Review Committee Research Articles

Foritinib in advanced ROS1-rearranged non-small-cell lung cancer in China: a multicentre, open-label, single-arm, phase 2 study

Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC. This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805. Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death. Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases. Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.

Assessment of antimicrobial stewardship programmes and antibiotic use among children admitted to two hospitals in Sierra Leone: a cross-sectional study

IntroductionAntimicrobial resistance (AMR) is a global public health concern and irrational use of antibiotics in hospitals is a key driver of AMR. Even though it is not preventable, antimicrobial stewardship (AMS) programmes will reduce or slow it down. Research evidence from Sierra Leone has demonstrated the high use of antibiotics in hospitals, but no study has assessed hospital AMS programmes and antibiotic use specifically among children. We conducted the first-ever study to assess the AMS programmes and antibiotics use in two tertiary hospitals in Sierra Leone.MethodsThis was a hospital-based cross-sectional survey using the World Health Organization (WHO) point prevalence survey (PPS) methodology. Data was collected from the medical records of eligible patients at the Ola During Children’s Hospital (ODCH) and Makeni Regional Hospital (MRH) using the WHO PPS hospital questionnaire; and required data collection forms. The prescribed antibiotics were classified according to the WHO Access, Watch, and Reserve (AWaRe) classification. Ethics approval was obtained from the Sierra Leone Ethics and Scientific Review Committee. Statistical analysis was conducted using the SPSS version 22.ResultsBoth ODCH and MRH did not have the required AMS infrastructure; policy and practice; and monitoring and feedback mechanisms to ensure rational antibiotic prescribing. Of the 150 patients included in the survey, 116 (77.3%) were admitted at ODCH and 34 (22.7%) to MRH, 77 (51.3%) were males and 73 (48.7%) were females. The mean age was 2 years (SD=3.5). The overall prevalence of antibiotic use was 84.7% (95% CI: 77.9% – 90.0%) and 77 (83.8%) of the children aged less than one year received an antibiotic. The proportion of males that received antibiotics was higher than that of females. Most (58, 47.2 %) of the patients received at least two antibiotics. The top five antibiotics prescribed were gentamycin (100, 27.4%), ceftriaxone (76, 20.3%), ampicillin (71, 19.5%), metronidazole (44, 12.1%), and cefotaxime (31, 8.5%). Community-acquired infections were the primary diagnoses for antibiotic prescription.ConclusionThe non-existence of AMS programmes might have contributed to the high use of antibiotics at ODCH and MRH. This has the potential to increase antibiotic selection pressure and in turn the AMR burden in the country. There is need to establish hospital AMS teams and train health workers on the rational use of antibiotics.

Clinical profile and complications seen in the patients in the later stages of chronic kidney disease presenting to the Emergency Department in a tertiary care center in Nepal: a cross-sectional study.

Chronic kidney disease (CKD) has an estimated prevalence of 6% in Nepal, which has resulted in a huge public health and socioeconomic burden for the country. People with different stages of CKD come to the Emergency Department (ED) with various clinical features and complications, which if detected and managed early can result in a decreased need for renal replacement therapy and thus decreased medical cost. The authors conducted a cross-sectional analysis taking nonprobability convenience sampling in the ED of a tertiary-level hospital of Nepal, after getting approval from the Institutional Review Committee and obtaining informed consent from the patient. Kruskal-Wallis test and χ 2 test of homogeneity were conducted to determine if there were differences in the continuous variables and categorical variables of three stages of CKD. Pairwise comparisons with a Bonferroni correction was done for both variables. Among 291 patients of CKD, 25 were in stage 3, 15 in stage 4, and 251 in stage 5. Significant differences between groups were found in continuous variables of SBP, pulse, temp, TLC, platelet, sodium, potassium, urea, and creatinine. Similarly, a significant difference was found for the categorical variables of hyperkalemia, hyponatremia, thrombocytopenia, leukocytosis, and high creatinine levels. Patients with CKD commonly present to the ED due to electrolyte imbalances, uremia, shortness of breath, and high SBP. Hyperkalemia, thrombocytopenia are more frequently observed in stage 5 CKD, whereas the incidence of hypertension significantly increase from stage 4 onwards. Hyponatremia, on the other hand, is more prevalent in stage 3 than in the later stages.

