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Background: Cystitis is commonly treated with antibiotics, although non-antibiotic options could be considered for healthy non-pregnant women. Shared decision making (SDM) can be used in cystitis management to discuss the various treatment options but is not frequently applied in general practice. Aim: To identify barriers and facilitators for applying SDM in cystitis management in general practice. Design & setting: Qualitative explorative research in general practice with healthcare professionals (HCPs; GPs and GP assistants) and healthy non-pregnant women with a recent history of cystitis (patients). Method: Individual semi-structured interviews were conducted between May and October 2022. We applied a combination of thematic and framework analysis. Results: Ten GPs, seven GP assistants, and 15 patients were interviewed. We identified the following three main barriers and one key facilitator: (1) applying SDM is deemed inefficient; (2) HCPs assume that patients expect antibiotic treatment and some HCPs consider non-antibiotic treatment inferior; (3) patients are largely unaware of the various non-antibiotic treatment options for cystitis; and (4) HCPs recognise some benefits of applying SDM in cystitis management, including reduced antibiotic use and improved patient empowerment, and patients appreciate involvement in treatment decisions, but preferences for SDM vary. Conclusion: SDM is infrequently applied in cystitis treatment in general practice owing to the current focus on efficient cystitis management that omits patient contact, HCPs’ perceptions, and patient unawareness. Nevertheless, both HCPs and patients recognise the long-term benefits of applying SDM in cystitis management. Our findings facilitate the development of tailored interventions to increase the application of SDM, which should be co-created with HCPs and patients, and fit into the current efficient cystitis management.

Abstract Background In out-of-hours primary care (OHS-PC), semi-automatic decision support tools are often used during telephone triage. In the Netherlands, the Netherlands Triage Standard (NTS) is used. The NTS is mainly expert-based and evidence on the diagnostic accuracy of the NTS’ urgency allocation against clinically relevant outcomes for patients calling with shortness of breath (SOB) is lacking. Methods We included data from adults (≥18 years) who contacted two large Dutch OHS-PC centres for SOB between 1 September 2020 and 31 August 2021 and whose follow-up data about final diagnosis could be retrieved from their own general practitioner (GP). The diagnostic accuracy (sensitivity and specificity with corresponding 95% confidence intervals (CI)) of the NTS’ urgency levels (high (U1/U2) versus low (U3/U4/U5) and ‘final’ urgency levels (including overruling of the urgency by triage nurses or supervising general practitioners (GPs)) was determined with life-threatening events (LTEs) as the reference. LTEs included, amongst others, acute coronary syndrome, pulmonary embolism, acute heart failure and severe pneumonia. Results Out of 2012 eligible triage calls, we could include 1833 adults with SOB who called the OHS-PC, mean age 53.3 (SD 21.5) years, 55.5% female, and 16.6% showed to have had a LTE. Most often severe COVID-19 infection (6.0%), acute heart failure (2.6%), severe COPD exacerbation (2.1%) or severe pneumonia (1.9%). The NTS urgency level had a sensitivity of 0.56 (95% CI 0.50–0.61) and specificity of 0.61 (95% CI 0.58–0.63). Overruling of the NTS’ urgency allocation by triage nurses and/or supervising GPs did not impact sensitivity (0.56 vs. 0.54, p = 0.458) but slightly improved specificity (0.61 vs. 0.65, p

