OBJECTIVE: To determine the frequency and clinical impact of loss-of-interruption (LOI) and duplication-of-interruption (DOI) modifier variants of the HTT CAG and CCG repeat in a cohort of individuals with Huntington disease (HD).
METHODS: We screened symptomatic HD participants from the UBC HD Biobank and five research sites for sequence variants. Following variant identification, we examined the clinical impact and frequency in the reduced penetrance range.
RESULTS: Participants with CAG-CCG LOI and CCG LOI variants have a similar magnitude of earlier onset of HD, by 12.5 years. The sequence variants exhibit ancestry-specific differences. Participants with the CAG-CCG LOI variant also have a faster progression of TMS by 1.9 units per year. Symptomatic participants with the CAG-CCG LOI variant show enrichment in the reduced penetrance range. The CAG-CCG LOI variant explains the onset of two symptomatic HD participants with diagnostic repeats below the pathogenetic range.
CONCLUSIONS: Our findings have significant clinical implications for participants with the CAG-CCG LOI variant who receive inaccurate diagnoses near diagnostic cut-off ranges. Improved diagnostic testing approaches and clinical management are needed for these individuals. We present the largest and most diverse HTT CAG and CCG sequence variant cohort and emphasize their importance in clinical presentation in HD.

BACKGROUND: Cytomegalovirus infection (CMV) is a common complication after allogeneic hematopoietic stem cell transplantation (AHSCT). CMV infection increases transplantation costs; however, the extent of the financial burden may vary in different countries. This study aims to determine the clinical and economic impact of CMV infection in patients undergoing AHSCT in a middle-income country.
METHODS: A total of 150 adult and pediatric patients post-AHSCT were included for analysis. In addition to incidence of CMV infections, data on graft versus host disease (GVHD) were also collected. Standard hospital charges for AHSCT and any additional transplantation-related expenditure within 12 months were also retrieved in 104 patients.
RESULTS: CMV infection, acute GVHD and chronic GVHD occurred in 38.7%, 60.7%, and 22.0% of patients, respectively. Patients with CMV infections had higher readmission rates compared to those who did not (67.2% vs. 47.8%; p = 0.020). Additional expenditure was seen in HLA-haploidentical AHSCT and CMV infection (MYR11 712.25/USD2 504.49; p < 0.0001 and MYR5 807.24/USD1 241.79; p = 0.036), respectively.
CONCLUSIONS: This single-center study demonstrated that patients who underwent HLA-haploidentical AHSCT and subsequently developed CMV infection had higher transplantation expenditures compared to those who had matched-related transplantation. Further studies should be conducted to evaluate if primary prophylaxis against CMV is cost-effective, especially in patients who undergo HLA-haploidentical AHSCT.

BACKGROUND: Clinical impact of plasma metagenomic next-generation sequencing (mNGS) on infection diagnosis and antimicrobial therapy in immunocompromised patients with suspected infection remains unclear.
METHODS: Between March and December 2022, 424 cases with fever, infection history, mechanical ventilation, or imaging abnormalities underwent plasma mNGS testing at a single center. Eleven patients have received solid organ transplantation, and the remaining patients were categorised into febrile neutropenia (FN), non-neutropenia (NN), and non-haematologic disease (NTHD) groups based on immunosuppression severity. The diagnostic rate of infection and the utilisation of antimicrobial agents based on mNGS were assessed.
RESULTS: The use of mNGS significantly improved the diagnostic rates for fungi in the FN (56.1%, P = 0.003) and NN (58.8%, P = 0.008) groups versus the NHD group (33.3%). Positive impacts associated with therapy were significantly greater than negative impacts across all three groups (all P < 0.001), and the utilisation of escalation therapy was significantly more frequent in the FN group than in the NN groups (P = 0.006). Over 70% of cases with negative mNGS results across the three groups underwent de-escalation therapy, with >1/3 being discontinued, preventing antimicrobial overuse.
CONCLUSIONS: Plasma mNGS has a clinically confirmed positive impact in immunocompromised patients with neutropenia, improving the diagnosis of fungal infections and antimicrobial therapy.

Solid organ transplant (SOT) recipients are particularly susceptible to infections caused by multidrug-resistant organisms (MDRO) and are often the first to be affected by an emerging resistant pathogen. Unfortunately, their prevalence and impact on morbidity and mortality according to the type of graft is not systematically reported from high-as well as from low and middle-income countries (HIC and LMIC). Thus, epidemiology on MDRO in SOT recipients could be subjected to reporting bias. In addition, screening practices and diagnostic resources may vary between countries, as well as the availability of new drugs. In this review, we aimed to depict the burden of main Gram-negative MDRO in SOT patients across HIC and LMIC and to provide an overview of current diagnostic and therapeutic resources.

