4.7%) and 31 patients (5%), respectively. The presence of valvular heart disease (VHD) (adjusted odds ratio (aOR) = 9.1, 95% confidence interval (CI): 1.7 to 55.1, p < .001), thyroid disease (aOR: 9.7, 95% CI = 1.2 to 91.6, p < .001) and chronic obstructive pulmonary disease (COPD) (aOR: 82, 95% CI: 12.7 to 71, p < .001) were independent risk factors of increased CV inpatient mortality. CONCLUSION: Syrian inpatients admitted with AF in Latakia are relatively younger than those in other countries. Active thyroid disease, COPD and VHD were independent risk factors of inpatient CV mortality with AF.

Nature-based solutions for coastal risk management in the Mediterranean basin: A literature review.

The Mediterranean basin is one of the most vulnerable regions worldwide due to its population density, the concentration of economic activities along the coasts and borderline climatic balance. It is identified as one of the most critical erosion hotspots in Europe, mainly due to the degradation of coastal areas, overexploitation and unsustainable practices affecting beach tourism, agriculture and fishing. The region is also affected by other phenomena such as storms and floods, which are exacerbated by climate change. To mitigate and adapt to these environmental and climatic changes, Nature based Solutions (NbSs) are considered a promising step-forward. However, despite their global recognition in both research and policy, few scientific papers and documents on the state of NbSs implementation for coastal risk management in the Mediterranean exist. This paper aims to provide an understanding of the status of NbS adoption for coastal risk management in the Mediterranean through a literature review. Out of 162 scientific papers and documents, only 23 were found to be relevant to the study. Through the definition and support of an innovative matrix-based approach, the analysis of the state of adoption of NbSs have been performed. Despite the limited information on the state of the adoption of NbSs for coastal risk management in the Mediterranean due to the low numbers of scientific research and documents available, some key considerations have been revealed.

Cassava retting ability and textural attributes of fufu for demand-driven cassava breeding.

BACKGROUND: Cassava retting ability and the textural qualities of cooked fufu are important quality traits. Cassava retting is a complex process in which soaking causes tissue breakdown, starch release, and softening. The rate at which various traits linked to it evolve varies greatly during fufu processing. According to the literature, there is no standard approach for determining retting ability. The retting indices and textural properties of fufu were measured using both manual and instrumental approaches. RESULTS: Different protocols were developed to classify 64 and 11 cassava genotypes into various groups based on retting ability and textural qualities, respectively. The retting protocols revealed considerable genetic dissimilarities in genotype classification: foaming ability and water clarity should be measured at 24 h, while penetrometer, hardness, turbidity, pH, and total titratable acidity data are best collected after 36 h. The stepwise regression model revealed that pH, foaming ability, and dry matter content are the best multivariates (with the highest R2) for predicting cassava retting. These predictors were used to develop an index for assessing the retting ability of cassava genotypes. The retting index developed showed a significant relationship with dry matter content and fufu yield. The study also showed significant correlations between instrumental cohesiveness and sensory smoothness (r = -0.75), moldability (r = -0.62), and stretchability (r = 0.78). Instrumental cohesiveness can correctly estimate fufu smoothness (R2 = 0.56, P = 0.008) and stretchability (R2 = 0.60, P = 0.005). CONCLUSION: pH, foaming ability, and dry matter content are the best traits for predicting cassava retting ability, while instrumental cohesiveness can effectively estimate fufu smoothness and stretchability. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Dose-Response Effects of MittEcho, a Measurement Feedback System, in an Indicated Mental Health Intervention for Children in Municipal and School Services in Norway.