Background Despite considerable research into COVID-19 sequelae, little is known about differences in illness duration and complications in patients presenting in primary care with symptoms of acute respiratory tract infections (RTI) that are and are not attributed to SARS-CoV-2 infection.Objective To explore whether aetiology impacted course of illness and prediction of complications in patients presenting in primary care with symptoms of RTI early in the COVID-19 pandemic.Methods Between April 2020-March 2021 general practitioners from nine European countries recruited consecutively contacting patients with RTI symptoms. At baseline, an oropharyngeal-nasal swab was obtained for aetiology determination using PCR after follow-up of 28 days. Time to self-reported recovery was analysed with Kaplan-Meier curves. Predictors (baseline variables of demographics, patient and disease characteristics) of a complicated course (composite of hospital admission and persisting signs/symptoms at 28 days follow-up) were explored with logistic regression modelling.Results Of 855 patients with RTI symptoms, 237 (27.7%) tested SARS-CoV-2 positive. The proportion not feeling fully recovered (15.6% vs 18.1%, p = 0.39), reporting being extremely tired (9.7% vs 12.8%, p = 0.21), and not having returned to usual daily activities (18.1% vs 14.4%, p = 0.18) at day 28 were comparable between SARS-CoV-2 positive (n = 237) and negative (n = 618) groups. However, among those feeling fully recovered (SARS-CoV-2 positive: 200 patients, SARS-CoV-2 negative: 506 patients), time to full recovery was significantly longer in SARS-CoV-2 patients (10.6 vs 7.7 days, p

AbstractBackground There is a paucity of prognostic models for COVID-19 that are usable for in-office patient assessment in general practice (GP).Objectives To develop and validate a risk prediction model for hospital admission with readily available predictors.Methods A retrospective cohort study linking GP records from 8 COVID-19 centres and 55 general practices in the Netherlands to hospital admission records. The development cohort spanned March to June 2020, the validation cohort March to June 2021. The primary outcome was hospital admission within 14 days. We used geographic leave-region-out cross-validation in the development cohort and temporal validation in the validation cohort.Results In the development cohort, 4,806 adult patients with COVID-19 consulted their GP (median age 56, 56% female); in the validation cohort 830 patients did (median age 56, 52% female). In the development and validation cohort respectively, 292 (6.1%) and 126 (15.2%) were admitted to the hospital within 14 days, respectively. A logistic regression model based on sex, smoking, symptoms, vital signs and comorbidities predicted hospital admission with a c-index of 0.84 (95% CI 0.83 to 0.86) at geographic cross-validation and 0.79 (95% CI 0.74 to 0.83) at temporal validation, and was reasonably well calibrated (intercept −0.08, 95% CI −0.98 to 0.52, slope 0.89, 95% CI 0.71 to 1.07 at geographic cross-validation and intercept 0.02, 95% CI −0.21 to 0.24, slope 0.82, 95% CI 0.64 to 1.00 at temporal validation).Conclusion We derived a risk model using readily available variables at GP assessment to predict hospital admission for COVID-19. It performed accurately across regions and waves. Further validation on cohorts with acquired immunity and newer SARS-CoV-2 variants is recommended.

Abstract Background Community-acquired lower respiratory tract infections (LRTI) are common in primary care and patients at particular risk of adverse outcomes, e.g., hospitalisation and mortality, are challenging to identify. LRTIs are also linked to an increased incidence of cardiovascular diseases (CVD) following the initial infection, whereas concurrent CVD might negatively impact overall prognosis in LRTI patients. Accurate risk prediction of adverse outcomes in LRTI patients, while considering the interplay with CVD, can aid general practitioners (GP) in the clinical decision-making process, and may allow for early detection of deterioration. This paper therefore presents the design of the development and external validation of two models for predicting individual risk of all-cause hospitalisation or mortality (model 1) and short-term incidence of CVD (model 2) in adults presenting to primary care with LRTI. Methods Both models will be developed using linked routine electronic health records (EHR) data from Dutch primary and secondary care, and the mortality registry. Adults aged ≥ 40 years with a GP-diagnosis of LRTI between 2016 and 2019 are eligible for inclusion. Relevant patient demographics, medical history, medication use, presenting signs and symptoms, and vital and laboratory measurements will be considered as candidate predictors. Outcomes of interest include 30-day all-cause hospitalisation or mortality (model 1) and 90-day CVD (model 2). Multivariable elastic net regression techniques will be used for model development. During the modelling process, the incremental predictive value of CVD for hospitalisation or all-cause mortality (model 1) will also be assessed. The models will be validated through internal-external cross-validation and external validation in an equivalent cohort of primary care LRTI patients. Discussion Implementation of currently available prediction models for primary care LRTI patients is hampered by limited assessment of model performance. While considering the role of CVD in LRTI prognosis, we aim to develop and externally validate two models that predict clinically relevant outcomes to aid GPs in clinical decision-making. Challenges that we anticipate include the possibility of low event rates and common problems related to the use of EHR data, such as candidate predictor measurement and missingness, how best to retrieve information from free text fields, and potential misclassification of outcome events.

