Suboptimal Treatment Research Articles

Bacteria/Nanozyme Composites: New Therapeutics for Disease Treatment.

Bacterial therapy is recognized as a cost-effective treatment for several diseases. However, its development is hindered by limited functionality, weak inherent therapeutic effects, and vulnerability to harsh microenvironmental conditions, leading to suboptimal treatment activity. Enhancing bacterial activity and therapeutic outcomes emerges as a pivotal challenge. Nanozymes have garnered significant attention due to their enzyme-mimic activities and high stability. They enable bacteria to mimic the functions of gene-edited bacteria expressing the same functional enzymes, thereby improving bacterial activity and therapeutic efficacy. This review delineates the therapeutic mechanisms of bacteria and nanozymes, followed by a summary of strategies for preparing bacteria/nanozyme composites. Additionally, the synergistic effects of such composites in biomedical applications such as gastrointestinal diseases and tumors are highlighted. Finally, the challenges of bacteria/nanozyme composites are discussed and propose potential solutions. This study aims to provide valuable insights to offer theoretical guidance for the advancement of nanomaterial-assisted bacterial therapy.

The use of psychotropic medication in the perinatal period

Key content: The perinatal period confers an elevated risk of both relapses and new onset of mental illness. Suboptimal treatment can have a profound impact on maternal mortality and morbidity, neonatal outcomes and longer term child development. Most psychotropic medication can be used safely in pregnancy, with some notable exceptions. While decisions on the use of psychotropic medications in pregnancy are often complex and should be multidisciplinary, it is imperative that obstetricians and gynaecologists familiarise themselves with current literature to provide evidence‐based counselling and care. Existing guidelines on the use of psychotropic medication are largely aimed at psychiatrists, and to date there has been a lack of concise, digestible information with a focus on core knowledge for obstetricians and gynaecologists. We summarise existing evidence on the use of antidepressants, antipsychotics, mood stabilisers and sedatives in the perinatal period. For each drug class we describe the teratogenicity, impact on pregnancy, breastfeeding and the newborn. Learning objectives: To be familiar with common psychotropic medication used in pregnancy and the postpartum period. To understand key evidence on the safety profile of psychiatric medication in the perinatal period and apply this to individualised counselling.

Familial hypercholesterolemia care by Dutch pediatricians—mind the gaps

PurposeFamilial hypercholesterolemia (FH) leads to elevated low-density lipoprotein cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). Since the first functional and morphologic changes of the arterial wall occur in childhood, treatment should start early in childhood to mitigate the elevated risk of ASCVD. Pediatricians play an important role in the detection and care of children with FH. In this study, we aim to explore potential gaps in FH care amongst Dutch pediatricians, in order to enhance their knowledge and awareness of detecting and treating children with FH.MethodsAn anonymous online survey, deployed using Google Forms, including 26 closed and semi-closed questions on FH care in children was distributed by the Dutch Association of Pediatrics via a newsletter to which the majority of the practicing Dutch pediatricians subscribe. In addition, we requested that the pediatric departments of all Dutch hospitals in the Netherlands distribute this survey personally among their employed pediatricians. Respondents were instructed to answer the questions without any help or use of online resources.ResultsBetween September 1st, 2023 and November 1st, 2023, 158 (an estimated 11% response rate) Dutch pediatricians completed the survey. They reported a median (IQR) of 15.0 (6.0–22.0) years of experience as a pediatrician, and 34 (21.5%) were working in academic hospitals. The majority (76.6%) of pediatricians correctly identified a typical FH lipid profile but 68 (43.0%) underestimated the true prevalence of FH (1:300). Underestimation and unawareness of the increased risk of FH patients for ASCVD were reported by 37.3% and 25.9% of pediatricians, respectively. Although 70.9% of the pediatricians correctly defined FH, only 67 (42.4%) selected statins and ezetimibe to treat severe hypercholesterolemia.Conclusions:The results of this study suggest significant gaps in knowledge and awareness of FH in children among Dutch pediatricians. FH care in children needs improvement through educational and training initiatives to mitigate the life-long risk of ASCVD from early life.What is Known:• Familial hypercholesterolemia (FH) leads to elevated LDL-cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD).• The process of atherosclerosis starts in childhood• Pediatricians play an important role in the detection and treatment of children with FH.What is New:• Our results highlight significant gaps in care for children with FH amongst pediatricians and this may lead to suboptimal detection and treatment.• FH care in children needs improvement by educational initiatives to ultimately prevent ASCVD in adulthood.

