Enrollment Criteria Research Articles

Physical rehabilitation in sarcopenia: modern approaches. (A literature review)

To determine the role of physical rehabilitation in sarcopenia. A systematic review including studies found in PubMed, MedLine, Scopus and Web of Science Core Collections databases for 2019-2022 was conducted. The used enrollment criteria were the following: systematic reviews, including cross-over or cohort studies targeting at persons aged from 40 to 90 years of both sexes, with available data on sarcopenia, its severe form or other combinations of physical performance markers called sarcopenia. The mandatory parameter for inclusion in the study was the presence of the effectiveness assessment of physical rehabilitation without limiting its parameters. The systematic review was performed in accordance with the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020. The best kind of training are 30-60-minute comprehensive methods with predominance of resistance exercises with minimum duration of the course of 3 months and frequency of 3 inconsistent in-person trainings per week under the supervision of a specialist for patients with sarcopenia in order to increase muscle strength and mass, as well as performance. The intensity should consist of the following parameters: start with fewer sets but more repetitions (12-15) with less intensity (55% of maximum) and move to more sets with less repetition (4-6) and greater intensity (>80% of maximum). This article describes the parameters of exercises that are most effective in terms of muscle strength and mass increase and safe for patients. The compilation and further study of this complex in practice are needed.

Treponema pallidum genetic diversity and its implications for targeted vaccine development: A cross-sectional study of early syphilis cases in Southwestern Colombia.

Venereal syphilis, caused by the spirochete Treponema pallidum subsp. pallidum (TPA), is surging worldwide, underscoring the need for a vaccine with global efficacy. Vaccine development requires an understanding of syphilis epidemiology and clinical presentation as well as genomic characterization of TPA strains circulating within at-risk populations. The aim of this study was to describe the clinical, demographic, and molecular features of early syphilis cases in Cali, Colombia. We conducted a cross-sectional study to identify individuals with early syphilis (ES) in Cali, Colombia through a city-wide network of public health centers, private sector HIV clinics and laboratory databases from public health institutions. Whole blood (WB), skin biopsies (SB), and genital and oral lesion swabs were obtained for measurement of treponemal burdens by polA quantitative polymerase chain reaction (qPCR) and for whole-genome sequencing (WGS). Among 1,966 individuals screened, 128 participants met enrollment criteria: 112 (87%) with secondary (SS), 15 (12%) with primary (PS) and one with early latent syphilis; 66/128 (52%) self-reported as heterosexual, while 48 (38%) were men who have sex with men (MSM). Genital ulcer swabs had the highest polA copy numbers (67 copies/μl) by qPCR with a positivity rate (PR) of 73%, while SS lesions had 42 polA copies/μl with PR of 62%. WB polA positivity was more frequent in SS than PS (42% vs 7%, respectively; p = 0.009). Isolation of TPA from WB by rabbit infectivity testing (RIT) was achieved in 5 (56%) of 9 ES WB samples tested. WGS from 33 Cali patient samples, along with 10 other genomic sequences from South America (9 from Peru, 1 from Argentina) used as comparators, confirmed that SS14 was the predominant clade, and that half of all samples had mutations associated with macrolide (i.e., azithromycin) resistance. Variability in the outer membrane protein (OMP) and vaccine candidate BamA (TP0326) was mapped onto the protein's predicted structure from AlphaFold. Despite the presence of mutations in several extracellular loops (ECLs), ECL4, an immunodominant loop and proven opsonic target, was highly conserved in this group of Colombian and South American TPA isolates. This study offers new insights into the sociodemographic and clinical features of venereal syphilis in a highly endemic area of Colombia and illustrates how genomic sequencing of regionally prevalent TPA strains can inform vaccine development.

The effect of an adapted digital mental health intervention for sickle cell disease on engagement: a pilot randomized controlled trial

IntroductionDespite promising outcomes, lack of engagement and poor adherence are barriers to treating mental health using digital CBT, particularly in minority groups. After conducting guided focus groups, a current mental health app was adapted to be more inclusive for minorities living with SCD.MethodsPatients between the ages of 16–35 with SCD who reported experiencing anxiety or depression symptoms were eligible for this study. Once enrolled, participants were randomly assigned to receive one of two versions of a mental health app: 1) the current version designed for the general population or 2) the adapted version. Baseline measures for depression, anxiety, pain, and self-efficacy were completed at the start of the study and again at post-intervention (minimum 4 weeks).ResultsCompared to baseline, mean scores for pain decreased an average of 3.29 (p = 0.03) on a 10-point scale, self-efficacy improved 3.86 points (p = 0.007) and depression symptoms decreased 5.75 points (p = 0.016) for the group that received the adapted app. On average, control participants engaged with the app 5.64 times while the participants in the experimental group engaged 8.50 times (p = 0.40). Regardless of group assignment, a positive relationship (r = 0.47) was shown between app engagement and a change in depression symptoms (p = 0.042).DiscussionTarget enrollment for this study sought to enroll 40 participants. However, after difficulties locating qualified participants, enrollment criteria were adjusted to expand the population pool. Regardless of these efforts, the sample size for this study was still smaller than anticipated (n = 21). Additionally, irrespective of group approximately 40% of participants did not engage with the app. However, despite a small sample size and poor engagement, this study 1) demonstrated the feasibility of implementing socially relevant changes into a mental health app and 2) indicated that participants in the intervention group displayed better outcomes and showed trends for greater app interaction.ConclusionThese promising results should encourage future researchers to continue exploring ideal adaptations for implementing digital CBT in minority populations. Future studies should also consider implementing post-intervention surveys to help identify common factors relating to a lack of engagement.Trial registrationThis trial (NCT04587661) was registered on August 12th, 2020.