Including routine client feedback can increase the effectiveness of mental health interventions for children, especially when implemented as intended. Rate of implementation, or dose, of such feedback interventions has been shown to moderate results in some studies. Variation in implementation and use of client feedback may also contribute to the mixed results observed within the feedback literature. This study evaluates dose-response associations of client feedback using a novel Measurement Feedback System (MFS) within an indicated group intervention. The primary aim was to determine whether the rate of MFS implementation predicts symptom reduction in anxiety and depression among school-aged children. The secondary aim was to assess whether the rate of MFS implementation influences children's satisfaction with the group intervention or their dropout rates. Data were collected via a randomized factorial study (clinicaltrials.gov NCT04263558) across 58 primary schools in Norway. Children aged 8 to 12 years (N = 701) participated in a group-based, transdiagnostic intervention targeting elevated symptoms of anxiety or depression. Half of the child groups also received the feedback intervention using the MittEcho MFS. Group leaders (N = 83), recruited locally, facilitated the interventions. The MFS dose was measured using the Implementation Index, which combines the use of MFS by both children and providers (group leaders) into a single dose variable. Results showed no significant additional effect of dose of MFS on change in depression or anxiety scores, on user satisfaction with the intervention or on intervention dropout. The discussion addresses potential reasons for these non-significant findings and implications for MFS implementation in preventive, group-based interventions in school settings.

Preclinical development of ZED8, an 89Zr immuno-PET reagent for monitoring tumor CD8 status in patients undergoing cancer immunotherapy.

BACKGROUND: ZED8 is a novel monovalent antibody labeled with zirconium-89 for the molecular imaging of CD8. This work describes nonclinical studies performed in part to provide rationale for and to inform expectations in the early clinical development of ZED8, such as in the studies outlined in clinical trial registry NCT04029181 [1]. METHODS: Surface plasmon resonance, X-ray crystallography, and flow cytometry were used to characterize the ZED8-CD8 binding interaction, its specificity, and its impact on T cell function. Immuno-PET with ZED8 was assessed in huCD8+ tumor-bearing mice and in non-human primates. Plasma antibody levels were measured by ELISA to determine pharmacokinetic parameters, and OLINDA 1.0 was used to estimate radiation dosimetry from image-derived biodistribution data. RESULTS: ZED8 selectively binds to human CD8α at a binding site approximately 9 Å from that of MHCI making mutual interference unlikely. The equilibrium dissociation constant (KD) is 5 nM. ZED8 binds to cynomolgus CD8 with reduced affinity (66 nM) but it has no measurable affinity for rat or mouse CD8. In a series of lymphoma xenografts, ZED8 imaging was able to identify different CD8 levels concordant with flow cytometry. In cynomolgus monkeys with tool compound 89Zr-aCD8v17, lymph nodes were conspicuous by imaging 24 h post-injection, and the pharmacokinetics suggested a flat-fixed first-in-human dose of 4 mg per subject. The whole-body effective dose for an adult human was estimated to be 0.48 mSv/MBq, comparable to existing 89Zr immuno-PET reagents. CONCLUSION: 89Zr immuno-PET with ZED8 appears to be a promising biomarker of tissue CD8 levels suitable for clinical evaluation in cancer patients eligible for immunotherapy.

Development of an 18F-labeled anti-human CD8 VHH for same-day immunoPET imaging.

PURPOSE: Cancer immunotherapies (CITs) have revolutionized the treatment of certain cancers, but many patients fail to respond or relapse from current therapies, prompting the need for new CIT agents. CD8+ T cells play a central role in the activity of many CITs, and thus, the rapid imaging of CD8+ cells could provide a critical biomarker for new CIT agents. However, existing 89Zr-labeled CD8 PET imaging reagents exhibit a long circulatory half-life and high radiation burden that limit potential applications such as same-day and longitudinal imaging. METHODS: To this end, we discovered and developed a 13-kDa single-domain antibody (VHH5v2) against human CD8 to enable high-quality, same-day imaging with a reduced radiation burden. To enable sensitive and rapid imaging, we employed a site-specific conjugation strategy to introduce an 18F radiolabel to the VHH. RESULTS: The anti-CD8 VHH, VHH5v2, demonstrated binding to a membrane distal epitope of human CD8 with a binding affinity (KD) of 500 pM. Subsequent imaging experiments in several xenografts that express varying levels of CD8 demonstrated rapid tumor uptake and fast clearance from the blood. High-quality images were obtained within 1 h post-injection and could quantitatively differentiate the tumor models based on CD8 expression level. CONCLUSION: Our work reveals the potential of this anti-human CD8 VHH [18F]F-VHH5v2 to enable rapid and specific imaging of CD8+ cells in the clinic.