Pre-existing cardiovascular disease in the intensive care population: a national data study in scotland

Abstract Introduction/Background Each year, nearly 17,000 patients are admitted to Intensive Care Units (ICU) in Scotland. Forty percent of these patients suffer from one or more pre-existing co-morbidity. Pre-existing co-morbid disease is a known risk factor for readmission to ICU, increased healthcare use, protracted recovery and reduced health-related quality of life. Nonetheless, it is unknown which group of patients is most affected. Given the heterogeneity of the ICU population and in consideration of more "targeted" care, understanding the influence of co-morbidities and identification of specific patient groups is necessary. In tandem, the association between cardiovascular disease and critical illness is under researched. Yet it is known that 20% of ICU patients suffer from cardiovascular disease (CVD), with some evidence to suggest CVD is linked to increased 5-year mortality in this group of patients. Purpose To understand the prevalence of pre-existing CVD and other pre-existing co-morbidities in the critically ill population and to determine the influence of pre-existing CVD on hospital readmission rates (within one year of index hospital discharge). Methods This study is a retrospective cohort analysis using routinely collected data on ICU admissions between 2010 and 2019 in Scotland. Following public benefit and privacy panel (PBPP) approval and university integrity committee review, data was accessed via a secure National Safe Haven platform. Demographic data are presented alongside correlation analysis. Results More than 100,000 patients were admitted to ICU between 2010 and 2019. Of these patients, around 10% suffered from pre-existing CVD, with 30% suffering from any co-morbid disease, as defined by Charlson Co-morbidity index. It was identified that around 10% of ICU patients were readmitted to ICU within one year and a further 20% readmitted to hospital within one year. Of those patients readmitted to ICU, 10% suffer from pre-existing CVD. Conclusion This study identified that CVD is prevalent amongst the critically ill population with many experiencing a further admission to ICU. Despite this, little is known about the follow-up care provided to these patients with regards to managing CVD.

Maternal mental health as a major contributor to maternal mortality

Perinatal mental health conditions affect up to 20 % of pregnant or postpartum individuals, and nearly 15 % of pregnant individuals meet criteria for substance use disorder (SUD). All providers taking care of pregnant or postpartum individuals will encounter patients in these scenarios. Maternal Mortality Review Committees (MMRCs) have determined maternal mental health conditions, including SUD, to be the leading cause of preventable maternal death during pregnancy or in the first year postpartum. Lessons learned from MMRCs to prevent these deaths include the recommendation that screening and identification of mental health conditions need to be linked with evidence-based, patient-centered, and accessible treatments. Obstetricians and gynecologists, midwives, family medicine providers, and pediatricians, are in unique positions not only to screen and diagnose, but also to treat individuals with mental health concerns, including SUD, during pregnancy and postpartum.

A randomized phase 2 study of HLX22 plus trastuzumab biosimilar HLX02 and XELOX as first-line therapy for HER2-positive advanced gastric cancer

Gastric cancer is the fifth most common cancer and the fourth most common cause of cancer death worldwide, yet the prognosis of advanced disease remains poor. This was a randomized, double-blinded, phase 2 trial (ClinicalTrials.gov: NCT04908813). Patients with locally advanced/metastatic HER2-positive gastric/gastroesophageal junction cancer and no prior systemic antitumor therapy were randomized 1:1:1 to 25mg/kg HLX22 (a novel anti-HER2 antibody)+ HLX02 (trastuzumab biosimilar)+ oxaliplatin and capecitabine (XELOX) (group A), 15mg/kg HLX22+ HLX02+ XELOX (group B), or placebo+ HLX02+ XELOX (group C) in 3-week cycles. Primary endpoints were progression-free survival (PFS) and objective response rate (ORR) assessed by independent radiological review committee (IRRC). Between November 29, 2021, and June 6, 2022, 82 patients were screened; 53 were randomized to group A (n= 18), B (n= 17), and C (n= 18). With 14.3months of median follow-up, IRRC-assessed median PFS was prolonged with the addition of HLX22 (A vs. C, 15.1 vs. 8.2months, hazard ratio [HR] 0.5 [95% confidence interval (CI) 0.17-1.27]; B vs. C, not reached vs. 8.2months, HR 0.1 [95% CI 0.04-0.52]). Confirmed ORR was comparable among groups (A vs. B vs. C, 77.8% vs. 82.4% vs. 88.9%). Treatment-related adverse events (TRAEs) were observed in 18 (100%), 16 (94.1%), and 17 (94.4%) patients, respectively. One (5.6%) patient in group C reported a grade 5 TRAE. Adding HLX22 to HLX02 and XELOX prolonged PFS and enhanced antitumor response in the first-line treatment of HER2-positive gastric cancer, with manageable safety. Shanghai Henlius Biotech, Inc.