Artificial intelligence-based detection of paediatric appendicular skeletal fractures: performance and limitations for common fracture types and locations

BackgroundResearch into artificial intelligence (AI)-based fracture detection in children is scarce and has disregarded the detection of indirect fracture signs and dislocations.ObjectiveTo assess the diagnostic accuracy of an existing AI-tool for the detection of fractures, indirect fracture signs, and dislocations.Materials and methodsAn AI software, BoneView (Gleamer, Paris, France), was assessed for diagnostic accuracy of fracture detection using paediatric radiology consensus diagnoses as reference. Radiographs from a single emergency department were enrolled retrospectively going back from December 2021, limited to 1,000 radiographs per body part. Enrolment criteria were as follows: suspected fractures of the forearm, lower leg, or elbow; age 0–18 years; and radiographs in at least two projections.ResultsLower leg radiographs showed 607 fractures. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were high (87.5%, 87.5%, 98.3%, 98.3%, respectively). Detection rate was low for toddler’s fractures, trampoline fractures, and proximal tibial Salter-Harris-II fractures. Forearm radiographs showed 1,137 fractures. Sensitivity, specificity, PPV, and NPV were high (92.9%, 98.1%, 98.4%, 91.7%, respectively). Radial and ulnar bowing fractures were not reliably detected (one out of 11 radial bowing fractures and zero out of seven ulnar bowing fractures were correctly detected). Detection rate was low for styloid process avulsions, proximal radial buckle, and complete olecranon fractures. Elbow radiographs showed 517 fractures. Sensitivity and NPV were moderate (80.5%, 84.7%, respectively). Specificity and PPV were high (94.9%, 93.3%, respectively). For joint effusion, sensitivity, specificity, PPV, and NPV were moderate (85.1%, 85.7%, 89.5%, 80%, respectively). For elbow dislocations, sensitivity and PPV were low (65.8%, 50%, respectively). Specificity and NPV were high (97.7%, 98.8%, respectively).ConclusionsThe diagnostic performance of BoneView is promising for forearm and lower leg fractures. However, improvement is mandatory before clinicians can rely solely on AI-based paediatric fracture detection using this software.Graphical

Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial

New treatments with new mechanisms are urgently needed for people with schizophrenia. Xanomeline is a dual M1 and M4-preferring muscarinic receptor agonist that does not block D2 dopamine receptors, unlike all currently approved treatments for schizophrenia. Xanomeline-trospium (KarXT) combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of ameliorating xanomeline-related adverse events associated with peripheral muscarinic receptors. The EMERGENT-2 trial aimed to assess the efficacy and safety of KarXT in people with schizophrenia experiencing acute psychosis. EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia. Participants were adults aged 18-65 years with a diagnosis of schizophrenia who had a recent worsening of psychosis warranting hospital admission, a Positive and Negative Syndrome Scale (PANSS) score of 80 or higher, and a Clinical Global Impression-Severity score of 4 or higher. The participants were recruited from 22 inpatient sites in the USA, and were randomly assigned (1:1) to KarXT or placebo twice per day. Participants randomly assigned to KarXT received 50 mg xanomeline and 20 mg trospium twice per day for the first 2 days and then 100 mg xanomeline and 20 mg trospium twice per day for days 3-7. Beginning on day 8, KarXT dosing was flexible with an optional increase to 125 mg xanomeline and 30 mg trospium twice per day and the option to return to 100 mg xanomeline and 20 mg trospium based on tolerability. The primary endpoint was change from baseline to week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population (all randomly assigned participants who received at least one trial medication dose and had at least one post-baseline PANSS assessment). Least squares mean change from baseline, SE, and least squares mean difference between the KarXT and placebo groups at week 5, along with the 95% CI and two-sided p values were calculated for the primary and secondary continuous efficacy endpoints. Safety analyses included all participants receiving at least one trial medication dose and used descriptive statistics. This trial is registered with ClinicalTrials.gov (NCT04659161). From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT; n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61). All secondary endpoints were also met, and favoured KarXT versus placebo (p<0·05). The most common adverse events with KarXT versus placebo were constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]). Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]). In the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well tolerated antipsychotic medicines based on activating muscarinic receptors, not the D2 dopamine receptor-blocking mechanism of all current antipsychotic medications. Results from additional trials, including the identical EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of KarXT in people with schizophrenia. Karuna Therapeutics.

Comparison of the Effectiveness of Intra-articular Infiltration of Hyaluronic Acid and Corticosteroids in the Management of Knee Osteoarthritis: A Prospective Comparative Study.

Background Knee osteoarthritis (KOA) is a chronic and progressive disease of the knee joint characterized by articular cartilage destruction. It is the most common cause of knee disability and pain globally. Various treatments are used for the management of KOA; however, the role of intra-articular injections in KOA management in Pakistan remains understudied. Therefore, this study aims to evaluate the effectiveness of intra-articular injections of hyaluronic acid (HA) and corticosteroids in the management of KOA. Methodology This randomized, prospective, comparative study was conducted among 88 patients diagnosed with KOA in the outpatient department clinic of orthopedics in Benazir Bhutto Hospital, Rawalpindi, from January 2022 to January 2023. For patient enrolment, structured inclusion and exclusion criteria and a simple random sampling technique were used. Before data collection, ethical approval and informed consent were obtained. Data collection was done via a self-structured and interview-based proforma. Data analysis was performed through descriptive statistics and independent t-tests using SPSS version 25 (IBM Corp., Armonk, NY, USA). Results KOA was more prevalent in women (60, 68.18%) than men (28, 31.82%). The means for study variables such as age, Visual Analog Scale (VAS) score, and Western Ontario and McMaster Universities (WOMAC) score were 58.08 ± 7.89 years, 7.66 ± 1.8, and 71.86 ± 8.90, respectively. The incidences of right-sided and left-sided KOA were 57 (64.77%) and 31 (35.23%), respectively. Likewise, the frequency of grade II KOA was 55 (62.50%), while the frequency of grade III KOA was 33 (37.50%). Differences in the mean scores of both VAS and WOMAC between study groups were statistically significant at the second-week, sixth-week, and third-month follow-up visits. However, the mean scores of VAS and WOMAC were lower in group B than in group A at the second-week follow-up visit, whereas the scores were lower in group A compared to group B after the sixth week and third month of intra-articular injections. Conclusions Intra-articular injections of both HA and corticosteroids were adequately effective in the management of KOA-associated pain and functional restrictions; nevertheless, the benefits of corticosteroids were acute and short-term, whereas the outcomes of HA were gradual and long-term.