Objective To identify and synthesise relevant existing prognostic factors (PF) and prediction models (PM) for hospitalisation and all-cause mortality within 90 days in primary care patients with acute lower respiratory tract infections (LRTI).Design Systematic review.Methods Systematic searches of MEDLINE, Embase and the Cochrane Library were performed. All PF and PM studies on the risk of hospitalisation or all-cause mortality within 90 days in adult primary care LRTI patients were included. The risk of bias was assessed using the Quality in Prognostic Studies tool and Prediction Model Risk Of Bias Assessment Tool tools for PF and PM studies, respectively. The results of included PF and PM studies were descriptively summarised.Results Of 2799 unique records identified, 16 were included: 9 PF studies, 6 PM studies and 1 combination of both. The risk of bias was judged high for all studies, mainly due to limitations in the analysis domain. Based on reported multivariable associations in PF studies, increasing age, sex, current smoking, diabetes, a history of stroke, cancer or heart failure, previous hospitalisation, influenza vaccination (negative association), current use of systemic corticosteroids, recent antibiotic use, respiratory rate ≥25/min and diagnosis of pneumonia were identified as most promising candidate predictors. One newly developed PM was externally validated (c statistic 0.74, 95% CI 0.71 to 0.78) whereas the previously hospital-derived CRB-65 was externally validated in primary care in five studies (c statistic ranging from 0.72 (95% CI 0.63 to 0.81) to 0.79 (95% CI 0.65 to 0.92)). None of the PM studies reported measures of model calibration.Conclusions Implementation of existing models for individualised risk prediction of 90-day hospitalisation or mortality in primary care LRTI patients in everyday practice is hampered by incomplete assessment of model performance. The identified candidate predictors provide useful information for clinicians and warrant consideration when developing or updating PMs using state-of-the-art development and validation techniques.PROSPERO registration number CRD42022341233.

Abstract Background A previous individual participant data meta-analysis (IPD-MA) of antibiotics for adults with clinically diagnosed acute rhinosinusitis (ARS) showed a marginal overall effect of antibiotics, but was unable to identify patients that are most likely to benefit from antibiotics when applying conventional (i.e. univariable or one-variable-at-a-time) subgroup analysis. We updated the systematic review and investigated whether multivariable prediction of patient-level prognosis and antibiotic treatment effect may lead to more tailored treatment assignment in adults presenting to primary care with ARS. Methods An IPD-MA of nine double-blind placebo-controlled trials of antibiotic treatment (n=2539) was conducted, with the probability of being cured at 8–15 days as the primary outcome. A logistic mixed effects model was developed to predict the probability of being cured based on demographic characteristics, signs and symptoms, and antibiotic treatment assignment. Predictive performance was quantified based on internal-external cross-validation in terms of calibration and discrimination performance, overall model fit, and the accuracy of individual predictions. Results Results indicate that the prognosis with respect to risk of cure could not be reliably predicted (c-statistic 0.58 and Brier score 0.24). Similarly, patient-level treatment effect predictions did not reliably distinguish between those that did and did not benefit from antibiotics (c-for-benefit 0.50). Conclusions In conclusion, multivariable prediction based on patient demographics and common signs and symptoms did not reliably predict the patient-level probability of cure and antibiotic effect in this IPD-MA. Therefore, these characteristics cannot be expected to reliably distinguish those that do and do not benefit from antibiotics in adults presenting to primary care with ARS.