Anti-rheumatic property and physiological safety of KMU-11342 in in vitro and in vivo models

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder characterized by joint destruction due to synovial hypertrophy and the infiltration of inflammatory cells. Despite substantial progress in RA treatment, challenges persist, including suboptimal treatment responses and adverse effects associated with current therapies. This study investigates the anti-rheumatic capabilities of the newly identified multi-protein kinase inhibitor, KMU-11342, aiming to develop innovative agents targeting RA. In this study, we synthesized the novel multi-protein kinase inhibitor KMU-11342, based on indolin-2-one. We assessed its cardiac electrophysiological safety using the Langendorff system in rat hearts and evaluated its toxicity in zebrafish in vivo. Additionally, we examined the anti-rheumatic effects of KMU-11342 on human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), THP-1 cells, and osteoclastogenesis in RAW264.7 cells. KMU-11342 demonstrated the ability to inhibit LPS-induced chemokine inhibition and the upregulation of pro-inflammatory cytokines, cyclooxygenase-2, inducible nitric oxide synthase, p-IKKα/β, p-NF-κB p65, and the nuclear translocation of NF-κB p65 in RA-FLS. It effectively suppressed the upregulation of NLR family pyrin domain containing 3 (NLRP3) and caspase-1 cleavage. Furthermore, KMU-11342 hindered the activation of osteoclast differentiation factors such as RANKL-induced TRAP, cathepsin K, NFATc-1, and c-Fos in RAW264.7 cells. KMU-11342 mitigates LPS-mediated inflammatory responses in THP-1 cells by inhibiting the activation of NLRP3 inflammasome. Notably, KMU-11342 exhibited minimal cytotoxicity in vivo and electrophysiological cardiotoxicity ex vivo. Consequently, KMU-11342 holds promise for development as a therapeutic agent in RA treatment.

Clinical features, immunologic parameter and treatment outcome of Chinese tuberculosis patients with or without DM.

The coexistence of diabetes mellitus (DM) and pulmonary tuberculosis (PTB) poses a significant health concern globally, with their convergence presenting a considerable challenge to healthcare systems. Previous research has highlighted that comorbidities can mutually influence and exacerbate immune disorders. However, there is a paucity of data on the impact of DM on immunological features and treatment responses in the TB population in China. From January 2020 to June 2022, 264 cases of pulmonary tuberculosis patients (82 DM patients and 182 non-DM patients) hospitalized in our center were selected. 80 patients with TB with DM (TB-DM) and 80 patients with TB without DM (TB-NDM) were enrolled into the final analysis by propensity score matching for age, gender and involved lung field at a ratio of 1:1. The clinical characteristics, immunological features and treatment response were compared between the two groups. After propensity score matching, no differences in the general features such as age gender, involved lung field, the incidence of retreatment and WBC count were found between the two groups. Compared to TB-NDM group, the TB-DM group exhibited a higher positive rate of sputum smear and incidence of cavitary lesions. Immunological features analysis revealed that the TB-DM patients had higher levels of TNF-α [pg/ml; 8.56 (7.08-13.35) vs. 7.64 (6.38-10.14) p = 0.033] and IL-8 [pg/ml; 25.85 (11.63-58.40) vs. 17.56 (6.44-39.08) p = 0.003] but lower CD8+ T lymphocyte count [cells/mm3; 334.02 (249.35-420.71) VS 380.95 (291.73-471.25) p = 0.038]. However, there was no significant difference in serum IL-6 concentration and CD4+ T lymphocyte count between the two groups. After 2 months of anti-tuberculosis treatment, 39 (24.4%) cases had suboptimal treatment response, including 23 (28.7%) TB-DM patients and 16 (20%) TB-NDM patients. There was no difference in suboptimal response rate (SRR) was found between the two groups (p = 0.269). The multivariate logistic regression analysis indicated that retreatment for TB [AOR: 5.68 (95%CI: 2.01-16.08), p = 0.001], sputum smear positivity [AOR: 8.01 (95%CI: 2.62-24.50), p = 0.001] were associated with SRR in all participants, and in TB-DM group, only sputum smear positivity [AOR: 16.47 (1.75-155.12), p = 0.014] was positive with SRR. DM is a risk factor for pulmonary cavity formation and sputum smear positivity in TB population. Additionally, TB-DM patients is characterized by enhanced cytokine responses and decreased CD8+ T lymphocytes. The retreatment for TB and sputum smear positivity were associated with the occurrence of suboptimal treatment response.