A multicenter evaluation of the HeartMate 3 risk score

BackgroundThe Heartmate 3 (HM3) risk score (HM3RS) was derived and validated internally from within the MOMENTUM 3 trial population and provides 1- and 2-year mortality risk prediction for patients in those prior to HM3 left ventricular assist device (LVAD) implantation. We aimed to evaluate the HM3RS in non-trial unselected patients, including those not meeting inclusion criteria for MOMENTUM 3 trial enrollment. MethodsPatients who underwent HM3 LVAD implant at one of 7 US centers between 2017-2021, with at least 1 year follow up, were included in this analysis. Patients were retrospectively assessed for their eligibility for the MOMENTUM 3 trial based on study inclusion and exclusion criteria. HM3RS risk discrimination was evaluated using time-dependent receiver operating characteristic (ROC) curve analysis for 1-year mortality for all patients, and further stratified by MOMENTUM 3 trial eligibility. Kaplan Meier curves were constructed using the HM3RS-based risk categories. ResultsOf 521 patients included in the analysis, 266 (51.1%) would have met enrollment criteria for MOMENTUM 3. The 1- and 2-year survival for the total cohort was 85% and 81%, respectively. There was no statistically significant difference in survival between those who met and did not meet enrollment criteria at 1 (87% vs 83%; P=0.21) and 2 years post-implant (80% vs 78%; P=0.39). For the total cohort, HM3RS predicted 1-year survival with an AUC of 0.63 (95% CI: 0.57-0.69, P<0.001). HM3RS performed better in the subset of patients meeting enrollment criteria: AUC 0.69 (95% CI:0.61-0.77, P<0.001) compared to the subset that did not: AUC 0.58 (95% CI: 0.49-0.66, P= 0.078). ConclusionIn this real-world evidence, multi-center cohort, 1- and 2-year survival after commercial HM3 LVAD implant was excellent, regardless of trial eligibility. The HM3RS provided adequate risk discrimination in “trial-like” patients, but predictive value was reduced in patients who did not meet trial criteria.

Microscopic hematuria as a risk factor for IgAN progression: considering this biomarker in selecting and monitoring patients.

Hematuria-either macroscopic hematuria or asymptomatic microscopic hematuria-is a clinical feature typical but not specific for immunoglobulin A nephropathy (IgAN). The only biomarker supported by the Kidney Disease: Improving Global Outcomes group as a predictor of progression, identifying patients needing treatment, is proteinuria >1g/day persistent despite maximized supportive care. However, proteinuria can occur in the setting of active glomerulonephritis or secondary to sclerotic renal lesions. Microscopic hematuria is observed in experimental models of IgAN after IgA-IgG immunocomplex deposition, activation of inflammation and complement pathways. Oxidative damage, triggered by hemoglobin release, is thought to contribute to the development of proteinuria and progression. Despite being a clinical hallmark of IgAN and having a rational relationship with its pathophysiology, the value of microscopic hematuria in assessing activity and predicting outcomes in patients with IgAN is still debated. This was partly due to a lack of standardization and day-to-day variability of microhematuria, which discouraged the inclusion of microhematuria in large multicenter studies. More recently, several studies from Asia, Europe and the USA have highlighted the importance of microhematuria assessment over longitudinal follow-up, using a systematic approach with either experienced personnel or automated techniques. We report lights and shadows of microhematuria evaluation in IgAN, looking for evidence for a more consistent consensus on its value as a marker of clinical and histological activity, risk assessment and prediction of treatment response. We propose that hematuria should be included as part of the clinical decision-making process when considering when to use immunosuppressive therapy and as part of criteria for enrollment into clinical trials to test drugs targeting the inflammatory reaction elicited by immune pathway activation in IgAN.

Prognostic Factors and Outcomes in Advanced Stage Lung Cancer Patients with COVID-19 Omicron Variant Infection.

We study the characteristics and outcomes in lung cancer patients with COVID-19 Omicron variant infection. Hospitalized lung cancer patients with advanced-stage disease and laboratory-confirmed COVID-19 Omicron infection were included. Pneumonitis involving at least 25% of lung parenchyma on CT scans, accompanied by symptoms and oxygen saturation below 93%, were criteria for enrollment. Pneumonitis severity was graded using CTCAE v5.0. Treatment included Paxlovid, prednisolone, anticoagulation, and ventilation. Initial data, radiographic findings, and outcomes were compared. Logistic regression was employed to determine risk factors for in-hospital mortality. Fifteen patients (median age: 65 years; 80.0% males) were included. 73.3% improved and were discharged, 20.0% died, and 6.7% remained intubated. Initial symptoms included cough (100.0%), fever (73.3%), and shortness of breath (53.3%). Symptoms resolved in discharged patients. Median fever duration was 3.5 days, and respiratory symptom recovery took 26 days. Three patients died due to respiratory failure from Omicron pneumonia. Lower oxygen saturation, reduced lymphocyte/neutrophil ratio on day 7, and diffuse bilateral lung lesions were poor prognostic factors. This study underscores the importance of prompt intervention and early diagnosis for lung cancer patients infected with the COVID-19 Omicron variant. Lower oxygen saturation, decreased lymphocyte/neutrophil ratio on day 7, and diffuse lung lesions on CT scans were associated with worse outcomes. Clinicians should prioritize timely and comprehensive management to improve survival rates in this population.

Development and implementation of an Enhanced Recovery After Cranial Surgery pathway following supratentorial tumor resection at a tertiary care center.

Controlling length of stay (LOS) reduces rates of nosocomial infections and falls, facilitates earlier return to daily activities, and decreases strain on the healthcare system. Complications following supratentorial tumor resection present early in the postoperative period, thereby enhancing the prospect of safe, early discharge. Here, the authors describe their initial experience with the development and implementation of an Enhanced Recovery After Cranial Surgery (ERACS) pathway following resection of supratentorial tumors in select patients. This was a nonrandomized, ambispective quality improvement study of patients undergoing elective craniotomy for supratentorial tumor resection at New York University Langone Health between November 17, 2020, and May 19, 2022. Eligible patients were prospectively enrolled in either the ERACS pathway or the standard pathway. These prospective cohorts were compared to a retrospective cohort of patients who met eligibility criteria for the pathway. Patients in the ERACS pathway cohort were targeted for discharge on postoperative day 2. The primary outcome metric was hospital LOS. Secondary outcome metrics included duration of intensive care unit (ICU) care and rates of 30-day emergency department visits, readmissions, and complications. Over the study period, 188 of 317 patients (59.3%) who underwent supratentorial tumor resection met inclusion criteria for ERACS pathway enrollment. Sixty-three patients were enrolled in the ERACS pathway, and 125 patients completed the standard pathway. The historical cohort consisted of 332 patients who would have been eligible for ERACS enrollment. Patients in the ERACS pathway cohort had a median LOS of 1.93 days compared with 2.92 and 2.88 days for patients in the standard pathway and historical cohort, respectively (p < 0.001). There was a significant reduction in ICU utilization in ERACS pathway patients (16.0 ± 6.53 vs 29.5 ± 53.0 vs 21.8 ± 18.2 hours, p = 0.005). There were no differences in the rates of 30-day emergency department visits (12.7% vs 9.6% vs 10.9%, p = 0.809) and readmissions (4.8% vs 4.0% vs 7.8%, p = 0.279) between groups. Patients in the ERACS pathway cohort experienced reduced LOS and ICU utilization, with similar rates of adverse outcomes compared to standard pathway patients. The authors' initial experience suggests that an accelerated recovery pathway can be safely implemented following supratentorial tumor resection in select patients.