Introduction During the COVID-19 pandemic, hospital capacity was strained. Home-based care could relieve the hospital care system and improve patient well-being if safely organised.We designed an intervention embedded in a regional collaborative healthcare network for the home-based management of acutely ill COVID-19 patients requiring oxygen treatment. Here, we describe the design and pilot protocol for the evaluation of the feasibility of this complex intervention.Methods and analysis Following a participatory action research approach, the intervention was designed in four consecutive steps: (1) literature review and establishment of an expert panel; (2) concept design of essential intervention building blocks (acute medical care, acute nursing care, remote monitoring, equipment and technology, organisation and logistics); (3) safety assessments (prospective risk analysis and a simulation patient evaluation) and (4) description of the design of the pilot (feasibility) study aimed at including approximately 15–30 patients, sufficient for fine-tuning for a large-scale randomised intervention.Ethics and dissemination All patients will provide written, informed consent. The study was approved by the Medical Ethics Review Committee of the University Medical Center Utrecht, the Netherlands (protocol NL77421.041.21). The preparatory steps (1–4) needed to perform the pilot are executed and described in this paper. The findings of the pilot will be published in academic journals. If we consider the complex intervention feasible, we aim to continue with a large-scale randomised controlled study evaluating the clinical effectiveness, safety and implementation of the complex intervention.

Abstract Background The diagnostic accuracy of unsupervised self-testing with rapid antigen diagnostic tests (Ag-RDTs) is mostly unknown. We studied the diagnostic accuracy of a self-performed SARS-CoV-2 saliva and nasal Ag-RDT in the general population. Methods This large cross-sectional study consecutively included unselected individuals aged $$\ge$$ ≥ 16 years presenting for SARS-CoV-2 testing at three public health service test sites. Participants underwent molecular test sampling and received two self-tests (the Hangzhou AllTest Biotech saliva self-test and the SD Biosensor nasal self-test by Roche Diagnostics) to perform themselves at home. Diagnostic accuracy of both self-tests was assessed with molecular testing as reference. Results Out of 2819 participants, 6.5% had a positive molecular test. Overall sensitivities were 46.7% (39.3–54.2%) for the saliva Ag-RDT and 68.9% (61.6–75.6%) for the nasal Ag-RDT. With a viral load cut-off (≥ 5.2 log10 SARS-CoV-2 E-gene copies/mL) as a proxy of infectiousness, these sensitivities increased to 54.9% (46.4–63.3%) and 83.9% (76.9–89.5%), respectively. For the nasal Ag-RDT, sensitivities were 78.5% (71.1–84.8%) and 22.6% (9.6–41.1%) in those symptomatic and asymptomatic at the time of sampling, which increased to 90.4% (83.8–94.9%) and 38.9% (17.3–64.3%) after applying the viral load cut-off. In those with and without prior SARS-CoV-2 infection, sensitivities were 36.8% (16.3–61.6%) and 72.7% (65.1–79.4%). Specificities were > 99% and > 99%, positive predictive values > 70% and > 90%, and negative predictive values > 95% and > 95%, for the saliva and nasal Ag-RDT, respectively, in most analyses. Most participants considered the self-performing and result interpretation (very) easy for both self-tests. Conclusions The Hangzhou AllTest Biotech saliva self Ag-RDT is not reliable for SARS-CoV-2 detection, overall, and in all studied subgroups. The SD Biosensor nasal self Ag-RDT had high sensitivity in individuals with symptoms and in those without prior SARS-CoV-2 infection but low sensitivity in asymptomatic individuals and those with a prior SARS-CoV-2 infection which warrants further investigation.

Already, the 21st century has seen an unprecedented increase in cross-border movements of people, goods, information, and financial capital. Numerous incentives and facilitators have expanded international interconnectedness and mobility, so altering the conventional nature and functions of state borders, as captured by the “new mobilities” paradigm. Yet the weaponization of global economic interdependencies and other trends towards deglobalization mean there is now a growing pressure on governments to re-establish the conventional attributes of borders. Against the current mobility and security backdrop, this collection of articles takes stock of the meaning, roles, and practices of border activities. Now is the moment to consider the special role that borders perform as an institution of state security in a contemporary world exposed to massive international flows of people and goods, as well as technologically-driven control and management systems.