Individual treatment selection for patients with post-traumatic stress disorder: External validation of a personalised advantage index

Objective To test the predictive accuracy and generalisability of a personalised advantage index (PAI) model designed to support treatment selection for Post-Traumatic Stress Disorder (PTSD). Method A PAI model developed by Deisenhofer et al. (2018) was used to predict treatment outcomes in a statistically independent dataset including archival records for N = 152 patients with PSTD who accessed either trauma-focussed cognitive behavioural therapy or eye movement desensitisation and reprocessing in routine care. Outcomes were compared between patients who received their PAI-indicated optimal treatment versus those who received their suboptimal treatment. Results The model did not yield treatment specific predictions and patients who had received their PAI-indicated optimal treatment did not have better treatment outcomes in this external validation sample. Conclusion This PAI model did not generalise to an external validation sample.

Evaluation of plasma-derived extracellular vesicles miRNAs and their connection with hippocampal mRNAs in alcohol use disorder

Alcohol use disorder (AUD) is a common mental illness with high morbidity and disability. The discovery of laboratory biomarkers has progressed slowly, resulting in suboptimal diagnosis and treatment of AUD. This study aimed to identify promising biomarkers, as well as the potential miRNA-mRNA networks associated with AUD pathogenesis. RNA sequencing was performed on plasma-derived small extracellular vesicles (sEVs) from AUD patients and healthy controls (HCs) to harvest miRNAs expression profiles. Machine learning (ML) models were built to screen characteristic miRNAs, whose target mRNAs were analyzed using TargetScan, miRanda and miRDB databases. Gene Expression Omnibus (GEO) datasets (GSE181804 and GSE180722) providing postmortem hippocampal gene expression profiles of AUD subjects were mined. A total of 247 differentially expressed (DE) plasma-derived sEVs miRNAs and 122 DE hippocampal mRNAs were obtained. Then, 22 overlapping sEVs miRNAs with high importance scores were gained by intersecting 5 ML models. As a result, we established a putative sEVs miRNA-hippocampal mRNA network that can effectively distinguish AUD patients from HCs. In conclusion, we proposed 5 AUD-representative sEVs miRNAs (hsa-miR-144-5p, hsa-miR-182-5p, hsa-miR-142-5p, hsa-miR-7-5p, and hsa-miR-15b-5p) that may participate in the pathogenesis of AUD by modulating downstream target hippocampal genes. These findings may provide novel insights into the diagnosis and treatment of AUD.

Association between financial fragility and treatment patterns in multiple myeloma.