Assessing LLIN distribution implementation using evidence-informed intervention core elements: a qualitative study in a resource-constrained setting

BackgroundThe National Malaria Elimination Programme implements the mass LLIN Distribution Campaigns in Ghana. Implementation science promotes the systematic study of social contexts, individual experiences, real-world environments, partnerships, and stakeholder consultations regarding the implementation of evidence-informed interventions. In this paper, we assess the core elements of the mass LLIN distribution campaign in a resource constrained setting to learn best implementation practices. Three core domains were assessed through the application of Galbraith’s taxonomy (i.e., implementation, content, and pedagogy) for evidence-informed intervention implementation.MethodsSix districts in two regions (Eastern and Volta) in Ghana participated in this study. Fourteen Focus Group Discussions (FGDs) were conducted across these communities. Eligible participants were purposively sampled considering age, occupation, gender, and care giving for children under 5 years and household head roles. All audio-recorded FGDs were transcribed verbatim, data was assessed and coded through deductive and inductive processes. NVivo software version 13 was used for the coding process. Themes were refined, legitimized, and the most compelling extracts selected to produce the results.ResultsSixty-nine (69) caregivers of children under 5 years and sixty (60) household heads participated in the FGDs. All caregivers were females (69), whilst household heads included more males (41). Core elements identified under implementation domain of the LLIN distribution campaign in Ghana include the registration and distribution processes, preceded by engagement with traditional authorities and continuous involvement of community health volunteers during implementation. For pedagogy domain, core elements include delivery of intervention through outreaches, illustrations, demonstrations, and the use of multiple communication channels. Core elements realized within the content domain include information on effective malaria prevention, and provision of information to enhance their self-efficacy. Yet, participants noted gaps (e.g., misuse) in the desired behavioural outcome of LLIN use and a heavy campaign focus on women.Conclusion and recommendationsAlthough the implementation of the mass LLIN distribution campaigns exhibit components of core elements of evidence informed interventions (implementation, content and pedagogy), it has not achieved its desired behavioural change intentions (i.e. continuous LLIN use). Future campaigns may consider use of continuous innovative pedagogical approaches at the community level and lessons learnt from this study to strengthen the implementation process of evidence-based health interventions. There is also the need for standardization of core elements to identify the number of core elements required within each domain to achieve efficacy.Ethical approvalEthical clearance was obtained from the Ghana Health Service Ethics Review Committee (GHS-ERC: 002/06/21) before the commencement of all data collection.

Implementation of an external female urinary catheter strategy on prevention of skin breakdown in acute care: A quality improvement study.

To evaluate the incidence of skin-related complications attributable to incontinence-associated dermatitis (IAD) using an external female urinary catheter device strategy for urinary incontinent (UI) patients in acute care. Multicenter quality improvement study. Randomized allocation of two commercially available external female urinary catheter devices was used in hospitalized UI female patients. Daily nursing skin assessments were documented in the electronic health record before, during and after external catheter device application. Methods and results were reported following SQUIRE guidelines. Three hundred and eighty-one patients from 57 inpatient care units were included in the analysis. Both catheter devices were associated with an overall low risk (5 %) of new or worsening skin breakdown. The overall benefit of external catheters is most persuasive for skin integrity, rather than infection prevention. Significant negative outcomes are associated with UI patients. External female urinary catheters are a non-invasive alternative strategy to reduce exposure of regional skin to urine contamination and IAD-related skin complications. Use of external female urinary catheters in hospitalized UI female patients offers low risk (5%) of new or worsening overall skin breakdown. Hospitalized UI female patients were screened for external catheter device eligibility by the bedside nurse. The quality improvement review committee waved consent because the intervention was considered standard care.

