Understanding Barriers to Diagnosis in a Rare, Genetic Disease: Delays and Errors Diagnosing Schwannomatosis

Diagnosis of rare, genetic diseases is challenging, but conceptual frameworks of the diagnostic process can be used to guide benchmarking and process improvement initiatives. Using the National Academy of Medicine diagnostic framework, we assessed the extent of, and reasons for, diagnostic delays and errors in schwannomatosis, a neurogenetic syndrome characterized by nerve sheath tumors and chronic pain. We reviewed the medical records of 97 patients with confirmed or probable schwannomatosis seen in two U.S. tertiary care clinics from 2005-2016. Survival analysis revealed a median time from first symptom to diagnosis of 16.7 years (95% CI, 7.5-26.0 years) and median time from first medical consultation to diagnosis of 9.8 years (95% CI, 3.5-16.2 years). Factors associated with longer times to diagnosis included initial signs/symptoms that were intermittent, non-specific, or occurred at younger ages (p<0.05). Thirty-six percent of patients experienced a misdiagnosis of underlying genetic condition (18.6%), pain etiology (16.5%) and/or tumor imaging/pathology (11.3%). One-fifth (19.6%) of patients had a clear missed opportunity for appropriate workup that could have led to an earlier schwannomatosis diagnosis. These results suggest that interventions in clinician education, genetic testing availability, expert review of pathology findings, and automatic triggers for genetics referrals may improve diagnosis in schwannomatosis.

Pattern of acquisition of hospital-associated pathogens in the ICU of an academic tertiary care hospital

BACKGROUND: Among hospitalized patients, a 48-hour window from time of hospitalization defines nosocomial infections and guides empiric antibiotic selection. This time frame may lead to overuse of broad-spectrum antibiotics. Our primary objective was to determine the earliest and median time since hospital admission to acquire antibiotic-resistant pathogens among patients admitted to the intensive care unit (ICU) of an academic, tertiary care hospital. METHODS: Retrospective chart review was conducted for adult patients admitted to the ICU from home or another hospital within the same health authority in 2018, to identify the time to acquisition of hospital-associated pathogens: methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci, extended-spectrum beta-lactamase (ESBL)–producing Enterobacterales, non-ESBL ceftriaxone-resistant Enterobacterales, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Patients transferred from hospitals outside the health authority, admitted to ICU after 14 days of hospitalization, who were solid organ or bone marrow transplant recipients, or who were otherwise immunocompromised were excluded. RESULTS: In 2018, 1,343 patients were admitted to this ICU; 820 met the inclusion criteria. Of these, 121 (14.76%) acquired a hospital-associated pathogen in the ICU. The probability of isolating a hospital-associated pathogen by 48 hours of hospital admission was 3%. The earliest time to isolate any of these pathogens was 29 hours, and the median was 9 days (interquartile range [IQR] 3.8–15.6 days). CONCLUSIONS: Most patients (85.3%) in this ICU never acquired a hospital-associated pathogen. The median time to acquire a hospital-associated pathogen among the remaining patients suggests that initiating empiric broad-spectrum antibiotics on the basis of a 48-hour threshold may be premature.

Risk factors for the accuracy of the initial diagnosis of malaria cases in China: a decision-tree modelling approach

Background Early accurate diagnosis and risk assessment for malaria are crucial for improving patients’ terminal prognosis and preventing them from progressing to a severe or critical stage. This study aims to describe the accuracy of the initial diagnosis of malaria cases with different characteristics and the factors that affect the accuracy in the context of the agenda for a world free of malaria. Methods A retrospective study was conducted on 494 patients admitted to hospitals with a diagnosis of malaria from January 2014 through December 2016. Descriptive statistics were calculated, and decision tree analysis was performed to predict the probability of patients who may be misdiagnosed. Results Of the 494 patients included in this study, the proportions of patients seeking care in county-level, prefecture-level and provincial-level hospitals were 27.5% (n = 136), 26.3% (n = 130) and 8.3% (n = 41), respectively; the proportions of patients seeking care in clinic, township health centre and Centres for Disease Control and Prevention were 25.9% (n = 128), 4.1% (n = 20), and 7.9% (n = 39), respectively. Nearly 60% of malaria patients were misdiagnosed on their first visit, and 18.8% had complications. The median time from onset to the first visit was 2 days (IQR: 0-3 days), and the median time from the first visit to diagnosis was 3 days (IQR: 0–4 days). The decision tree classification of malaria patients being misdiagnosed consisted of six categorical variables: healthcare facilities for the initial diagnosis, time interval between onset and initial diagnosis, region, residence type, insurance status, and age. Conclusions Insufficient diagnostic capacity of healthcare facilities with lower administrative levels for the first visit was the most important risk factor in misdiagnosing patients. To reduce diagnostic errors, clinicians, government decision-makers and communities should consider strengthening the primary care facilities, the time interval between onset and initial diagnosis, residence type, and health insurance status.