Abstract Solid interfacing biomaterials is a crucial aspect of bionanotechnology and important for applications such as biosensing. Because of their potentially large contact area, flat solenoidal proteins are ideal scaffolds for designing proteins binding to surfaces of man‐made solids such as minerals, metals, and plastics. To explore this opportunity, a naturally occurring flat solenoidal protein: the Rhagium inquistor Antifreeze Protein from the insect Rhagium inquisitor is re‐designed. By mutating 4, 6, and 10 out of its 4 × 5 arrays of threonines into arginines, it have arrived at the silica‐binding proteins RiSiBP‐4, RiSiBP‐6, and RiSiBP‐10. Variants with increasing numbers of arginines bind stronger to silica, but are also less stable and increasingly difficult to produce. It is found that the RiSiBP‐6 variant binds strongly to silica yet still has good stability and easy production. It is shown that sfGFP‐RiSiBP‐6 fusions allow for the functional display of a monolayer of sfGFP cargo on silica surfaces, suggesting the general usefulness of flat solenoidal proteins as scaffolds for designing solid‐binding proteins.

Background: Delay eyeblink conditioning is an extensively studied motor learning paradigm that critically depends on the integrity of the cerebellum. In healthy individuals, modulation of cerebellar excitability using transcranial direct current stimulation (tDCS) has been reported to alter the acquisition and/or timing of conditioned eyeblink responses (CRs). It remains unknown whether such effects can also be elicited in patients with cerebellar disorders. Objective: To investigate if repeated sessions of cerebellar tDCS modify acquisition and/or timing of CRs in patients with spinocerebellar ataxia type 3 (SCA3) and to evaluate possible associations between disease severity measures and eyeblink conditioning parameters. Methods: Delay eyeblink conditioning was examined in 20 mildly to moderately affected individuals with SCA3 and 31 healthy controls. After the baseline assessment, patients were randomly assigned to receive ten sessions of cerebellar anodal tDCS or sham tDCS (i.e., five days per week for two consecutive weeks). Patients and investigators were blinded to treatment allocation. The same eyeblink conditioning protocol was administered directly after the last tDCS session. The Scale for the Assessment and Rating of Ataxia (SARA), cerebellar cognitive affective syndrome scale (CCAS-S), and disease duration were used as clinical measures of disease severity. Results: At baseline, SCA3 patients exhibited significantly fewer CRs than healthy controls. Acquisition was inversely associated with the number of failed CCAS-S test items but not with SARA score. Onset and peak latencies of CRs were longer in SCA3 patients and correlated with disease duration. Repeated sessions of cerebellar anodal tDCS did not affect CR acquisition, but had a significant treatment effect on both timing parameters. While a shift of CRs toward the conditioned stimulus was observed in the sham group (i.e., timing became more similar to that of healthy controls, presumably reflecting the effect of a second eyeblink conditioning session), anodal tDCS induced a shift of CRs in the opposite direction (i.e., toward the unconditioned stimulus). Conclusion: Our findings provide evidence that cerebellar tDCS is capable of modifying cerebellar function in SCA3 patients. Future studies should assess whether this intervention similarly modulates temporal processing in other degenerative ataxias.