The impact of a culturally adapted lifestyle intervention on the glycaemic profile of mothers with GDM one year after delivery – a community-based, cluster randomized trial in Sri Lanka

BackgroundA woman with a history of GDM has a high risk of developing type two diabetes (T2DM) in her future life. Lifestyle modifications are known to attenuate the progression of GDM to T2DM. Therefore, the aim of this study was to assess the impact of a simple, cost effective, culturally acceptable lifestyle intervention programme on the trajectory towards T2DM in women with a history of GDM.MethodsThis cluster randomized trial was conducted in 100 postpartum women in three selected districts of Sri Lanka. The subjects were divided into intervention (n = 50) and control groups (n = 50) by cluster randomization method. A culturally adapted protocol (comprised of dietary and physical activity modifications) was administered to the intervention group. The glycemic profile was assessed using fasting and 2-hour post-OGTT plasma glucose and HbA1c, and insulin resistance by HOMA-IR at baseline and after one year of intervention.ResultsThe mean age (SD) of the subjects in the intervention and control groups were 33.0 (5.1) and 34.3 (6.5) years respectively. All glycemic and insulin resistance parameters (i.e. Fasting plasma glucose- FPG, 2-hour post-OGTT plasma glucose, HbA1c and HOMA-ir) were comparable (p > 0.05) between the two groups at baseline. FPG, 2 h post OGTT, HbA1c and HOMA-ir values between intervention vs. control (p) at 12 months were 87.3 vs. 123.2 (< 0.01); 106.5 vs. 156.1 (0.01); 5.3 vs. 6.8 (< 0.01) and 0.9 vs. 2.3 (< 0.01) respectively. All glycemic parameters showed a significant reduction in the intervention group at 12 months compared to baseline. In contrast, the control group showed a significant increase in FPG, 2-hour post-OGTT plasma glucose and HbA1c at 12 months compared to baseline. In multiple linear regression model adjusted for age, parity and family history, the control group showed an approximately 33 times risk of developing insulin resistance compared to the intervention group.ConclusionThe culturally acceptable and individualized lifestyle intervention was able to produce remarkable reductions in glycaemic and insulin resistance parameters among postpartum women with a history of GDM.Trial registrationEthical clearance was obtained from the Ethics Review Committee of the University of Sri Jayewardenepura, Sri Lanka (ERC 52/14), Sri Lanka Clinical trial registration number Sri Lanka Clinical Trials Registry (SLCTR/2015/021 date 25.09.2015).

Modified D2 Gastrectomy operation in Gastric Cancer Patients and Outcome

Gastric cancer remains the fifth most commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide. In 2018, there were an estimated 1,033,701 newly diagnosed cases and 782,685 related deaths. The aim of this study was to evaluate outcome of modified D2 gastrectomy operation in gastric cancer patients with or without comorbidities. This prospective observational study was conducted at the Department of Surgical Oncology, National Institute of Cancer Research and Hospital, Mohakhali, Dhaka, from July 2019 to March 2021. A total of 53 patients were included in the study. The outcome of the surgery was assessed by monitoring postoperative complications for a period of 30 days. Statistical analysis was performed using SPSS (Statistical Package for the Social Sciences) version 28. Prior to the commencement of the study, the research protocol was approved by the Research Review Committee of the Department of Surgical Oncology and the Ethical Committee of the National Institute of Cancer Research and Hospital, Dhaka. There was no significant association observed between postoperative complications of modified D2 gastrectomy and patients’ age, gender, or smoking status. Among the 53 patients, the highest proportion (92.45%) experienced anorexia, followed by vomiting (81.13%), and approximately 71.69% had dyspepsia. Among the patients, 52.83% had diabetes mellitus (DM) and 45.28% had hypertension (HTN). Patients with gastric cancer and DM were found to be more susceptible to developing wound infections. Based on the analysis of the study results, it can be concluded that modified D2 gastrectomy is a safe procedure that yields acceptable postoperative outcomes for the treatment of gastric cancer in a tertiary care center. Mugda Med Coll J. 2024; 7(1): 31-35