OBJECTIVE: Transthoracic echocardiography is recommended in all patients with acute coronary syndrome but is time-consuming and lacks an evidence base. We aimed to assess the feasibility, diagnostic accuracy and time-efficiency of hand-held echocardiography in patients with acute coronary syndrome and describe the impact of echocardiography on clinical management in this setting.
RESULTS: Patients with acute coronary syndrome underwent both hand-held and transthoracic echocardiography with agreement between key imaging parameters assessed using kappa statistics. The immediate clinical impact of hand-held echocardiography in this population was systematically evaluated.Overall, 262 patients (65±12 years, 71% male) participated. Agreement between hand-held and transthoracic echocardiography was good-to-excellent (kappa 0.60-1.00) with hand-held echocardiography having an overall negative predictive value of 95%. Hand-held echocardiography was performed rapidly (7.7±1.6 min) and completed a median of 5 [interquartile range 3-20] hours earlier than transthoracic echocardiography. Systematic hand-held echocardiography in all patients with acute coronary syndrome identified an important cardiac abnormality in 50% and the clinical management plan was changed by echocardiography in 42%. In 85% of cases, hand-held echocardiography was sufficient for patient decision-making and transthoracic echocardiography was no longer deemed necessary.
CONCLUSIONS: In patients with acute coronary syndrome, hand-held echocardiography provides comparable results to transthoracic echocardiography, can be more rapidly applied and gives sufficient imaging information for decision-making in the vast majority of patients. Systematic echocardiography has clinical impact in half of patients, supporting the clinical utility of echocardiography in this population, and providing an evidence-base for current guidelines.

UNASSIGNED: To evaluate the effectiveness of the role of advanced nurse practitioners compared to physicians-led/ usual care (care managed by medical doctors or non-advanced nurse practitioners).
UNASSIGNED: Advanced nurse practitioners contribute to the improvement of quality patient care and have substantial potential to optimise the health of people globally. Since the formal recognition of advanced nurse practitioners by the International Council of Nurses, among others, the role has been adopted across most departments and clinical specialties, particularly in high-income countries.
UNASSIGNED: Systematic review of primary research evidence.
UNASSIGNED: MEDLINE, EMBASE, CINAHL, Cochrane registry, Cochrane trials, and Cochrane EPOC (PDQ Evidence) were searched for randomised controlled trials (RCTs) of patient care and health resource utilisation outcomes associated with advanced nurse practitioners.
UNASSIGNED: The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The chosen articles were restricted to full-text English language trials published in the last 20 years, incorporating comparators of usual care. Search terms were limited to variations of advanced nurse practitioner role and practice. The eligible studies were bias risk assessed and quality assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE). Clinical and service outcomes were analysed using narrative synthesis as the marked heterogeneity between studies precluded meta-analysis.
UNASSIGNED: Thirteen RCTs were reviewed. All of them were conducted across high-income countries within primary care and hospital settings involving paediatric and adult patients. Five trials were assessed as high quality, and eight were of low to moderate quality. Positive effects were demonstrated for the impact of advanced nurse practitioners on usual care; for indigestion, mean difference [MD] 2.3: 95% CI 1.4, 3.1]), perceptions of health status [ (MD -140.6; 95% CI -184.8, -96.5)], satisfaction levels [ (MD ranged from -8.79; 95% CI -13.59, -3.98 to 0.61; 95% CI -4.84, 6.05)], physical function (1.58 [SD 0.76] v. 1.81 [SD 0.90]), and blood pressure control (systolic [133 [SD 21] v. 135 [SD 19] mmHg p = 0.04] and diastolic [77 [SD 10] v. 80 [SD 11] mmHg p = 0.007]) were looked at. Positive effects related to service provision included improved patient satisfaction and reductions in waiting times and costs, which significantly favored advanced nurse practitioners (all p < 0.05).
UNASSIGNED: The evidence of this review supports the positive impact of advanced nurse practitioners on clinical and service-related outcomes: patient satisfaction, waiting times, control of chronic disease, and cost-effectiveness especially when directly compared to medical practitioner-led care and usual care practices - in primary, secondary and specialist care settings involving both adult and pediatric populations.