Abstract Background Rapid antigen diagnostic tests (Ag-RDTs) are the most widely used point-of-care tests for detecting SARS-CoV-2 infection. Since the accuracy may have altered by changes in SARS-CoV-2 epidemiology, indications for testing, sampling and testing procedures, and roll-out of COVID-19 vaccination, we evaluated the performance of three prevailing SARS-CoV-2 Ag-RDTs. Methods In this cross-sectional study, we consecutively enrolled individuals aged >16 years presenting for SARS-CoV-2 testing at three Dutch public health service COVID-19 test sites. In the first phase, participants underwent either BD-Veritor System (Becton Dickinson), PanBio (Abbott), or SD-Biosensor (Roche Diagnostics) testing with routine sampling procedures. In a subsequent phase, participants underwent SD-Biosensor testing with a less invasive sampling method (combined oropharyngeal-nasal [OP-N] swab). Diagnostic accuracies were assessed against molecular testing. Results Six thousand nine hundred fifty-five of 7005 participants (99%) with results from both an Ag-RDT and a molecular reference test were analysed. SARS-CoV-2 prevalence and overall sensitivities were 13% (188/1441) and 69% (129/188, 95% CI 62–75) for BD-Veritor, 8% (173/2056) and 69% (119/173, 61–76) for PanBio, and 12% (215/1769) and 74% (160/215, 68–80) for SD-Biosensor with routine sampling and 10% (164/1689) and 75% (123/164, 68–81) for SD-Biosensor with OP-N sampling. In those symptomatic or asymptomatic at sampling, sensitivities were 72–83% and 54–56%, respectively. Above a viral load cut-off (≥5.2 log10 SARS-CoV-2 E-gene copies/mL), sensitivities were 86% (125/146, 79–91) for BD-Veritor, 89% (108/121, 82–94) for PanBio, and 88% (160/182, 82–92) for SD-Biosensor with routine sampling and 84% (118/141, 77–89) with OP-N sampling. Specificities were >99% for all tests in most analyses. Sixty-one per cent of false-negative Ag-RDT participants returned for testing within 14 days (median: 3 days, interquartile range 3) of whom 90% tested positive. Conclusions Overall sensitivities of three SARS-CoV-2 Ag-RDTs were 69–75%, increasing to ≥86% above a viral load cut-off. The decreased sensitivity among asymptomatic participants and high positivity rate during follow-up in false-negative Ag-RDT participants emphasise the need for education of the public about the importance of re-testing after an initial negative Ag-RDT should symptoms develop. For SD-Biosensor, the diagnostic accuracy with OP-N and deep nasopharyngeal sampling was similar; adopting the more convenient sampling method might reduce the threshold for professional testing.

Introduction Ear pain is the most prominent symptom of childhood acute otitis media (AOM). To control the pain and reduce reliance on antibiotics, evidence of effectiveness for alternative interventions is urgently needed. This trial aims to investigate whether analgesic ear drops added to usual care provide superior ear pain relief over usual care alone in children presenting to primary care with AOM.Methods and analysis This is a pragmatic, two-arm, individually randomised, open, superiority trial with cost-effectiveness analysis and nested mixed-methods process evaluation in general practices in the Netherlands. We aim to recruit 300 children aged 1–6 years with a general practitioner (GP) diagnosis of AOM and ear pain. Children will be randomly allocated (ratio 1:1) to either (1) lidocaine hydrochloride 5 mg/g ear drops (Otalgan) one to two drops up to six times daily for a maximum of 7 days in addition to usual care (oral analgesics, with/without antibiotics); or (2) usual care. Parents will complete a symptom diary for 4 weeks as well as generic and disease-specific quality of life questionnaires at baseline and 4 weeks. The primary outcome is the parent-reported ear pain score (0–10) over the first 3 days. Secondary outcomes include proportion of children consuming antibiotics, oral analgesic use and overall symptom burden in the first 7 days; number of days with ear pain, number of GP reconsultations and subsequent antibiotic prescribing, adverse events, complications of AOM and cost-effectiveness during 4-week follow-up; generic and disease-specific quality of life at 4 weeks; parents’ and GPs’ views and experiences with treatment acceptability, usability and satisfaction.Ethics and dissemination The Medical Research Ethics Committee Utrecht, the Netherlands, has approved the protocol (21-447/G-D). All parents/guardians of participants will provide written informed consent. Study results will be submitted for publication in peer-reviewed medical journals and presented at relevant (inter)national scientific meetings.Trial registration The Netherlands Trial Register: NL9500; date of registration: 28 May 2021. At the time of publication of the study protocol paper, we were unable to make any amendments to the trial registration record in the Netherlands Trial Register. The addition of a data sharing plan was required to adhere to the International Committee of Medical Journal Editors guidelines. The trial was therefore reregistered in ClinicalTrials.gov (NCT05651633; date of registration: 15 December 2022). This second registration is for modification purposes only and the Netherlands Trial Register record (NL9500) should be regarded as the primary trial registration.