Characteristics of patients with burn injuries managed at a tertiary care centre

IntroductionBurn injuries are becoming a growing burden, negatively impacting both individuals and society. They affect a person’s health and lead to psychosocial and economic problems. This study evaluates the prevalence, characteristics, and short-term outcomes of patients with burn injuries admitted to a tertiary care hospital in Northern Sri Lanka. MethodsThis prospective cross-sectional study was conducted on patients with burn injuries admitted to Tertiary care centre Jaffna over six months in 2023. Ethical clearance was obtained from the Ethics Review Committee of the Faculty of Medicine, University of Jaffna. Baseline characteristics and clinical features during hospitalisation were recorded. Categorical variables were compared using the Chi-square test, with post hoc Tukey tests conducted where applicable. ResultsThis study included 57 patients aged 1 to 88 years, with a mean age of 35.19 ± 21.16 years. Most participants were female (53.4 %), and most had completed secondary education (62.1 %). Approximately 65.5 % were employed in unskilled jobs, with the remainder in skilled professions. Accidental burns were the most common cause (72.4 %), with 84.5 % of injuries occurring at home, though suicide-related burns accounted for 24.1 %. Flame-related burns constituted 50 % of injuries, with first-degree burns being the most common (44.8 %). The availability of first aid significantly influenced outcomes, with 74.1 % receiving assistance, primarily through removing clothing (43.8 %) and using running water (15.8 %). A combined approach of care was received by most patients (52.7 %), while 8.8 % were hospitalised in the plastic and reconstructive surgery department. Many patients had burns covering less than 10 % of their body surface area (46.6 %). ConclusionThe findings of this study on patients with burn injuries underscore the importance of understanding the causes of burns, administering appropriate first aid, recognising different injury types and severities, assessing the total burn surface area, and tailoring patient treatment. These insights are crucial for informing prevention strategies and healthcare planning, aiming to mitigate the impact of burn injuries and improve patient outcomes.

Association of ET1 and APE1 Genes Polymorphism with Coronary Artery Disease

AbstractCoronary artery disease (CAD) is one of the most common cardiovascular diseases (CVDs), being the foremost reason for mortality and disability globally. It is a cascade of polygenic architecture of various disorders as a resultant of complexities between various genetic factors and environmental factors. The aim of the present study was to investigate whether the ET1 and APE1 gene polymorphism is associated with the susceptibility to CAD. This study was approved by the Ethical Review Committee of Era Medical College and Hospital. Three milliliters of venous blood sample was collected in ethylenediaminetetraacetic acid-coated vials, and genomic DNA was isolated by using the standard phenol-chloroform extraction method for restriction fragment length polymorphism-polymerase chain reaction study. The APE1 gene AA, AG, GG, and AG + GG genotypes frequencies were 13.91, 40.87, 45.22, and 86.99% in CAD cases and 13, 50, 37, and 87% in controls, respectively. The ET1 gene GG, GT, TT, GT + TT genotypes frequencies were 6.67, 37.5, 55.8, and 93.34% in CAD cases and 6.67, 25.33, 68, and 93.34% in controls. The ET1 and APE1 gene polymorphisms were not significantly associated with the risk of CAD.

P-562 Molecular aspects of preimplantation genetic testing (PGT) for Neurofibromatosis type 1 (NF1) in three large European PGT centers: challenges and pitfalls