Amyloid and Tau PET Positivity in Progressive Apraxia of Speech and Agrammatic Aphasia

AbstractBackgroundThe spectrum of what is referred to as nonfluent/agrammatic primary progressive aphasia includes patients with isolated apraxia of speech (PPAOS), progressive agrammatic aphasia (PAA), or a combination thereof (AOS‐PAA). When AOS is present, there is typically an underlying 4R tauopathy (corticobasal degeneration; progressive supranuclear palsy); isolated PAA is more often associated with a 3R tauopathy (Pick’s disease). While pathological studies confirm the clinical syndrome is the sequela of these proteinopathies, beta‐amyloid (Aβ) deposition has also been observed. Given the growing number of treatment options, it is important to better understand the incidence of Alzheimer’s disease (AD) in PPAOS‐PAA spectrum disorders.Methods65 patients recruited by the Neurodegenerative Research Group at Mayo Clinic underwent Aβ‐PET imaging using Pittsburgh Compound B (PiB) and tau‐PET imaging with [18F]flortaucipir at the same visit (PPAOS = 23; PAA = 6; AOS‐PAA = 36). A global PiB SUVR (standardized uptake value ratio)≥1.48 and temporal lobe tau meta‐ROI SUVR≥1.25 were deemed Aβ and tau positive, respectively. The incidence of Aβ and tau positivity and clinical‐demographic profiles were compared among groups.ResultsThere was no difference in age, sex, APOE status, tau/Aβ positivity or PET SUVRs across clinical groups (Table 1). Patients differed on indices of aphasia and AOS severity, in concordance with group membership; there was no difference on a memory measure. Eight patients (12%) were both Aβ and tau positive (indicative of the presence of AD), with an additional 20 patients (31%) positive on only one biomarker (Table 1). Of the eight Aβ and tau positive patients, seven had AOS (six prosodic predominant AOS). Aβ more than tau SUVRs increased with age and were related to each other (Figure 1).ConclusionsAβ and tau positivity is not uncommon in AOS and/or PAA patients, particularly in older patients. Enrollment criteria for Aβ or tau targeted pharmacological trials should consider concordance of biological variables and clinical presentations, rather than simply biological biomarkers. Alternatively, if such patients are enrolled, the outcome measures should reflect the clinical impairments, as it is not yet known if or how concomitant AD influences the clinical presentation.

Potential utility of using both APOEε4 and Aβ positivity to enrich clinical trials of tau‐targeting therapies

AbstractBackgroundThe use of enrichment strategies is crucial for selecting individuals with the highest probability of Alzheimer’s disease (AD)‐related progression in typical clinical trial time frames. Although both amyloid‐ß (Aß) pathology and the apolipoprotein E e4 (APOEe4) genotype have been shown to accelerate tau accumulation, it is still not clear whether assessing both APOEe4 genotype and Aß positivity is useful to enrich tau‐targeting trials using tau positron emission tomography (PET) as outcome. Here, we investigated the implications of considering APOEe4 carriership for population enrichment in trials testing drug effects on tau tangle deposition in cognitively impaired (CI) individuals across the AD continuum.MethodWe studied 29 Aß positive CI individuals (16 with mild cognitive impairment [MCI] and 13 with AD dementia) from the McGill Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Study participants underwent clinical assessments, APOE genotyping, magnetic resonance imaging, PET for Aß ([18F]AZD4694) and tau ([18F]MK6240) at baseline, as well as a follow‐up tau‐PET scan (mean follow‐up, 2.2 years). Aß positivity was determined as global [18F]AZD4694 SUVR = 1.55.ResultNo demographic differences were observed between APOEe4 carriers and noncarriers (Table 1). Regression analysis revealed that APOEe4 carriers had higher tau‐PET SUVR increase in temporal regions compared to APOEe4 noncarriers (Figure 1). The use of Aß positivity alone for population enrichment of a clinical trial focusing on CI individuals would require a sample size of 436 individuals per study arm to test a 25% drug effect on tau‐PET accumulation (Figure 2). A similar clinical trial with a population enrichment strategy using Aß positivity plus APOEe4 carriership would require a sample size of as few as 158 individuals per study arm (reduction of 64% in relation to using only Aß positivity) to test the same drug effect (Figure 2).ConclusionOur results reveal that APOEe4 carriership is associated with increased tau tangle accumulation in CI individuals who are Aß positive. Clinical trials testing drug effects on tangle deposition may benefit from assessing both APOEe4 carriership and Aß positivity statuses as enrollment criteria to select individuals at higher risk of fast tau accumulation, resulting in a more cost‐effective trial.

Potential utility of using both APOEε4 and Aβ positivity to enrich clinical trials of tau‐targeting therapies