11085 Background: Multiple myeloma (MM) drugs are associated with significant out-of-pocket costs. We hypothesize that patients with financial fragility (FF) may receive suboptimal MM treatment, as they might be less likely to be able to access and afford these medications compared to patients in good financial standing. We examined the association between FF and MM treatment by using a novel database that links patient-level credit records to cancer and claims data in Washington (WA) state. Methods: We conducted a retrospective analysis of newly diagnosed patients with MM (2012-2020) with Medicare and commercial health insurance, via a database linking WA cancer registry data (including Western WA SEER), health insurance claims, and depersonalized credit reports (TransUnion). All eligible patients received combination therapy with an oral immunomodulatory drug and at least one injectable medication within 6 months of diagnosis. FF was defined as evidence of at least one of the following in credit reporting around diagnosis (50 days before or after): charge-offs, collections, liens, foreclosures, repossessions, and bankruptcy in the last 12 months. Patients were categorized as receiving suboptimal treatment (the composite outcome) if they experienced at least one of the following: delay in time to treatment initiation (>40 days from diagnosis), treatment interruption (gap of >30 days without treatment in the first 6 months), or lack of autologous stem cell transplantation (ASCT, within the first 12 months). We performed chi-squared tests followed by multivariable logistic regressions, adjusting for age, sex, race (white/nonwhite), insurance type, and Area Deprivation Index (dichotomized; 1-5 and 6-10). Results: A total of 204 eligible patients (median age 69 years, 60% male, 91% White, and 60% Medicare-insured) met eligibility criteria. Of these, 39 patients (19%) had evidence of FF and 120 patients (59%) met the composite outcome. FF was significantly associated with the composite outcome of suboptimal treatment in bivariate analysis (74% vs. 55%, p=0.03) and adjusted multivariable analysis (OR 2.41 [95% CI: 1.05-5.51], p=0.04). As 182 (89%) patients received ASCT within 12 months in this cohort, we performed a sensitivity analysis by removing ASCT as a component outcome; in this analysis, 108 patients (53%) met the composite outcome. FF was associated with the composite outcome of suboptimal treatment in bivariate analysis (69% vs. 49%, p=0.02) and adjusted multivariable analysis (OR 2.31 [95% CI: 1.05-5.10], p=0.04). Conclusions: FF is significantly associated with suboptimal MM treatment patterns, including delay to treatment initiation, treatment interruption, and decreased receipt of ASCT. Larger prospective studies with more diverse demographic representation and incorporation of clinical data are in development to elucidate the mechanisms through which FF leads to suboptimal MM treatment.

Knowledge and representations of sex workers by GPs in Brussels: a qualitative study using semi-structured interviews.

A majority of sex-workers (SWers) do not have a GP aware of their professional activity, which prevents appropriate support to this group. One of the reasons is fear of the doctors' judgment. The objective of this research is to identify how sex-work is perceived by primary care practitioners, and how they follow-up this public. This qualitative study using semi-structured interviews with 12 GPs practicing in Brussels was conducted from October 2021 to March 2023. Results show a lack of understanding of what SW is, of the legal context and of the people who practice it. Doctors know about related health issues, but not about their proportion or origin. The main factor identified as leading to SW is economic insecurity. Sample analysis shows theoretical positions close to a pro-sex stance (néo-réglementarisme). This study demonstrates that primary care doctors' knowledge of SW is limited, and that these limitations can lead to stigmatisation and suboptimal treatment. The following recommendations are to: draw up a list of doctors who can welcome SWers without being judgmental and make this list available to associations active in the field of SW; co-construct a training course, in partnership with SWers, aimed at GPs (it would include sections on the historical and legal context, the approach to harm reduction and substance abuse, PreP, PEP, and a communication guide); and teach courses on marginalised populations with specific health needs during the initial training of medical students.

Multivariate functional principal component analysis and k-means clustering to identify kinematic foot types during gait in children with cerebral palsy

BackgroundChildren with neuromuscular disorders, such as cerebral palsy, frequently develop foot deformities, such as equinopronovalgus and equinosupovarus, leading to walking difficulties and discomfort. Traditional assessment methods, including clinical measures and radiographs, often fail to capture the dynamic nature of these deformities, resulting in suboptimal treatment. 3D gait analysis using multisegment foot models offers a more detailed understanding of these deformities. Research questionTo determine whether the combination of multisegment foot models, multivariate functional principal component analysis, and k-means cluster analyses could identify distinct, clinically relevant foot types in a large pediatric cohort with cerebral palsy. MethodsThis was a retrospective analysis of 3D gait data from 197 patients with cerebral palsy collected using a multisegment foot model. Multivariate functional principal component analysis was used to reduce these data prior to using k-means clustering to identify foot posture clusters. Further analyses, including ANOVA and Fisher's Exact tests, were used to evaluate demographic, radiographic, and gait characteristics to explain the clinical relevance of each cluster. ResultsAnalysis of kinematic data from 371 feet revealed six clinically significant clusters, with a low misclassification rate of 2 %. One-factor ANOVAs demonstrated significant differences across clusters for all MPCs, whereas no significant differences were noted in basic anthropometric variables. Significant variations were observed in radiographic and gait function variables, and a strong association between GMFCS levels and cluster categorization was identified. SignificanceThe novel approach of integrating multivariate functional principal component analysis and k-means clustering identified a spectrum of foot deformities in children with CP, ranging from equinosupovarus to marked equinopronovalgus. This methodology provides an objective classification based on kinematic data and can facilitate improved diagnosis and treatment of cerebral palsy-related foot deformities.