PDGRFA-mutant gastrointestinal stromal tumours (GISTs) in Eastern England: clinicopathological features and outcomes of 50 patients diagnosed between 2008-2021

Background PDGRFA-mutant gastrointestinal tumours (GISTs) comprise approximately 10% of GISTs and are mostly gastric. Targeted therapies against these tumours have historically been limited by tyrosine kinase inhibitor (TKI)-resistance. We reviewed the characteristics and outcome of all PDGRFA-mutant patients seen at our centre over the last 13 years. Methods All PDGRFA-mutant patients seen at the Cambridge University Hospitals NHS Foundation Trust GIST clinic from July 2008-July 2021 were retrospectively reviewed and followed up. Results: 50 PDGRFA-mutant GIST patients were diagnosed during the 13-year period. 60% were male. Median tumour size was 5 cm and the majority were epithelioid (44%) or mixed (36%) type. Commonest primary location was the gastric body (52%). In non-metastatic patients the low-risk modified AFIP risk group was the most common (65.2%). PDGFRA exon 18 (86%) were the most common PDGFRA mutations, most being imatinib resistant. None harboured a KIT mutation. 38% of cases had high KIT expression (immunohistochemistry), whilst 48% had patchy expression and 14% were negative. Most were positive for DOG1 (94%). CD34 was highly expressed in 48% of cases. 13% developed metastases during the 13-year follow-up period: liver (80%) being the commonest site. 76% of all patients underwent radical resection. 14% received TKI therapy. After a median follow-up of 55.1 months, 82% remained alive: 6 patients died from metastatic GIST; 3 from other causes. Median time to metastatic disease was 30.1 months, and median time from metastatic diagnosis to death was 18.5 months. Patients who presented with metastatic disease had the poorest survival outcome (p=0.001) Conclusion To date this is the largest single-centre European PDGRFA-mutant GIST cohort. Results highlight the generally indolent nature of PDGRFA-mutant disease (contrasted to the poor outcome of those who present with metastatic disease), male and gastric preponderance (unlike KIT-mutant GISTs), and variable KIT expression.

The effect of radiological imaging on treatment delay and hospitalisation in patients with peritoneal dialysis-related peritonitis: A secondary analysis of the PROMPT study

Background: In peritoneal dialysis-related peritonitis (peritonitis), delayed antibiotic therapy is associated with adverse outcomes. Identifying barriers to timely treatment may improve outcomes. Aim: To determine the impact of radiological investigations on treatment delay and predictors of hospitalisation and length of stay (LOS). Methods: Retrospective review of patients with presumed peritonitis in Western Australia. Results: In 153 episodes of peritonitis, 79 (51.6%) resulted in admission with a median LOS of 3 days (Q1, Q3: 1, 6). In a multivariable model, significant predictors of admission were abnormal exit-site (odds ration (OR) 5.7; 95% confidence interval (CI): 1.4, 23.6; p = 0.02), failure to detect a cloudy bag (OR 11.9; 95%CI: 3.2, 44.7; p < 0.001), female sex (OR 3.3; 95% CI: 1.4, 9.7; p = 0.027), radiological imaging within 24 h (OR 8.8; 95% CI: 2.2, 34.8; p = 0.002) and contact with ambulant care facility (OR 0.32, 95% CI: 0.11, 0.98; p = 0.04). Imaging within 24 h of presentation occurred in 41 (27%) episodes of peritonitis, mostly plain X-rays (91%), of which 83% were clinically irrelevant. Imaging performed within 24 h of presentation increased the median time to antibiotic treatment (2.9 h (Q1, Q3: 1.6, 6.4) vs 2.0 h (Q1, Q3: 1, 3.8; p = 0.046)). Imaging performed prior to administering antibiotics significantly increased the median time to treatment (4.7 h (Q1, Q3: 2.9, 25) vs 1.5 h (Q1, Q3: 0.75, 2.5; p < 0.001)) in those where imaging followed antibiotic treatment. Conclusions: Half of all presentations with peritonitis result in hospital admission. Radiological imaging was associated with an increased risk of hospitalisation, potentially contributes to treatment delay, and was mostly clinically unnecessary. When required, imaging should follow antibiotic therapy.