Abstract Study question What are the technical challenges and pitfalls of PGT for NF1 (n = 296 families) as experienced by three large European PGT centers? Summary answer The high (de novo) mutation rate and presence of germline mosaicism, especially in case of deletions, is challenging in PGT test development for NF1. What is known already NF1 is a neurocutaneous disorder with complete penetrance and extreme clinical variability. It is one of the most frequently requested autosomal dominant indications for PGT. The NF1 gene is large and has a high mutation rate. A high number of variants occur de novo, are mostly unique and more frequently associated with germline mosaicism in the index. These characteristics can pose difficulties in counseling, test development and PGT treatment. Large NF1 deletions are associated with a more severe phenotype and relative frequent mosaicism, but this has not been described in literature for intragenic deletions. Study design, size, duration Retrospective analysis of data on all test development procedures with the indication NF1 completed by August 2022 (n = 296). The data on test development were collected from medical files by the laboratories of the three participating PGT centers. The study was approved by the Medical and Ethical Review Committee of all three centers. The Medical Research Involving Human Subjects Act was not applicable. Participants/materials, setting, methods The three participating PGT centers were Maastricht University Medical Center (the Netherlands), University Hospital Brussels (Belgium) and Strasbourg University Hospital (France). Techniques applied were locus specific PCR-STR with or without the specific causative variant or genome wide haplotyping methods (NGS based OnePGT or karyomapping) or a combination of the above. Main results and the role of chance Test development was completed for 296 cases involving 228 different variants in the NF1 gene (125 truncating, 31 missense, 47 splice and 7 in-frame or synonymous variants, 8 larger deletions, 1 translocation, 9 awaiting further classification). We observed 36 recurring variants for 104 couples, of which 55 were sporadic cases, The majority of the 296 cases were sporadic (60%), signs of mosaicism were observed in 14 of these cases (8%). In our cohort, 6 sporadic cases involved a complete gene deletion (n = 1) or a deletion of ≥ 1 exons in the NF1 gene (n = 5). Mosaicism was detected in 4 of these cases (67%). In one case, the mutation was not detected in sperm cells during test set-up. PGT treatment was started for 10 couples with signs of mosaicism, in 6 no affected embryos were detected in 1-2 cycles and 1 resulted in a misdiagnosis because of phasing based on unaffected offspring. Two cases had NF1 caused by a different variant in the NF1 gene than their affected family members. A successful PGT test was developed in 289 cases (98%), 5 couples opted out during test development and in only 2 cases, development of a test was not possible for technical reasons. Limitations, reasons for caution The observed challenges and pitfalls depend on the techniques used and local procedures, so results may not be applicable to all PGT laboratories. However, due to the large sample size with exhaustive data and the fact that ESHRE guidelines were followed, there is probably little reason for caution. Wider implications of the findings Our findings could improve broader reproductive counseling of NF1 patients. Also, this large cohort contains previously unpublished variants in the NF1 gene, which is relevant for genetic diagnosis in NF1 patients in general. Our findings could possibly aid in test development for other autosomal dominant PGT indications with similar characteristics. Trial registration number Not applicable.

Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial

Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n = 130); and paclitaxel with cisplatin (TP group; n = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1–32.0, P < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7–18.1, P = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034.

Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial

Neoadjuvant short-course radiotherapy (SCRT) followed by CAPOX and camrelizumab (a programmed cell death protein 1 monoclonal antibody) has shown potential clinical activity for locally advanced rectal cancer (LARC) in a phase II trial. This study aimed to further confirm the efficacy and safety of SCRT followed by CAPOX and camrelizumab compared to long-course chemoradiotherapy (LCRT) followed by CAPOX alone as neoadjuvant treatment for LARC. In this randomized, phase III trial, patients with T3-4/N+ rectal adenocarcinoma were randomly assigned (1 : 1) to receive SCRT or long-course chemoradiotherapy (LCRT), followed by two cycles of camrelizumab and CAPOX or CAPOX alone, respectively. After surgery, each arm underwent either six cycles of camrelizumab and CAPOX, followed by up to 17 doses of camrelizumab, or six cycles of CAPOX. The primary endpoint was pathological complete response (pCR) rate (ypT0N0) assessed by a blinded independent review committee. Key secondary endpoints tested hierarchically were 3-year event-free survival (EFS) rate and overall survival (OS). Between July 2021 and March 2023, the intention-to-treat population comprised 113 patients in the experimental arm and 118 patients in the control arm, with surgery carried out in 92% and 83.9%, respectively. At data cut-off (11 July 2023), the pCR rates were 39.8% [95% confidence interval (CI) 30.7% to 49.5%] in the experimental arm compared to 15.3% (95% CI 9.3% to 23.0%) in the control arm (difference, 24.6%; odds ratio, 3.7; 95% CI 2.0-6.9; P < 0.001). In each arm, surgical complication rates were 40.0% and 40.8%, and grade ≥3 treatment-related adverse events were 29.2% and 27.2%. Three-year EFS rate and OS continue to mature. In LARC patients, neoadjuvant SCRT followed by camrelizumab plus CAPOX demonstrated a significantly higher pCR rate than LCRT followed by CAPOX, with a well-tolerated safety profile. SCRT followed by camrelizumab and chemotherapy can be recommended as a neoadjuvant treatment modality for these patients.