Multi-omics analysis reveals mechanism of Schisandra chinensis lignans and acteoside on EMT in hepatoma cells via ERK1/2 pathway.

Hepatocellular carcinoma (HCC), a globally common cancer, often presents late and shows high resistance to chemotherapy, resulting in suboptimal treatment efficacy. Components from traditional Chinese medicines have been recognized for their anti-cancer properties. Exploring the mechanism of Schisandra chinensis lignans and acteoside in suppressing Epithelial-Mesenchymal Transition (EMT) in hepatoma cells through the Extracellular signal-Regulated Kinases (ERK)1/2 pathway and identifying biomarkers, molecular subtypes, and targets via multi-omics for precision oncology. Proliferation was assessed using cell counting kit-8 (CCK-8) assays, with scratch and transwell assays for evaluating invasion and migration. Flow cytometry quantified apoptosis rates. Expression levels of CCL20, p-ERK1/2, c-Myc, Vimentin, and E-cadherin/N-cadherin were analyzed by real-time PCR and Western blot. Tumor volume was calculated with a specific formula, and growth. The Schisandra chinensis lignans and acteoside combination decreased CCL20 expression, inhibited hepatoma proliferation and migration, and enhanced apoptosis in a dose- and time-dependent manner. Molecular analysis revealed increased E-cadherin and decreased N-cadherin, p-ERK1/2, c-Myc, and Vimentin expression, indicating ERK1/2 pathway modulation. In vivo, treated nude mice showed significantly reduced tumor growth and volume. Schisandra chinensis lignans and acteoside potentially counteract CCL20-induced EMT, invasion, and migration in hepatocellular carcinoma cells via the ERK1/2 pathway, enhancing apoptosis. Multi-omics analysis further aids in pinpointing novel biomarkers for precision cancer therapy.

NeoTRACT: Phase II trial of neoadjuvant tumor infiltrating lymphocyte- and response-adapted chemoimmunotherapy for triple-negative breast cancer (TNBC).

TPS629 Background: Neoadjuvant chemoimmunotherapy is recommended for patients with high risk early stage TNBC. The 5 drug KEYNOTE-522 neoadjuvant chemoimmunotherapy regimen involves 5-6 months of treatment and is associated with suboptimal treatment completion due to toxicity. Approaches to deescalate chemoimmunotherapy without compromising outcomes for patients with highly chemosensitive disease are needed. Stromal tumor infiltrating lymphocyte (sTIL) enrichment is positively associated with pathologic complete response (pCR) in TNBC and may be useful to identify patients for whom de-escalation of neoadjuvant chemoimmunotherapy might be acceptable. NeoTRACT trial investigates deescalating neoadjuvant chemoimmunotherapy based on degree of pretreatment sTIL enrichment. We hypothesize that baseline immune upregulation assessed by sTILs can guide neoadjuvant treatment optimization in TNBC patients. Specifically, in patients with immune enriched TNBC (sTILs ≥30%), short anthracycline free taxane–platinum chemoimmunotherapy will yield high pCR rate. Methods: NeoTRACT is an ongoing open label phase II trial for patients with previously untreated TNM stage I (T>1cm)–III TNBC. TNBC is defined as estrogen and progesterone receptor ≤10% and HER2 negative per ASCO/CAP criteria. Patients with T4 or N3 breast cancer are excluded. Patients must have adequate organ function and no contraindication to pembrolizumab. All participants initiate carboplatin (AUC 6) + docetaxel (75mg/m2) + pembrolizumab (200mg) (CbD+P) every 21 days. After registration, sTILs are evaluated centrally on pretreatment H&E core needle biopsy slide using standard criteria. Participants are assigned to three neoadjuvant treatment regimens (A, B, or C) based on sTIL enrichment. Regimen A (sTILs ≥30%) includes four cycles CbD+P. All participants assigned to regimen A undergo breast MRI after four cycles: those with complete MRI response proceed to breast surgery; those with less than complete MRI response receive two additional cycles of CbD+P. Regimen B (sTILs 5-29%) includes six cycles of CbD+P. Regimen C (sTILs <5%) includes four cycles of CbD+P followed by four cycles of doxorubicin (60mg/m2) + cyclophosphamide (600mg/m2) + P (200mg) (AC+P). All patients undergo surgery after completing the assigned neoadjuvant regimen. Breast/axillary surgery, adjuvant systemic therapy, and radiotherapy are recommended per standard of care. pCR is defined as absence of residual invasive disease in breast and axilla. Primary endpoint is pCR rate among participants with ≥30% sTILs. Secondary endpoints include residual cancer burden (RCB) rates in patients with ≥30% sTILs, pCR and RCB rates in patients with 5-29% and <5% sTILs, and event free and overall survival for all patients. As of January 2024, 45 of 139 participants have been enrolled. Clinical trial information: NCT05645380 .