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BACKGROUND: Biomarker-informed criteria were proposed for the diagnosis of Alzheimer\'s disease (AD) by the National Institute on Aging and the Alzheimer\'s Association (NIA-AA) in 2011; however, the adequacy of this criteria has not been sufficiently evaluated.
METHODS: ReDeMa (Red de Demencias de Madrid) is a regional cohort of patients attending memory and neurology clinics. Core cerebrospinal fluid biomarkers were obtained, NIA-AA diagnostic criteria were considered, and changes in diagnosis and management were evaluated.
RESULTS: A total of 233 patients were analyzed (mean age 70 years, 50% women, 73% AD). The diagnostic language was modified significantly, with a majority assumption of NIA-AA definitions (69%). Confidence in diagnosis increased from 70% to 92% (p < 0.0005) and management was changed in 71% of patient/caregivers. The influence of neurologist\'s age or expertise on study results was minimal.
CONCLUSIONS: The NIA-AA criteria are adequate and utile for usual practice in memory and neurology clinics, improving diagnostic confidence and significantly modifying patient management.
CONCLUSIONS: Alzheimer\'s disease (AD) cerebrospinal fluid (CSF) biomarkers increase diagnostic certainty regardless of the neurologist.AD CSF biomarkers lead to changes in disease management .Biomarker-enriched, 2011 NIA-AA diagnostic criteria are adequate for usual practice.

Flow cytometry-based immunophenotyping is a mainstay of diagnostics in acute myeloid leukaemia (AML). Aberrant CD56 and T-cell antigen expression is observed in a fraction subset of AML cases, but the clinical relevance remains incompletely understood. Here, we retrospectively investigated the association of CD56 and T-cell marker expression with disease-specific characteristics and outcome of 324 AML patients who received intensive induction therapy at our centre between 2011 and 2019. We found that CD2 expression was associated with abnormal non-complex karyotype, NPM1 wild-type status and TP53 mutation. CD2 also correlated with a lower complete remission (CR) rate (47.8% vs. 71.6%, p = 0.03). CyTdT and CD2 were associated with inferior 3-year event-free-survival (EFS) (5.3% vs. 33.5%, p = 0.003 and 17.4% vs. 33.1%, p = 0.02, respectively). CyTdT expression was also correlated with inferior relapse-free survival (27.3% vs. 48.8%, p = 0.04). In multivariable analyses CD2 positivity was an independent adverse factor for EFS (HR 1.72, p = 0.03). These results indicate a biological relevance of aberrant T-cell marker expression in AML and provide a rationale to further characterise the molecular origin in T-lineage-associated AML.

OBJECTIVE: To accurately evaluate non-ST-elevated acute cardiac syndrome (NSTE-ACS), the quality of high-sensitive cardiac troponin (hs-cTn) assays is of vital importance. The 2020 revision of the NSTE-ACS guideline includes clinical decision-limits (CDL\'s) to both rule-in and rule-out NSTE-ACS for most commercially available platforms, providing both 0/1 h and 0/2 h delta limits. Our study evaluated whether laboratories are able to meet the analytical performance specifications for imprecision (APS) for hs-cTnT.
METHODS: Results from external quality assurance (EQA) in commutable samples were used to evaluate the current and historic performance of analyzers. The performance of analyzers that either passed or failed to comply with 0/1 h-APS were used on a real-world dataset of first hs-cTnT-values to simulate 10.000 samples of t=0, t=1 and t=2 h values with multiple delta\'s for all relevant CDL\'s. We compared the simulated values to the input values to obtain the percentage of aberrant results simulated.
RESULTS: The majority of analyzers complies with APS for rule-in in 2022 (0/1 h: 90.4 % and 0/2 h: 100 %), compliance for the 0/1 h rule-out is still far from optimal (0/1 h: 30.7 %, 0/2 h: 75.4 %), with improving compliance over the past years (rule-in p=<0.0001, rule-out p=0.011, χ2). Whilst 0/1 h-APS-passing analyzers have a minute risk to falsely rule-out patients whom should be ruled-in (0.0001 %), failing performance increases this risk to 2.1 % upon using 0/1 h CDL\'s. Here, adopting 0/2 h CDL\'s is favorable (0.01 %).
CONCLUSIONS: Laboratories that fail to meet hs-cTnT 0/1 h-APS should improve their performance to the required and achievable level. Until performance is reached clinics should adopt the 0/2 h CDL\'s.