AbstractBackgroundThe use of enrichment strategies is crucial for selecting individuals with the highest probability of Alzheimer’s disease (AD)‐related progression in typical clinical trial time frames. Although both amyloid‐β (Aβ) pathology and the apolipoprotein E ε4 (APOEε4) genotype have been shown to accelerate tau accumulation, it is still not clear whether assessing both APOEε4 genotype and Aβ positivity is useful to enrich tau‐targeting trials using tau positron emission tomography (PET) as outcome. Here, we investigated the implications of considering APOEε4 carriership for population enrichment in trials testing drug effects on tau tangle deposition in cognitively impaired (CI) individuals across the AD continuum.MethodWe studied 29 Aβ positive CI individuals (16 with mild cognitive impairment [MCI] and 13 with AD dementia) from the McGill Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Study participants underwent clinical assessments, APOE genotyping, magnetic resonance imaging, PET for Aβ ([18F]AZD4694) and tau ([18F]MK6240) at baseline, as well as a follow‐up tau‐PET scan (mean follow‐up, 2.2 years). Aβ positivity was determined as global [18F]AZD4694 SUVR ≥ 1.55.ResultNo demographic differences were observed between APOEε4 carriers and noncarriers (Table 1). Regression analysis revealed that APOEε4 carriers had higher tau‐PET SUVR increase in temporal regions compared to APOEε4 noncarriers (Figure 1). The use of Aβ positivity alone for population enrichment of a clinical trial focusing on CI individuals would require a sample size of 436 individuals per study arm to test a 25% drug effect on tau‐PET accumulation (Figure 2). A similar clinical trial with a population enrichment strategy using Aβ positivity plus APOEε4 carriership would require a sample size of as few as 158 individuals per study arm (reduction of 64% in relation to using only Aβ positivity) to test the same drug effect (Figure 2).ConclusionOur results reveal that APOEε4 carriership is associated with increased tau tangle accumulation in CI individuals who are Aβ positive. Clinical trials testing drug effects on tangle deposition may benefit from assessing both APOEε4 carriership and Aβ positivity statuses as enrollment criteria to select individuals at higher risk of fast tau accumulation, resulting in a more cost‐effective trial.

Level of Satisfaction of Geriatric People about Services Provided by an Old Home at Gajipur, Bangladesh

Background &amp; objective: With increased life expectancy and an increased proportion of older people, the demand for old-age homes is increasing. A satisfactory quality of service provision from old age homes can enhance the overall quality of life of an old person. This study aims to assess the level of satisfaction of geriatric people, with the services provided by the Bayaska Punarbasan Kendroy (an old home), situated at Gajipur, Bangladesh. Methods: This descriptive study was designed to evaluate the level of satisfaction of the residents of the Bayaska Punarbasan Kendro about the services provided there. The study was carried out at the Department of Community Medicine, Rajshahi Medical College, Rajshahi over a period of 1 year from January 2019 to December 2019. A total of 200 respondents (residents) were consecutively included in the study based on predefined enrollment criteria. To determine the level of satisfaction of the residents of the Bayaska Punarbasan Kendro about the services provided there, the respondents’ opinion was sought about how well they were satisfied with each of those services. The responses given to each discrete question were scored from 0-4 using Likert Scale, where 0 meant “highly dissatisfied”, and 4 meant “highly satisfied”, with 1 “dissatisfied”, 2 “neither dissatisfied nor satisfied”, and 3 “satisfied” in between them. The scores obtained thus were then summed up to find an integrated score, which ranged from 0-32. The total score was then subdivided into five categories as scores 0-6 (highly dissatisfied), scores 7-12 (dissatisfied), scores13-18 (neutral), scores 19-25 (satisfied), and scores 26-32 (highly satisfied). Result: About two-thirds of the residents of the Bayaska Punarbasan Kendro were Muslim and in their 7th decade of life. More than 55% had already lost their spouses. Fifty percent of the residents came from rural regions. Half of the respondents did not have any income source and the rest half were facing economic hardship. About one-quarter (24.5%) of the respondents were illiterate, nearly two-fifths (37.5%) were primary-level educated and 9% were graduate-level educated. Day labourers comprised almost one-third followed by housewives and service holders. Residents of the old homes were invariably suffering from some sort of physical and mental illnesses concurrently with42% having multiple physical ailments. The major chronic disease was CHD followed by diabetes and osteoarthritis. Nearly half (47%) of the respondents were satisfied with the services provided by the old home, 25.5% were dissatisfied and the rest 27.5% were neither satisfied nor dissatisfied. Probing about the status of living of the old home residents revealed that over one-third (35.5%) had been residing there for &lt; 1 year, 28.5% for 1-3 years, 30% for 3-5years, and only 5.5% for 5 years or more. More than one-third of the respondents had been residing there for &lt; 1 year and only 5% for 5 years or more. Over three-quarters never communicated with their family members since they were admitted to the Bayaska Punarbasan Kendro. However, their children, spouses, or siblings communicated with the moccasionally. They passed their leisure time working (22%), gossiping (29%), watching TV (35.5%), and hangout orreading books (13.5%). Regarding the level of satisfaction, less than half (47%) of the respondents were satisfied with the overall services. The respondents’ level of dissatisfaction was highest with healthcare facilities (37%), followed by accommodation (28%), food service (21%), clothing (17.5%), and leisure time activities (10.5%). The majority (95%) of the respondents was satisfied with the security system and the social media services. Conclusion: The study concluded that the old-home residents time and again miss their family members and are not happy living there. Nearly one-third of the old-home residents are forced to stay there by their family members and half live there for none of their children or close relatives live in the country and one-quarter do not have any residence to live. None of them has any interest to live there. Almost half are satisfied with the services provided by the old home, over one-quarter are dissatisfied and another one-quarter are neither satisfied nor dissatisfied. The respondents’ level of dissatisfaction is mostly with healthcare facilities. Ibrahim Card Med J 2022; 12 (2): 46-52

High Rate of Disease Progression in Patients with Low-Risk Myelofibrosis (MF) Enrolled in the Prospective, Real-World MOST Study