Enhancing patient safety in radiotherapy: Implementation of a customized electronic checklist for radiation therapists

IntroductionThe radiotherapy workflow involves the collaboration of multiple professionals and the execution of several steps to results in an effective treatment. In this study, we described the clinical implementation of an electronic checklist, developed to standardize the process of the chart review prior to the first treatment fraction by the radiation therapists (RTTs). Materials and MethodsA customized electronic checklist was developed based on the recommendations of American Association of Physicists in Medicine (AAPM) Task Groups 275 and 315 and integrated into the Record and Verify System (RVS). The checklist consisted of 16 items requiring binary (yes/no) responses, with mandatory completion and review by RTTs prior to treatment. The utility of the checklist and its impact on workflow were assessed by analysing checklist reports, and by soliciting feedback to RTTs through an anonymized survey. ResultsDuring the first trial phase, from June to November 2023, 285 checklists were completed with a 98% compilation rate and 94.4% review rate. Forty errors were detected, mainly due to missing signed treatment plans and absence of Beam’s Eye View documentation. Ninety percent of detected errors were fixed before the treatment start. In 4 cases, the problem could not be fixed before the first fraction, resulting in a suboptimal first treatment. The feedback survey showed that RTTs described the checklist as useful, with minimal impact on workload, and supported its implementation. DiscussionThe introduction of a customized electronic checklist improved the detection and correction of errors, thereby enhancing patient safety. The positive response from RTTs and the minimal impact on workflow underscore the value of the checklist as standard practice in radiotherapy departments.

A Review of Personalised Cardiac Computational Modelling Using Electroanatomical Mapping Data.

Computational models of cardiac electrophysiology have gradually matured during the past few decades and are now being personalised to provide patient-specific therapy guidance for improving suboptimal treatment outcomes. The predictive features of these personalised electrophysiology models hold the promise of providing optimal treatment planning, which is currently limited in the clinic owing to reliance on a population-based or average patient approach. The generation of a personalised electrophysiology model entails a sequence of steps for which a range of activation mapping, calibration methods and therapy simulation pipelines have been suggested. However, the optimal methods that can potentially constitute a clinically relevant in silico treatment are still being investigated and face limitations, such as uncertainty of electroanatomical data recordings, generation and calibration of models within clinical timelines and requirements to validate or benchmark the recovered tissue parameters. This paper is aimed at reporting techniques on the personalisation of cardiac computational models, with a focus on calibrating cardiac tissue conductivity based on electroanatomical mapping data.

Brood indicators are an early warning signal of honey bee colony loss-a simulation-based study.