Background Integrin α7β1 is a major laminin receptor in skeletal and cardiac muscle. In skeletal muscle, integrin α7β1 plays an important role during muscle development and has been described as an important modifier of skeletal muscle diseases. The integrin α7β1 is also highly expressed in the heart, but its precise role in cardiac function is unknown. Mutations in the integrin α7 gene (ITGA7) have been reported in children with congenital myopathy. Methods and Results In this study, we described skeletal and cardiac muscle pathology in Itga7−/− mice and 5 patients from 2 unrelated families with ITGA7 mutations. Proband in family 1 presented a homozygous c.806_818del [p.S269fs] variant, and proband in family 2 was identified with 2 intron variants in the ITGA7 gene. The complete absence of the integrin α7 protein in muscle supports the ITGA7 mutations are pathogenic. We performed electrocardiography, echocardiography, or cardiac magnetic resonance imaging, and histological biopsy analyses in patients with ITGA7 deficiency and Itga7−/− mice. The patients exhibited cardiac dysrhythmia and dysfunction from the third decade of life and late‐onset respiratory insufficiency, but with relatively mild limb muscle involvement. Mice demonstrated corresponding abnormalities in cardiac conduction and contraction as well as diaphragm muscle fibrosis. Conclusions Our data suggest that loss of integrin α7 causes a novel form of adult‐onset cardiac dysfunction indicating a critical role for the integrin α7β1 in normal cardiac function and highlights the need for long‐term cardiac monitoring in patients with ITGA7‐related congenital myopathy.

Abstract Epigenomic dysregulation is a common pathological feature in human hematological malignancies. H3K9me3 emerges as an important epigenomic marker in acute myeloid leukemia (AML). Its associated methyltransferases, such as SETDB1, suppress AML leukemogenesis, whilst H3K9me3 demethylases KDM4C is required for mixed-lineage leukemia rearranged AML. However, the specific role and molecular mechanism of action of another member of the KDM4 family, KDM4A has not previously been clearly defined. In this study, we delineated and functionally validated the epigenomic network regulated by KDM4A. We show that selective loss of KDM4A is sufficient to induce apoptosis in a broad spectrum of human AML cells. This detrimental phenotype results from a global accumulation of H3K9me3 and H3K27me3 at KDM4A targeted genomic loci thereby causing downregulation of a KDM4A-PAF1 controlled transcriptional program essential for leukemogenesis, distinct from that of KDM4C. From this regulatory network, we further extracted a KDM4A-9 gene signature enriched with leukemia stem cell activity; the KDM4A-9 score alone or in combination with the known LSC17 score, effectively stratifies high-risk AML patients. Together, these results establish the essential and unique role of KDM4A for AML self-renewal and survival, supporting further investigation of KDM4A and its targets as a potential therapeutic vulnerability in AML.

Abstract Background Acute otitis media (AOM) is among the most common paediatric conditions managed in primary care. Most recent estimates of the cost of AOM date from a decade ago and lack a full societal perspective. We therefore explored the societal cost of childhood AOM in the Netherlands within the setting of a trial comparing the effectiveness of an intervention aimed at educating general practitioners (GPs) about pain management in AOM compared to usual care. Methods Economic analysis alongside a cluster randomised controlled trial conducted between February 2015 and May 2018 in 37 practices (94 GPs). In total, 224 children with AOM were included of which 223 (99%) completed the trial (intervention: n = 94; control: n = 129). The cost of AOM due to health care costs, patient and family costs, and productivity losses by parent caregivers were retrieved from study diaries and primary care electronic health records, during 28-day follow-up. We calculated mean cost (€ and $) per AOM episode per patient with standard deviations (SD, in €) regardless of study group assignment because there was no clinical effect of the trial intervention. In sensitivity analysis, we calculated cost in the intervention and usual care group, after exclusion of extreme outliers. Results Mean total AOM cost per patient were €565.93 or $638.78 (SD €1071.01); nearly 90% of these costs were due to productivity losses experienced by parents. After exclusion of outliers, AOM cost was €526.70 or $594.50 (SD €987.96) and similar in the intervention and usual care groups: €516.10 or $582.53 (SD €949.69) and €534.55 or $603.36 (SD €920.55) respectively. Conclusions At €566 or $639 per episode, societal cost of AOM is higher than previously known and mainly driven by productivity losses by children’s parents. Considering its high incidence, AOM poses a significant economic burden that extends beyond direct medical costs. Trial registration Netherlands Trial Register no. NTR4920: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4920 .