Harnessing the Power of Big Data Analytics-Estimation of Reference Intervals for Neonatal Serum TSH in Pakistan Using RefineR Algorithm.

To estimate the population-specific reference intervals (RIs) for neonatal thyroid stimulating hormone (TSH) in Pakistani neonates, utilising the refineR algorithm. Observational study. Place and Duration of the Study: Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, Pakistan, from 17th May to 30th November 2023. A data mining analysis was conducted on serum TSH results of neonates (≤1 month) over a period of six years, following approval from the Institutional Ethical Review Committee. Two subgroups were assessed based on the age as 0 - 5 days and 6 - 30 days. The refineR algorithm was implemented using refineR package (version 1.0.0), ensuring accurate analysis and insights. A total of non-duplicate 82,299 neonatal serum TSH tests were retrieved, including 70,788 (88%) aged 0 - 5 days and 11,511 (12%) aged ranging from 6 - 30 days. The estimated RI was from 0.67 µIU/mL (90% CI 0.641 - 0.72) to 15.0 µIU/mL (90% CI 13.2 - 17.3) for the first age group and 0.65 µIU/mL (90% CI 0.6 - 0.84) to 8.6 µIU/mL (90% CI 8.05 - 9.71) for the second age group. Reference intervals for neonatal serum TSH of the Pakistani population were estimated, considering the genetic differences of this demographic in comparison to the Western population. Results aligned with global literature, validating the refineR indirect approach's applicability. Reference intervals, Neonatal, Thyroid stimulating hormone, RefineR algorithm, Big data, Pakistan.

Discharge Against Medical Advice Among Neonates Admitted to the Neonatal Intensive Care Unit of a Tertiary Care Hospital

Discharge against medical advice is a condition where patient leaves the hospital against physician’s advice and is a serious public health issue, especially among neonates and a challenge faced commonly by physicians. It is a risk factor that can lead to adverse events like mortality and readmissions in neonatal units. To decrease neonatal mortality rate, it is necessary to investigate the causes leading to self-discharge. This study aimed to find out prevalence and reasons for discharge against medical advice among neonates admitted to neonatal intensive care units of a tertiary care hospital. A descriptive cross-sectional study was conducted among neonates admitted to the Neonatal Intensive Care Units who were discharge against medical advice (DAMA) from 15th March 2022 to 14th March 2023 after obtaining ethical approval from the Institutional Review Committee (Reference number: F-NMC/544/078-079). Neonatal demographic information and reason for self discharged were recorded. A convenience sampling method was used among neonates who met eligibility criteria. Data were presented as frequency with percentage. A point estimate with 95% confidence interval was calculated. Out of 910 neonates admitted to NICU, 86 (9.4%; 95% CI:7.62-11.53) were discharged against medical advice. Among these, 72 (83.7%) were outborn neonates and 51 (59.3%) male. The most common morbidity was sepsis 53 (61.6%). The common reasons for parents to take DAMA was poor financial condition 72 (83.7%). The prevalence of discharge against medical advice among neonates admitted in the neonatal intensive care units was similar to other studies done in similar settings.

Hematological parameters of hypertensive patients in northeast Ethiopia: A comparative cross-sectional study