Bayesian belief network modelling approach for predicting and ranking risk factors for malaria infections among children under 5 years in refugee settlements in Uganda.

BACKGROUND: Malaria risk factors at household level are known to be complex, uncertain, stochastic, nonlinear, and multidimensional. The interplay among these factors, makes targeted interventions, and resource allocation for malaria control challenging. However, few studies have demonstrated malaria's transmission complexity, control, and integrated modelling, with no available evidence on Uganda's refugee settlements. Using the 2018-2019 Uganda's Malaria Indicator Survey (UMIS) data, an alternative Bayesian belief network (BBN) modelling approach was used to analyse, predict, rank and illustrate the conceptual reasoning, and complex causal relationships among the risk factors for malaria infections among children under-five in refugee settlements of Uganda. METHODS: In the UMIS, household level information was obtained using standardized questionnaires, and a total of 675 children under 5 years were tested for malaria. From the dataset, a casefile containing malaria test results, demographic, social-economic and environmental information was created. The casefile was divided into a training (80%, n = 540) and testing (20%, n = 135) datasets. The training dataset was used to develop the BBN model following well established guidelines. The testing dataset was used to evaluate model performance. RESULTS: Model accuracy was 91.11% with an area under the receiver-operating characteristic curve of 0.95. The model's spherical payoff was 0.91, with the logarithmic, and quadratic losses of 0.36, and 0.16 respectively, indicating a strong predictive, and classification ability of the model. The probability of refugee children testing positive, and negative for malaria was 48.1% and 51.9% respectively. The top ranked malaria risk factors based on the sensitivity analysis included: (1) age of child; (2) roof materials (i.e., thatch roofs); (3) wall materials (i.e., poles with mud and thatch walls); (4) whether children sleep under insecticide-treated nets; 5) type of toilet facility used (i.e., no toilet facility, and pit latrines with slabs); (6) walk time distance to water sources (between 0 and 10 min); (7) drinking water sources (i.e., open water sources, and piped water on premises). CONCLUSION: Ranking, rather than the statistical significance of the malaria risk factors, is crucial as an approach to applied research, as it helps stakeholders determine how to allocate resources for targeted malaria interventions within the constraints of limited funding in the refugee settlements.

On Parameter Identifiability in Network-Based Epidemic Models.

Modelling epidemics on networks represents an important departure from classical compartmental models which assume random mixing. However, the resulting models are high-dimensional and their analysis is often out of reach. It turns out that mean-field models, low-dimensional systems of differential equations, whose variables are carefully chosen expected quantities from the exact model provide a good approximation and incorporate explicitly some network properties. Despite the emergence of such mean-field models, there has been limited work on investigating whether these can be used for inference purposes. In this paper, we consider network-based mean-field models and explore the problem of parameter identifiability when observations about an epidemic are available. Making use of the analytical tractability of most network-based mean-field models, e.g. explicit analytical expressions for leading eigenvalue and final epidemic size, we set up the parameter identifiability problem as finding the solution or solutions of a system of coupled equations. More precisely, subject to observing/measuring growth rate and final epidemic size, we seek to identify parameter values leading to these measurements. We are particularly concerned with disentangling transmission rate from the network density. To do this, we give a condition for practical identifiability and we find that except for the simplest model, parameters cannot be uniquely determined, that is, they are practically unidentifiable. This means that there exist multiple solutions (a manifold of infinite measure) which give rise to model output that is close to the data. Identifying, formalising and analytically describing this problem should lead to a better appreciation of the complexity involved in fitting models with many parameters to data.

Understanding the effect of gender-based violence on uptake and utilisation of HIV prevention, treatment, and care services among transgender women: a qualitative study in the greater Kampala metropolitan area, Uganda.