Background: Patients (pts) with low-risk MF are typically excluded from interventional clinical trials, thus data regarding the prognosis of this pt population are largely derived from retrospective analyses. The Myelofibrosis and Essential Thrombocythemia Observational Study (MOST; NCT02953704) is a prospective observational study that enrolled pts with low-risk MF defined by Dynamic International Prognostic Scoring System (DIPSS) criteria. In this analysis, we report disease progression, defined by worsening of clinical or laboratory parameters, in MF pts during the MOST study. Methods: Criteria for enrollment in MOST were confirmed locally and centrally, and included a physician-reported diagnosis of MF (PMF, post-PV, or post-ET) and lack of any DIPSS risk factors except for age &amp;gt;65 y. Of the 232 MF pts enrolled, 205 met this criteria upon central review and were included in this analysis as Cohort A; the remaining 27 pts were enrolled despite having ≥1 DIPSS risk factor (other than age &amp;gt;65 y) and were analyzed separately as Cohort B. Data were collected as previously described (Gerds A. CLML. 2022;22:e532). Disease progression on study was defined as the acquisition of 1 of the following criteria: hemoglobin (Hb) &amp;lt;10 g/dL, platelets &amp;lt;100×10 9/L, presence of constitutional symptoms (weight loss, fever, or sweats), new or worsening splenomegaly, blasts &amp;gt;1%, WBC count &amp;gt;25×10 9/L, death due to disease progression, leukemic transformation (LT), or &amp;gt;1 RBC transfusion. Median (range) follow-up was 52.9 months (42-68). Results: In Cohort A, 120/205 pts (58.5%) had evidence of disease progression during the study. Baseline characteristics comparing pts with vs without disease progression were similar; although compared with pts without progression, those who progressed were older at diagnosis (median [range], 65.9 [21-88] vs 62.9 [35-86] y), older at enrollment (median [range], 70.5 [35-88] vs 66.0 [35-88] y), and had longer median (range) time from diagnosis to enrollment (1.9 [0-38] vs 1.4 [0-24] y). Similar percentages of pts with vs without progression were receiving MF-directed therapy at enrollment (59.2% vs 61.2%); most common treatments were ruxolitinib (33.3% vs 14.1%) and hydroxyurea (22.5% vs 36.5%). Of pts in Cohort A tested for JAK2 mutations, 66/93 (71.0%) with disease progression and 42/65 (64.6%) without were positive. Of pts tested for CALR mutations, 16/21 (76.2%) with disease progression and 17/23 (73.9%) without were positive. Among the 120 pts with progression, 64 (53.3%) met 1 criteria, 27 (22.5%) met 2 criteria, and 29 (24.2%) met ≥3 criteria during the study. The most common progression criteria met were Hb &amp;lt;10 g/dL (47.5%), platelets &amp;lt;100×10 9/L (31.7%), constitutional symptoms (30.8%), and new/worsening splenomegaly (28.3%) (Table 1). Median (95% CI) durations to 1st, 2nd, and 3rd progression criteria were 24.9 (19.2-34.7), 28.2 (14.3-NE), and 11.6 (8.9-26.5) months, respectively (Figure 1). Of pts who progressed, 6 (5.0%) developed LT and 12 (10.0%) died due to disease progression. In Cohort B at time of enrollment, 25/27 pts (92.6%) met 1 progression criteria. The most frequent was Hb &amp;lt;10 g/dL (13/27 [48.1%]), followed by WBC count &amp;gt;25×10 9/L (7/27 [25.9%]); constitutional symptoms (4/27 [14.8%]), and blasts &amp;gt;1% (1/27 [3.7%]); 1 pt (3.7%) met 2 progression criteria (Hb &amp;lt;10 g/dL and constitutional symptoms), and 1 pt (3.7%) met 3 progression criteria (blasts &amp;gt;1%, constitutional symptoms, and WBC count &amp;gt;25×10 9/L). Eight of 27 pts (29.6%) had evidence of further disease progression while on study (Table 1). The most common new progression criteria met were Hb &amp;lt;10 g/dL and platelets &amp;lt;100×10 9/L (each 5/8 [62.5%]) and constitutional symptoms and new/worsening splenomegaly (each 3/8 [37.5%]). Conclusions: This real-world observational analysis from MOST is the first prospective analysis of disease progression in low-risk myelofibrosis. The results show that with over 4 y of follow-up, nearly 60% of pts with low-risk MF had evidence of disease progression; 17/205 pts (8.3%) developed LT or died (both occurred in 1 pt). Median time to acquisition of 1st and 2nd disease progression criteria was approximately 2 y, respectively, decreasing to approximately 1 y for the 3rd criteria; this indicates a slow but increasing rate of progression over the course of the study. These data provide real-world insight into disease progression rate in pts with low-risk myelofibrosis.

A Real-World Evaluation of Risk Factors for Disease Progression in Patients with Polycythemia Vera (PV) Enrolled in REVEAL

Background: PV is a myeloproliferative neoplasm complicated by symptom burden, splenomegaly, vascular events, and disease progression to myelofibrosis (MF). Current risk models for PV include advanced age and history of thrombotic events (TEs), yet information on risk factors for PV progression is limited. In this analysis, we assessed the rate of PV progression to MF during the P rospective Obs ervational Study of Patients With Polycythemia Vera in US Clinic al Practices Trial (REVEAL) and assessed baseline demographics and disease characteristics as risk factors for PV progression. Methods: Criteria for enrollment in REVEAL included a physician-reported PV diagnosis. PV progression was defined by meeting any of the following criteria during the study: 1) Death from MF/myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML); 2) new/worsening splenomegaly, plus 2 of the following criteria: white blood cell (WBC) count &amp;gt;11×10 9/L, platelets (PLT) &amp;lt;100×10 9/L, hemoglobin (Hb) &amp;lt;10 g/dL; 3) evidence of progression to MF from bone marrow (BM) biopsy; 4) new/worsening splenomegaly, plus blasts &amp;gt;1%. Univariate and multivariate logistic regressions were performed to assess risk factors of PV progression. Results: Of the 2510 patients enrolled in REVEAL, 1191 (47.5%) were reported to have a JAK2 mutation at enrollment. To confirm PV diagnosis, digital droplet PCR for JAK2 p.V617F was performed on all patients with the first available biospecimen from an optional biological specimen substudy; 1520/1871 (81.2%) were positive. A further 367 patients with a physician-reported JAK2 mutation and 135 with a PV diagnosis confirmed by BM aspirate/biopsy were included; 488 patients (19.4%) who did not meet any criteria were excluded. Of the 2022 patients with confirmed diagnosis, median (range) follow-up was 44.1 (0-59.5) months; 134 (6.6%) progressed to MF (BM evidence of MF, n=69 [3.4%]; new/worsening splenomegaly, plus 2 of the following criteria WBC count &amp;gt;11×10 9/L, PLT &amp;lt;100×10 9/L, Hb &amp;lt;10 g/dL, n=44 [2.2%]; new/worsening splenomegaly, plus blasts &amp;gt;1%, n=37 [1.8%]; death from MF/MDS/AML, n=22 [1.1%]). A nonsignificant trend toward higher mean JAK2 p.V617F variant allele frequency was observed in patients with vs without progression (Table 1). Compared with patients without progression to MF, patients with progression were of similar age (69.5 vs 68.0 y) and had a longer time from PV diagnosis to enrollment (median, 7.2 vs 3.7 y; P&amp;lt;0.0001; Table 1). The percentage of patients with vs without progression enrolled via academic practices was 23.1% vs 16.9%; the percentage of patients with vs without progression who had no cytoreductive treatment prior to enrollment was 85.1% vs 91.2%. PV risk stratification (age &amp;gt;60 y or history of TEs) at enrollment was similar for patients with vs without progression (high risk, 61.9% vs 63.5%). However, a higher percentage of patients with vs without progression had a history of TEs at enrollment (29.9% vs 19.7%; P=0.0050). Univariate analysis also identified hematocrit (HCT) ≤0.45 L/L (63.9% vs 53.5%; P=0.0288) and WBC count &amp;gt;11×10 9/L (50.4% vs 31.8%; P&amp;lt;0.0001) at enrollment as significantly different between patients with vs without progression, respectively (Figure 1). In univariate analyses, time from PV diagnosis, TE history, HCT ≤0.45 L/L, WBC count &amp;gt;11×10 9/L at enrollment were each associated with increased PV progression risk (Figure 1). These factors were retained as significant covariates in multivariate analyses with stepwise model selection (OR [90% CI]: time from PV diagnosis to enrollment, 1.030 [1.016-1.044], P&amp;lt;0.0001; history of TEs at enrollment, 1.96 [1.281-2.998], P=0.0019; HCT &amp;gt;0.45 vs ≤0.45 L/L, 0.637 [0.421-0.964], P=0.0330; WBC &amp;gt;11 vs ≤11×10 9/L, 2.205 [1.477-3.292], P&amp;lt;0.0001). Conclusions: This real-world analysis of prospective data from REVEAL found that 6.6% of patients with PV progressed to MF over the median 44.1 months of follow-up. Time from diagnosis to enrollment and history of TEs were each significantly associated with an increased risk of PV progression; the latter finding regarding TE history was unexpected and represents a potentially novel risk factor for PV progression. HCT ≤0.45 L/L and WBC &amp;gt;11×10 9/L at enrollment were also significantly associated with an increased progression risk. Additional analysis is ongoing to better understand the causal relationships between these risk factors and PV progression.