Comparative longitudinal variation of total IgG and IgA anti-SARS-CoV-2 antibodies in recipients of BNT162b2 vaccination

Objectives This article aims to summarize the 6-month variation of a vast array of anti-SARS-CoV-2 antibodies in recipients of BNT162b2 mRNA-based vaccination. Methods The study population consisted of 84 baseline SARS-CoV-2 seronegative healthcare employees (median age 45 years, 53.6% females), receiving mRNA-based BNT162b2 primary vaccination cycle. Blood was collected before the first and second BNT162b2 vaccine doses, as well as 1, 3 and 6 months afterwards. The serum titers of the following anti-SARS-CoV-2 antibodies were assayed: total anti-RBD (receptor binding domain), anti-spike trimeric IgG, anti-RBD IgG and anti-spike S1 IgA. Results All antibodies’ levels peaked 1 month after vaccination, but then displayed a considerable decrease. The median rates of 6-month decline were −95% for IgG anti-SARS-CoV-2 RBD, −85% for IgG anti-SARS-CoV-2 trimeric spike, −73% for IgA anti-SARS-CoV-2 S1 and −56% for total anti-SARS-CoV-2 RBD antibodies, respectively. The median time of seronegativization was estimated at 579 days for total anti-SARS-CoV-2 RBD antibodies, 271 days for IgG anti-SARS-CoV-2 trimeric spike, 264 days for IgG anti-SARS-CoV-2 RBD and 208 days for IgA anti-SARS-CoV-2 S1, respectively. The rate of seropositive subjects declined from 98–100% at the peak to 50–100% after 6 months. The inter-individual variation of anti-SARS-CoV-2 antibodies reduction at 6 months was 3–44% from the peak. Conclusions The results of this longitudinal serosurvey demonstrate that the titer of anti-SARS-CoV-2 antibodies declined 6 months after BNT162b2 vaccination, with median time of IgG/IgA seronegativization estimated between 7 and 9 months, thus supporting the opportunity of administering vaccine boosters approximately 5 to 6 months after the last dose of the primary vaccination cycle.

Randomized Trial of Molnupiravir or Placebo in Patients Hospitalized with Covid-19

Molnupiravir is an oral agent a metabolite of which has activity against SARS-CoV-2. In a controlled trial in adults hospitalized for Covid-19 who had symptoms for 10 days or less prior to randomization, patients received placebo (n=75) or varying doses of molnupiravir (n=218) administered twice-daily for 5 days. There was no impact of treatment on death. Median time to sustained recovery was 9 days in all groups, with day 29 recovery rates ranging from 81.5%-85.2%. There were no dose-limiting side effects or adverse events.

Treatment Dynamics in People Who Initiate Metformin or Sulfonylureas for Type 2 Diabetes: A National Cohort Study

Aim: To investigate the incidence of, and factors associated with addition and switching of glucose-lowering medications within 12-months of initiating metformin or a sulfonylurea for type 2 diabetes (T2D).Methods: We identified 109,573 individuals aged 18–99 years who initiated metformin or a sulfonylurea between July 2013 and April 2015 using Australian National Diabetes Service Scheme (NDSS) data linked with national dispensing data. Cox proportional hazards regression was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CI) for factors associated with time to addition to or switch from metformin or sulfonylurea over a 12-months follow-up.Results: Treatment addition or switching occurred in 18% and 4% of individuals who initiated metformin and in 28% and 13% of individuals who initiated sulfonylureas. Median time to addition was 104 days for metformin and 82 days for sulfonylureas. Median time to switching was 63 days for metformin and 52 days for sulfonylureas. Congestive heart failure, nicotine dependence, end stage renal disease and dispensing of systemic corticosteroids were associated with higher likelihood of treatment additions and switching in individuals initiating metformin. Antipsychotic dispensing was associated with a higher likelihood of treatment addition in individuals initiating sulfonylureas. Women initiating metformin were less likely to receive treatment additions but more likely to switch treatment than men.Conclusion: Nearly one quarter of Australians who initiate treatment for T2D with metformin or sulfonylureas switch or receive additional treatment within 12-months, with those who initiate sulfonylureas more likely to switch or receive additional treatment than those who initiate metformin.