Honey bees (Apis mellifera) are exposed to multiple stressors such as pesticides, lack of forage, and diseases. It is therefore a long-standing aim to develop robust and meaningful indicators of bee vitality to assist beekeepers While established indicators often focus on expected colony winter mortality based on adult bee abundance and honey reserves at the beginning of the winter, it would be useful to have indicators that allow detection of stress effects earlier in the year to allow for adaptive management. We used the established honey bee simulation model BEEHAVE to explore the potential of different indicators such as population size, number of capped brood cells, flight activity, abundance of Varroa mites, honey stores and a brood-bee ratio. We implemented two types of stressors in our simulations: 1) parasite pressure, i.e. sub-optimal Varroa treatment by the beekeeper (hereafter referred as Biotic stress) and 2) temporal forage gaps in spring and autumn (hereafter referred as Environmental stress). Neither stressor type could be detected by bee abundance or honey reserves at the end of the first year. However, all response variables used in this study did reveal early warning signals during the course of the year. The most reliable and useful measures seem to be related to brood and the abundance of Varroa mites at the end of the year. However, while in the model we have full access to time series of variables from stressed and unstressed colonies, knowledge of these variables in the field is challenging. We discuss how our findings can nevertheless be used to develop practical early warning indicators. As a next step in the interactive development of such indicators we suggest empirical studies on the importance of the number of capped brood cells at certain times of the year on bee population vitality.

Opinion review of drug resistant tuberculosis in West Africa: tackling the challenges for effective control.

Drug-resistant (DR) tuberculosis (TB) is a major public health concern globally, complicating TB control and management efforts. West Africa has historically faced difficulty in combating DR-TB due to limited diagnostic skills, insufficient access to excellent healthcare, and ineffective healthcare systems. This has aided in the emergence and dissemination of DR Mycobacterium tuberculosis complex (MTBC) strains in the region. In the past, DR-TB patients faced insufficient resources, fragmented efforts, and suboptimal treatment outcomes. However, current efforts to combat DR-TB in the region are promising. These efforts include strengthening diagnostic capacities, improving access to quality healthcare services, and implementing evidence-based treatment regimens for DR-TB. Additionally, many West African National TB control programs are collaborating with international partners to scale up laboratory infrastructure, enhance surveillance systems, and promote infection control measures. Moreso, novel TB drugs and regimens, such as bedaquiline and delamanid, are being introduced to improve treatment outcomes for DR-TB cases. Despite these obstacles, there is optimism for the future of DR-TB control in West Africa. Investments are being made to improve healthcare systems, expand laboratory capacity, and support TB research and innovation. West African institutions are now supporting knowledge sharing, capacity building, and resource mobilization through collaborative initiatives such as the West African Network for TB, AIDS, and Malaria (WANETAM), the West African Health Organization (WAHO), and other regional or global partners. These efforts hold promise for improved diagnostics, optimized treatment regimens, and provide better patient outcomes in the future where drug-resistant TB in WA can be effectively controlled, reducing the burden of the disease, and improving the health outcomes of affected individuals.

Mpox (Monkeypox) Virus and Its Co-Infection with HIV, Sexually Transmitted Infections, or Bacterial Superinfections: Double Whammy or a New Prime Culprit?

Epidemiologic studies have established that mpox (formerly known as monkeypox) outbreaks worldwide in 2022-2023, due to Clade IIb mpox virus (MPXV), disproportionately affected gay, bisexual, and other men who have sex with men. More than 35% and 40% of the mpox cases suffer from co-infection with HIV and sexually transmitted infections (STIs) (e.g., Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum, and herpes simplex virus), respectively. Bacterial superinfection can also occur. Co-infection of MPXV and other infectious agents may enhance disease severity, deteriorate outcomes, elongate the recovery process, and potentially contribute to the morbidity and mortality of the ensuing diseases. However, the interplays between MPXV and HIV, bacteria, other STI pathogens and host cells are poorly studied. There are many open questions regarding the impact of co-infections with HIV, STIs, or bacterial superinfections on the diagnosis and treatment of MPXV infections, including clinical and laboratory-confirmed mpox diagnosis, suboptimal treatment effectiveness, and induction of antiviral drug resistance. In this review article, we will discuss the progress and knowledge gaps in MPXV biology, antiviral therapy, pathogenesis of human MPXV and its co-infection with HIV, STIs, or bacterial superinfections, and the impact of the co-infections on the diagnosis and treatment of mpox disease. This review not only sheds light on the MPXV infection and co-infection of other etiologies but also calls for more research on MPXV life cycles and the molecular mechanisms of pathogenesis of co-infection of MPXV and other infectious agents, as well as research and development of a novel multiplex molecular testing panel for the detection of MPXV and other STI co-infections.