Development of a Clinical Trial Methodology and Appraisal Curriculum for Hematology Fellows

Background: The past few decades have seen dramatic clinical advances in benign and malignant hematology. From genomically-targeted diagnostics and therapeutics to novel cellular and immune-based therapies, scientific concepts move to investigational products with astonishing speed. In parallel, clinical trials have become more complex, reflecting both the increasing complexity of the clinical landscape as well as improvements in trial design and standards. To effectively practice in this environment, hematology fellows need to develop a functional understanding of clinical trial methodology and appraisal. However, whereas there are many educational materials focused on content knowledge of hematology topics, there is a paucity of formal resources for better understanding trial methodology. We report the development of a longitudinal, multimodal clinical trial methodology curriculum for hematology fellows grounded in Self-Determination Theory (SDT). Methods: We developed a longitudinal clinical trial methodology curriculum for hematology fellows. The multimodal curriculum consists of both interactive didactic sessions as well as longitudinal integration of methodology teaching into the existing fellow-led journal club. Within the framework of SDT, the curriculum is designed to move fellows from stages of extrinsic motivation to understand and implement critical appraisal (e.g., avoidance of shame) to intrinsic motivation, i.e., integrating critical appraisal into one's professional identity and practice (Th.J. ten Cate et al., Medical Teacher 2011) Conceptually, this is effected by providing adequate content knowledge, a safe space to practice and explore difficult concepts, and serial reinforcement of both the cognitive and social nature of critical appraisal through fellow-led journal club. Progress will be assessed through the first 3 stages of the Kirkpatrick model: reaction, learning, behavior. Results: The concept, teaching modalities, assessment schema and theoretical underpinnings were developed through the ASH MEI program over the 2022-2023 academic year. Iterative review of the course content and modalities occurred through both ASH MEI small group meetings throughout the year, as well as with the directors of the UW Madison Hematology/Oncology fellowship program. Three of the didactics focus on content knowledge, starting with general methodology principles (e.g., validity) before focusing on the hematology-specific challenges of implementing and balancing these principles in therapeutic trials (e.g., enrollment criteria, endpoint selection, etc.) The final didactic is a guided review of a cooperative group trial protocol by clinical trialists from UW Madison, focusing on practical aspects of trial design and implementation. The journal club curriculum includes a methodology rubric trainees can apply during the development of their journal club presentation, as well as a one-on-one debrief session with faculty after their presentation to discuss challenges. Evaluations throughout the curriculum include pre/post survey of learners' comfort and identification with critical appraisal, as well as pre/post knowledge assessment with multiple choice test at beginning and end of curriculum. Conclusion: This curriculum is a proof-of-concept theory-based methodology curriculum for hematology/oncology fellows. The curriculum is being implemented in the first half of the 2023-24 academic year and will report out initial results by ASH 2023. If successful, this curriculum could potentially be expanded to a more extensive array of methodology topics within hematology/oncology and be applied on a larger scale.

Why We Fail: An Analysis of Terminated Interventional Clinical Trials in Lymphoma