BACKGROUND: Transwomen (also known as transgender women) are disproportionately affected by all forms of gender-based violence (GBV). The high prevalence of physical, sexual and emotional violence not only predisposes transwomen to HIV infection but also limits the uptake/access to HIV prevention, care, and treatment services. Despite the high prevalence of HIV infection and GBV among transwomen, there is limited evidence on how GBV affects the uptake and utilisation of HIV prevention, care, and treatment services. Therefore, this qualitative study explored how GBV affects uptake and utilisation of HIV prevention, treatment, and care services among transwomen in the Greater Kampala Metropolitan Area (GKMA), Uganda. METHODS: This participatory qualitative study was conducted among transwomen in the GKMA. A total of 20 in-depth interviews, 6 focus group discussions, and 10 key informant interviews were conducted to explore how GBV affects the uptake and utilisation of HIV prevention, treatment, and care services among transwomen. Data were analysed using a thematic content analysis framework. Data were transcribed verbatim, and NVivo version 12 was used for coding. RESULTS: At the individual level, emotional violence suffered by transwomen led to fear of disclosing their HIV status and other health conditions to intimate partners and healthcare providers respectively; inability to negotiate condom use; and non-adherence to antiretroviral therapy (ART). Sexual violence compromised the ability of transwomen to negotiate condom use with intimate partners, clients, and employers. Physical and emotional violence at the community level led to fear among transwomen traveling to healthcare facilities. Emotional violence suffered by transwomen in healthcare settings led to the limited use of pre-exposure prophylaxis and HIV testing services, denial of healthcare services, and delays in receiving appropriate care. The fear of emotional violence also made it difficult for transwomen to approach healthcare providers. Fear of physical violence such as being beaten while in healthcare settings made transwomen shun healthcare facilities. CONCLUSION: The effects of GBV on the uptake and utilisation of HIV prevention, care, and treatment services were observed in individual, community, and healthcare settings. Across all levels, physical, emotional, and sexual violence suffered by transwomen led to the shunning of healthcare facilities, denial of healthcare services, delays in receiving appropriate care, and the low utilisation of post-exposure prophylaxis, and HIV testing services. Given its effects on HIV transmission, there is a need to develop and implement strategies/ interventions targeting a reduction in GBV. Interventions should include strategies to sensitize communities to accept transwomen. Healthcare settings should provide an enabling environment for transwomen to approach any healthcare provider of their choice without fear of experiencing GBV.

Using digital platforms to promote a healthcare provider community of practice for abortion care in Uganda.

BACKGROUND: A community of practice (CoP) is defined as a group of people who share a concern, set of problems, or a passion about a topic, and who deepen their knowledge and expertise by interacting on an ongoing basis. The paper presents a case study on the design, implementation and management of a CoP. The objective is to share experiences, opportunities, challenges and lessons learnt in using digital platforms for clinical mentorships to establish a CoP that promotes enhanced service provision of abortion care. METHODS: We employed competence-based training and ongoing virtual mentorship for abortion care, employing the abortion harm reduction model, and using several digital platforms to create and nurture community of practice for abortion care. Using the Capability-Opportunity-Motivation for Behavior (COM-B) model and textual data analysis, we evaluated the performance of the CoP as a tool to support abortion care, using data from in-depth interviews and information shared on the platforms. The data was analyzed by thematic analysis using text data analytical approach. RESULTS: CoPs have much unrealized potential for networking to improve abortion care, as they are more inclusive, interactive and equalizing than typical webinars, yet less expensive and can complement (though not replace) physical mentorships. CoPs' focus on sharing best practices and creating new knowledge to advance professional practice, faces challenges of maintaining regular interaction on an ongoing basis. CoP members need to share a passion for their practice and mutual trust is key to success. CONCLUSION: Though it faced initial challenges of connectivity, and limited interaction, the CoP approach using digital platforms promoted shared experiences, personal connections, communication, collaboration and application of knowledge for improved abortion care.