A Phase 2 randomized, double-blind, placebo-controlled trial of the monoclonal antibody MHAA4549A in patients with acute uncomplicated influenza A infection

Background MHAA4549A, a human monoclonal antibody targeting the influenza A hemagglutinin stalk, neutralizes influenza A virus in animal and human volunteer challenge studies. We investigated MHAA4549A safety and tolerability, efficacy, and pharmacokinetics in outpatients with acute, uncomplicated influenza A infection. Methods This was a Phase 2, randomized, double-blind, placebo-controlled trial of single intravenous (IV) doses of 3600 mg or 8400 mg MHAA4549A, or IV placebo in adult outpatients testing positive for influenza A. Patients were enrolled across 35 sites in 6 countries. Randomization and dosing occurred ≤ 72 hours of symptom onset; study duration was 14 weeks. The primary endpoint was the nature and frequency of adverse events (AEs). Secondary endpoints included median time to alleviation of all influenza symptoms, effects on nasopharyngeal viral load and duration of viral shedding, and MHAA4549A serum pharmacokinetics. Results Of 125 randomized patients, 124 received study treatment, with 99 confirmed positive for influenza A by central testing. Frequency of AEs between MHAA4549A and placebo groups was similar; nausea was most common (8 patients; 6.5%). MHAA4549A serum exposure was confirmed in all MHAA4549A-treated patients and was dose proportional. No hospitalizations or deaths occurred. Between MHAA4549A and placebo groups, no statistically significant differences occurred in median time to alleviation of all symptoms, nasopharyngeal viral load, or duration of viral shedding. Conclusions While MHAA4549A was safe and well-tolerated with confirmed exposure, the antibody did not improve clinical outcomes in patients with acute uncomplicated influenza A infection.

Effect of CD34+ cell dose on neutrophil and platelet engraftment kinetics in haematopoietic stem cell transplantation – A single-centre experience

Objectives: Haematopoietic stem cell transplantation (SCT) is curative for a number of benign and malignant hematological disorders. CD34 expression on haematopoietic progenitor cells is used to assess stem cell content in peripheral blood stem cell and bone marrow grafts. This study evaluated the relationship between numbers of CD34+ cells infused per kg and the timing of neutrophil and platelet engraftment. Materials and Methods: The effect of cell dose was studied in consecutive HSCT patients transplanted between November 2008 and December 2017. Neutrophil engraftment was defined as the first of 2 consecutive days with an absolute neutrophil count >0.5 × 109/L and platelet engraftment as unsupported platelet count >20 × 109/L for 7 days. Results: Of a total of 131 patients, 26 (19.8%) underwent an autologous SCT, while 105 (80.2%) underwent an allogeneic SCT. The median CD34 dose infused in the auto-SCT group was 5.29 × 106 CD34+cells/kg (IQR = 2.95–10.98) and 6.42 × 106 CD34+cells/kg (IQR = 4.20–9.20) in the allo-SCT group (P = 0.773). The median time to neutrophil engraftment in the auto-SCT group was 11 days (range 9.5–12) and in the allo-SCT group was 15 days (range 13–17), P ≤ 0.001. The median time to platelet engraftment in both groups was similar (12 days). When patients were divided into three groups based on CD34 dose (<5, 5–8 and >8), no difference was observed in the time to ANC or platelet engraftment. Similarly, no differences in time to engraftment were noted in each quartile of CD34 dosage in auto- and allo-SCT. Conclusion: Thus, it was concluded that a cell dose of approximately 5 × 106/kg provides reasonably rapid engraftment, with no advantage seen for a higher cell dose of >5.