Introduction: Clinical trials serve as the cornerstone for advancing therapeutic and clinical strategies in Lymphoma. Learning from prematurely terminated trials provides valuable insights for researchers and drug developers. This study analyses interventional clinical trials in lymphoma terminated between 2010 and 2023, aiming to identify common factors contributing to their failure and improve future research in Lymphoma. Methods The study identified clinical trials in Lymphoma registered in the US between 01/01/2010, and 01/07/2023, using the InovaSight platform. The analysis included trials investigating drugs in phases I-III with at least one recruited patient. Phase 4 studies, early access programs, and trials examining medical devices were excluded, as were trials terminated early due to positive efficacy signals. Natural language processing (NLP) &amp; classification algorithms were used to categorize trials into distinct phases of clinical development and were also applied to identify reasons for trial termination from official registrations and relevant publications. These reasons were then characterized using the InovaSight trial ontology for thematic analysis. Enriching features, including mechanism of action information, design characteristics, target enrolment, and inclusion criteria, were generated and linked for each eligible trial. The analysis was conducted using the InovaSight drug development platform, which employs responsible artificial intelligence to expedite the development of novel therapeutics for haematological malignancies. Results: A total of 306 trials met the inclusion criteria, with phase II trials being most frequently withdrawn (49.3%), followed by phase I (42.5%) and phase III (8.2%). The trials spanned from 2010-01-31 to 2021-12-15. Among terminated studies, single-arm trials were most frequent (64%), followed by two-armed designs (21.2%) and three or more arms (14.7%). A concentration of mechanisms of action were observed across all phases (further described in poster). Reasons for early termination included enrolment issues, sponsor decisions, lack of efficacy, safety concerns, funding withdrawal, investigator-related issues, study irrelevance, drug supply problems, COVID-19, and unspecified reasons. The most common reason for early termination was enrolment issues in Phase I and Phase II studies, and sponsor decisions in Phase III studies. Detailed results are presented in Figure 1. Discussion: Our analysis identified a total of 306 trials that met the inclusion criteria, encompassing different phases of clinical development. Interestingly, phase II trials were the most frequently withdrawn, followed by phase I and phase III trials. This observation suggests that a considerable number of trials face challenges during the intermediate stages of development, which could be attributed to various factors such as safety concerns, lack of efficacy, or financial constraints. Our analysis revealed a concentration of similar mechanisms of action across all trial phases. This finding suggests that certain therapeutic areas or drug targets may be more prone to early termination. Exploring the underlying reasons for this pattern could provide valuable insights for future trial planning and design (This is further elucidated in the full presentation). Among the various reasons for early termination, enrolment issues emerged as the most common factor in both Phase I and Phase II studies. This highlights the critical need for in depth and principled approaches to study feasibility assessment routed in an evidence-based methodology. In contrast, sponsor decisions were the leading cause of termination in Phase III trials. This finding suggests that late-stage trials are more susceptible to decisions made by the trial sponsors, which could be influenced by factors such as financial considerations or market dynamics. The results underscore the importance of careful trial planning, patient recruitment strategies, and effective collaboration between sponsors, investigators, and regulatory bodies. Understanding the challenges and factors contributing to trial termination can aid in optimizing future trial designs, mitigating risks, and improving the efficiency of drug development processes.

Small-Dose Trimethoprim-Sulfamethoxazole Prevents Pneumocystis Jiroveci Pneumonia in B-Cell Lymphoma Patients Receiving Chemotherapy: Analysis of a Randomized Controlled Clinical Trial

B-cell lymphoma is the most common non-Hodgkin lymphoma and is usually treated with the R-CHOP regimen. However, some patients might develop interstitial pneumonitis (IP), which has led to death in some patients. With advances in detection techniques, infections are now considered to be an important etiologic factor in IP, particularly the common opportunistic causative agent Pneumocystis jiroveci. A retrospective cohort analysis at our center has tentatively elucidated that TMP-SMX can achieve effective IP prevention. There are no prospective studies to confirm the preventive effect of TMP-SMX and its mechanism. A single-arm, single-center, randomized controlled clinical trial of TMP-SMX for the prevention of interstitial pneumonitis was conducted at our center. Prophylactic treatment with TMP-SMX in patients in the treatment group was turned on immediately after starting chemotherapy and continued until one month after the end of chemotherapy. The dose of prophylactic treatment was 0.16 g of TMP/0.8 g of SMX once daily. From April 26, 2022, to July 25, 2023, a total of 198 patients with the diagnosis of B-cell lymphoma met the criteria for enrollment and were randomly assigned to the control and treatment groups. Eleven were lost to follow-up before completing 4 courses of chemotherapy, 19 did not complete 4 courses of chemotherapy as of July 25, 2023, and 3 were excluded from the evaluation when they were switched to chemotherapy with other regimens not based on R-CHOP because of poor efficacy after 1 course of chemotherapy, among other reasons. 80 patients in the treatment group and 85 in the control group were finally included in the assessment (Figure 1, Figure 2). There were no statistical differences between patients in the control and treatment group in terms of baseline clinical characteristics such as gender, age, smoking history, lung disease, type of pathology, Ann Arbor stage, LDH level, ECOG score, IPI score, chemotherapy regimen, and group B symptoms. Observation of the primary outcome events in this study showed a significant reduction in the incidence of IP (5.0% vs 47.1%, P&amp;lt;0.001) and PJP (0.0% vs 28.2%, P&amp;lt;0.001) in the patients in the treatment group (Figure 2). IP occurred in 4 (5.0%) in the treatment group, and retrospective patient characteristics revealed that all were COVID-19, in addition to no patients developing IP. Forty (47.1%) in the control group developed IP, 16 were COVID-19, and 24 patients had a complete bronchoscopy with alveolar lavage sent for NGS, all of which revealed PJs or concomitant other pathogens. As of July 25, 2023, 1 patient discontinued TMP-SMX because of the development of renal insufficiency. There have been no deaths due to PJP in patients enrolled in this clinical trial at our center. The results of the subgroup analyses showed that TMP-SMX prophylaxis in any subgroup significantly reduced the risk of IP and there was no interaction. Of the 44 patients who developed IP, 24 underwent bronchoscopy, and PJ was detected by alveolar lavage NGS in all of them, and other pathogens such as Streptococcus pneumoniae, human herpesvirus, Catamoeba, and Candida albicans were detected in some patients. The median number of chemotherapy cycles in which IP occurred was 4 (Figure 1). In the control group, between patients who developed IP and those who did not, there were statistically significant differences in LDH levels (IP 237.0 (194.5, 398.0) vs Non-IP 198.0 (161.0, 278.0), P=0.032), R-CDOP chemotherapy regimen (IP 67.5% vs Non-IP 42.2%, P=0.004) difference, and the rest of the factors did not differ between the two groups. Binary logistic regression analysis of risk factors for the development of IP in the control group showed that patients on the R-CDOP chemotherapy regimen had a significantly increased risk of IP (OR=2.72, 95% CI 1.09-6.80, P=0.033), whereas there was no significant difference between age and LDH. As the chemotherapy cycle progressed, the patients' CD4 + T-cell counts gradually decreased, with the same trend in the control group as in the treatment group. In patients receiving chemotherapy with R-CHOP/R-CDOP-based regimens, the majority of IP that occurs is PJP and prevention with TMP-SMX is safe and effective. Patients treated with PLD have a higher risk of IP occurrence.

Clinical definition of secondary resistance to immunotherapy in non-small cell lung cancer.

Immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 blockade) have revolutionized the treatment landscape in non-small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO-IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.