The (dis)organization of leg ulcer care: A realist synthesis.

Venous leg ulcers affect 1.5% of the UK adult population. Leg ulcers are painful, can be malodourous and are associated with poor quality of life. Leg ulcers are predominantly cared for by nurses in the community. Frequently, patients receive suboptimal treatment through unwanted variations in care and simple ulcers deteriorate to become hard-to-heal wounds. It is important to understand the current UK system of care and how nurses and patients navigate through it. The aim of this paper was to understand how, when, for whom and in what context leg ulcers are cared for in the United Kingdom and specifically, the current system of care, the nurses' role and the patients' experience in this system of care. A realist synthesis of the literature was undertaken, reported following the RAMESES publication standards: Realist syntheses. An iterative literature search was conducted across three recognized health collections from January 2010 to January 2022 that included descriptive studies as well as primary research. 73 papers were included. In the absence of UK national guidance that recommends how leg ulcer care is organized and delivered, care is commissioned locally, with variable outcomes. Patients with venous leg ulcers would like to be looked after by knowledgeable, skilled and confident nurses, in well-equipped and staffed clinics; nurses who have the ability to make clinical judgements to alter their treatment when necessary and are empowered to refer to specialist centres when further support is required. This synthesis offers guidance to commissioners and providers to change how leg ulcer care is organized. The views of a patient and public group was sought at each stage of the synthesis.

Centralization of care for rare genetic syndromes associated with cancer: improving outcomes and advancing research on VHL disease.

Von Hippel-Lindau (VHL) disease is a rare genetic syndrome caused by a germline pathogenic variant in one VHL allele. Any somatic event disrupting the other allele induces VHL protein (pVHL) loss of function, ultimately leading to patients developing multiple tumours in multiple organs at multiple timepoints, and reducing life expectancy. Treatment of this complex, rare disease is often fragmented, as patients visit specialist clinicians in isolation at different medical centres. Consequently, patients can receive sub-optimal treatment that results in decreased quality of life and a poor experience of health care systems. In 2021, we established a comprehensive clinical centre at San Raffaele Hospital, Milan, devoted to VHL disease. The centre provides a structured programme for the diagnosis, surveillance and treatment of patients alongside research into VHL disease and involves a multidisciplinary team of dedicated physicians. This programme demonstrates the benefits of care centralization, including concentration of knowledge and services, synergy and multidisciplinary management, improved networking and patient resources, reducing health care costs, and fostering research and innovation. VHL disease provides an ideal model to assess the advantages of centralizing care for rare disease and represents an unparalleled opportunity to broaden our understanding of cancer biology in general.

Seeking Cells, Targeting Bacteria: A Cascade-Targeting Bacteria-Responsive Nanosystem for Combating Intracellular Bacterial Infections.

Intracellular bacteria pose a great challenge to antimicrobial therapy due to various physiological barriers at both cellular and bacterial levels, which impede drug penetration and intracellular targeting, thereby fostering antibiotic resistance and yielding suboptimal treatment outcomes. Herein, a cascade-target bacterial-responsive drug delivery nanosystem, MM@SPE NPs, comprising a macrophage membrane (MM) shell and a core of SPE NPs. SPE NPs consist of phenylboronic acid-grafted dendritic mesoporous silica nanoparticles (SP NPs) encapsulated with epigallocatechin-3-gallate (EGCG), a non-antibiotic antibacterial component, via pH-sensitive boronic ester bonds are introduced. Upon administration, MM@SPE NPs actively home in on infected macrophages due to the homologous targeting properties of the MM shell, which is subsequently disrupted during cellular endocytosis. Within the cellular environment, SPE NPs expose and spontaneously accumulate around intracellular bacteria through their bacteria-targeting phenylboronic acid groups. The acidic bacterial microenvironment further triggers the breakage of boronic ester bonds between SP NPs and EGCG, allowing the bacterial-responsive release of EGCG for localized intracellular antibacterial effects. The efficacy of MM@SPE NPs in precisely eliminating intracellular bacteria is validated in two rat models of intracellular bacterial infections. This cascade-targeting responsive system offers new solutions for treating intracellular bacterial infections while minimizing the risk of drug resistance.