IntroductionHypertension has emerged as a significant public health concern, ranking among the leading causes of mortality in low- and middle-income countries. Moreover, it is closely associated with structural and functional alterations in hematopoietic cells. Therefore, this study aimed to evaluate the hematological parameters of hypertensive patients in Northeast Ethiopia. MethodsA comparative cross-sectional study was conducted from January to March 2023, involving 248 participants. This included 124 hypertensive patients and 124 apparently healthy controls selected using a systematic random sampling technique. Socio-demographic and clinical data were collected through a structured questionnaire, and anthropometric measurements were obtained following established guidelines. Ethical approval was obtained from the Ethical Review Committee of the College of Medicine and Health Sciences at Wollo University. After obtaining informed consent, approximately 5 ml of venous blood was drawn from each participant for complete blood count and fasting blood glucose analysis, performed using the Mindray BC-3000 Plus hematology analyzer and the DIRUI CS-T240 automated clinical chemistry analyzer, respectively. Data analysis involved independent t-tests, Mann-Whitney U-tests, correlation tests, and logistic regression. A p-value of <0.05 was considered statistically significant. ResultsThe study found that white blood cell count, platelet count, platelet distribution width, red cell distribution width, and mean platelet volume were significantly higher in hypertensive patients compared to the control group (p < 0.05). Conversely, red blood cell count, hematocrit, and hemoglobin levels were significantly higher in the control group than in hypertensive patients (p < 0.05). Additionally, white blood cells and platelets exhibited a positive correlation with systolic and diastolic blood pressure (p < 0.05), while red blood cell count, hematocrit, and hemoglobin demonstrated a negative correlation with blood pressure indices and body mass index. Anemia was observed in 20.2 % of hypertensive patients. Notably, an abnormal body mass index (AOR: 3.5, 95 % CI: 1.3–9.6, p = 0.011) and high systolic blood pressure (AOR: 4.6, 95 % CI: 1.3–15.5, p = 0.013) were significantly associated with anemia among hypertensive patients. ConclusionThis study identified significant differences in various hematological parameters between hypertensive patients and the control group. Routine assessments of hematological parameters should be considered to effectively manage hypertension-related complications in hypertensive patients.

Comparison of Work Relative Value Units Assigned to Urological and Gynecological Surgical Procedures.

We sought to determine if work relative value unit differences exist between analogous, sex-specific procedures. Representatives from the AUA and the American College of Obstetricians and Gynecologists independently reviewed the entire procedural code set and identified sex-specific procedures that had an analogous procedure in the opposite sex. These pairs were then evaluated and compared using current American Medical Association Relative Value Scale Update Committee methodology. Comparable code pair values were then examined to determine any systemic bias in the work relative value units assigned between the procedures. Mean differences and 95% confidence intervals were used to determine any differences in procedure or physician time values. The methodology used considered global period, intraservice time, total time, hospital days, postoperative office visits, and the date of the committee review. Of the 10 directly analogous code pairs reviewed, 7 of the female procedures had higher work relative value unit differences (range 0.29-6.47), and 3 of the male procedures had higher work relative value unit differences (range 1.23-2.34). There was no statistical difference between the code pair work relative value units. The work relative value unit per minute of intraservice time and total time were not statistically different. In this study, we compared operative procedures performed in women with clinically comparable operative procedures performed in men that had similar surgical approaches, global periods, and valuation methodologies. Overall, no statistical differences in work relative value units were demonstrated.

Anxiety Inventory for Respiratory Disease: Cross-Cultural Adaptation and Semantic Validity of the Brazilian Version for Individuals with Chronic Obstructive Pulmonary Disease.

Most instruments available to screen for anxiety in people with chronic obstructive pulmonary disease (COPD) are not disease specific. Therefore, the Anxiety Inventory for Respiratory Disease (AIR) was developed to measure anxiety for this patient group; however, it requires cross-cultural adaptation for use in non-English speaking countries. To carry out cross-cultural adaptation of the AIR scale for Brazilian patients with COPD and to analyze its semantic validity. This methodological study followed six stages: 1) Initial translation by two independent translators fluent in English; 2) Synthesis of translations; 3) Back translation by two English first language translators; 4) Expert committee review (eight healthcare professionals, a methodologist, the translators, and back-translators); 5) Pre-final version evaluation with 30 patients with COPD through a cognitive interview; and 6) Submission of documents. Semantic validity was analyzed by agreement rate and content validity index (CVI) for the committee equivalence assessments. 1) Initial translation: the two translated versions presented eight divergences; 2) Synthesis of translations: the differences were discussed to reach consensus; 3) Back-translation: there were no important inconsistencies; 4) Expert Committee: the experts proposed eight and the instrument developer proposed three changes, which were analyzed and voted on, resulting in the pre-final version; 5) Evaluation of the pre-final version: data collection allowed for other changes and the formulation of instructions by applying the adapted instrument in an interview format. Patients rated the questions as clear or very clear; 6) The expert committee and the developer approved the final documents. The agreement rate and CVI were ≥ 0.80 for all items of the scale final version. The process of cross-cultural adaptation followed all necessary stages and the semantic validity results were adequate, providing the Brazilian version of the AIR to assess anxiety symptoms in patients with COPD.