Background: Cerebellar ataxia generally results from a lesion disrupting the corticopontocerebellar or cerebellothalamocortical tract. The cerebellar inhibition (CBI) paradigm represents a dual-coil transcranial magnetic stimulation protocol that interrogates the integrity of the latter pathway. Whether CBI has clinical relevance in ataxia patients remains largely unknown because associations with pertinent disease severity measures in etiologically homogeneous cohorts have not been previously examined. Objective: To investigate if CBI correlates with clinical and functional indices of disease severity in individuals with spinocerebellar ataxia type 3 (SCA3). Methods: CBI was assessed in fourteen SCA3 patients by paired-pulse cerebellar-motor cortex (M1) stimulation using interstimulus intervals of 3, 5, and 10 ms. Correlation coefficients were determined between CBI and ataxia severity, manual dexterity, and walking speed. Results: Suppression of M1 excitability occurred 5 ms following a contralateral cerebellar conditioning stimulus in SCA3 patients, but, on average, CBI was significantly reduced as compared to a healthy control group from the literature (p

The degenerative ataxias comprise a heterogeneous group of inherited and acquired disorders that are characterized by a progressive cerebellar syndrome, frequently in combination with one or more extracerebellar signs. Specific disease-modifying interventions are currently not available for many of these rare conditions, which underscores the necessity of finding effective symptomatic therapies. During the past five to ten years, an increasing number of randomized controlled trials have been conducted examining the potential of different non-invasive brain stimulation techniques to induce symptomatic improvement. In addition, a few smaller studies have explored deep brain stimulation (DBS) of the dentate nucleus as an invasive means to directly modulate cerebellar output, thereby aiming to alleviate ataxia severity. In this paper, we comprehensively review the clinical and neurophysiological effects of transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and dentate nucleus DBS in patients with hereditary ataxias, as well as the presumed underlying mechanisms at the cellular and network level and perspectives for future research.

BACKGROUND: The safety, tolerability, and immunogenicity of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% (dual-vial unit of human immunoglobulin 10% and recombinant human hyaluronidase [rHuPH20]) were assessed in children with primary immunodeficiency diseases (PIDs). METHODS: This phase 4, post-authorization, prospective, interventional, multicenter study (NCT03116347) conducted in the European Economic Area, enrolled patients aged 2 to < 18 years with a documented PID diagnosis who had received immunoglobulin therapy for ≥ 3 months before enrollment. New fSCIG 10% starters underwent fSCIG 10% dose ramp-up for ≤ 6 weeks (epoch 1) before receiving fSCIG 10% for ≤ 3 years (epoch 2); patients pretreated with fSCIG 10% entered epoch 2 directly. The primary outcome was the number and rate (per infusion) of all noninfectious treatment-related serious and severe adverse events (AEs). RESULTS: In total, 42 patients were enrolled and dosed (median [range] age: 11.5 [3-17] years; 81% male; 23 new starters; 19 pretreated). Overall, 49 related noninfectious, treatment-emergent AEs (TEAEs) were reported in 15 patients; most were mild in severity (87.8%). No treatment-related serious TEAEs were reported. Two TEAEs (infusion site pain and emotional distress) were reported as severe and treatment-related in a single new fSCIG 10% starter. The rate of local TEAEs was lower in pretreated patients (0.1 event/patient-year) versus new starters (1.3 events/patient-year). No patients tested positive for binding anti-rHuPH20 antibodies (titer of ≥ 1:160). CONCLUSIONS: No safety signals were identified, and the incidence of local AEs declined over the duration of fSCIG 10% treatment. This study supports fSCIG 10% long-term safety in children with PIDs. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT03116347.