Human epidermal growth factor receptor 2 (HER2) status in breast cancer: practice points and challenges.

Human epidermal growth factor receptor 2 (HER2)-enriched breast cancer benefits significantly from anti-HER2 targeted therapies. This highlights the critical need for precise HER2 immunohistochemistry (IHC) interpretation serving as a triage tool for selecting patients for anti-HER2 regimens. Recently, the emerging eligibility of patients with HER2-low breast cancers for a novel HER2-targeted antibody-drug conjugate (T-DXd) adds challenges to HER2 IHC scoring interpretation, notably in the 0-1+ range, which shows high interobserver and interlaboratory staining platform variability. In this review, we navigate evolving challenges and suggest practical recommendations for HER2 IHC interpretation.

Sociodemographic determinants of gender disparity in primary percutaneous coronary intervention in Pakistan.

OBJECTIVES: This study aims to contribute to the body of literature on gender disparities after acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PPCI). METHODS: We identified all adult patients who had AMI between January 2017, and December 2022 and were in follow-up at our institute. We collected data on PPCI, revascularization strategy, sociodemographic characteristics, and in-hospital complications in the years following the procedure. RESULTS: A total of 5,872 patients who underwent PCI for AMI were included in the study, out of which 2,058 (35%) were women and 3,814 (65%) were men. Regarding the timing of PCI, female patients had a significantly longer median door-to-balloon time compared to male patients (136 minutes vs 108 minutes, P-value = 0.006). Female patients had a significantly higher rate of in-hospital mortality compared to male patients (5.5% vs 1.2%, P-value = 0.011). Multivariate logistic regression analysis showed that female gender, older age, and lower household income were independent predictors of longer door-to-balloon time. CONCLUSION: This study highlights gender disparities in PPCI in Pakistan, with female patients facing longer door-to-balloon times and higher in-hospital mortality rates. The findings suggest the need for targeted interventions to improve the access and quality of care for female patients with AMI.

Pediatric Appendicitis Score for Identifying Acute Appendicitis in Children Presenting With Acute Abdominal Pain to the Emergency Department.

OBJECTIVE: To determine the diagnostic accuracy of Pediatric Appendicitis Score (PAS) in predicting appendicitis in children presenting with acute abdominal pain to the Emergency Department (ED) of a private hospital in Pakistan. METHODS: This validation study was through retrospective chart review of children between 4-18 years of age with clinical suspicion of acute appendicitis, presenting to the pediatric ED. Diagnostic accuracy was determined using sensitivity, specificity, predictive values, and area under the curve (AUC). RESULTS: 104 children (76% boys) with mean (SD) age of 10.9 (3.5) years met the eligibility criteria. 91% (n=95) patients had moderate to high PAS (score ³4), and 95% (n=99) had biopsy-proven appendicitis. The likelihood ratio calculated for low, equivocal and high-risk PAS was 0.10, 2.17 and 2.53, respectively. An equivocal PAS (score 4-6) showed a sensitivity of 96.8%, specificity of 80%, positive predictive value of 98.9% and AUC of 0.84 for predicting acute appendicitis. CONCLUSION: PAS showed good diagnostic accuracy in predicting acute appendicitis in children presenting to the ED.

A Rare Case of Gastrointestinal Amyloidosis Presenting as Dysphagia.

A 74-year-old male with an unintentional 20-pound weight loss over the past year presented with new-onset dysphagia to solid foods. Esophagogastroduodenoscopy showed a subtle stricture with ill-defined scar tissue-like findings in the distal esophagus and erosions in the antrum of the stomach without masses. Pathologic findings showed the presence of amyloidosis involving the proximal and distal esophagus, as well as gastric mucosa with chronic inflammation and reactive epithelial changes. We present a rare case of dysphagia as the initial presentation of gastrointestinal amyloidosis.

Mindfulness in the Emergency Department (MED): An Asynchronous Learning Course to Practise Mindfulness and Resilience in the Emergency Room of Low Resource Setting.

Owing to the fast-paced, stressful, and frequent crucial rapid decisions that trigger cognitive exhaustion, emergency physicians are especially vulnerable to burnout. Mindfulness practices have been defined in the literature and it focuses on the well-being and resilience. Mindfulness is characterised as the ability to use tools and expertise to mentally respond to environmental problems to fulfil psychological needs. To overcome burnout, a self-directed learning course was developed for emergency physicians that will include learning goals on mindfulness, peer group discussions and tasks, role playing and practising meditation exercises. It would concentrate on the foundations of mindfulness and resilience, learning and incorporating mindfulness, understanding the coping mechanisms and establishing a pathway to minimise anxiety and depression. Key Words: Mindfulness, Resilience, Burnout, Emergency medicine, Emergency department, Wellness.

Knowledge and attitude towards identification and management of sepsis among resident physicians in a tertiary care teaching hospital in Pakistan.

This study was conducted to determine the compliance and knowledge of sepsis guidelines among resident physicians in a tertiary care hospital of a developing country. A self-structured validated questionnaire was prepared to evaluate compliance and knowledge of the Surviving Sepsis Campaign (SSC) guidelines. A total of 76 resident physicians completed the questionnaire; out of these, 51 (67%) were from Internal Medicine department and 25 (33%) were from Emergency Medicine department of the Aga Khan University Hospital, Karachi. A total of 71 (93%) participants claimed to be aware of the SSC guidelines but only 20 (26%) considered themselves very knowledgeable on the subject. Thirty-five (46%) physicians claimed that they were using the guidelines regularly. We concluded that the overall knowledge and compliance of sepsis guidelines was suboptimal. This emphasises the need for increased awareness and teaching of sepsis and SSC guidelines to improve patient outcomes in developing countries.

MED12 is frequently mutated in breast phyllodes tumours: a study of 112 cases.

AIM: To determine the frequency of MED12 mutations in a series of 112 breast phyllodes tumours, and to correlate the findings with clinicopathological parameters and survival outcomes. METHODS: Phyllodes tumours from the Department of Pathology, Singapore General Hospital, were classified into benign, borderline and malignant categories. Genomic DNA from formalin-fixed paraffin-embedded phyllodes tumours was extracted, purified and subjected to ultra-deep-targeted amplicon sequencing across exon 2 of the MED12 gene. Sequencing was performed on the Illumina MiSeq next-generation sequencing platform and bioinformatics analysis applied. Appropriate statistical analyses were carried out. RESULTS: There were 66 benign, 32 borderline and 14 malignant tumours, with 43 (65.1%), 21 (65.6%) and 6 (42.8%) disclosing MED12 mutations (missense, splice site, indel), respectively. For 97 cases with available follow-up, there were 10 (10.3%) recurrences. Patients with phyllodes tumours that harboured MED12 mutations experienced improved disease-free survivals, with higher recurrence likelihood in those without MED12 mutations (HR 9.99, 95% CIs 1.55 to 64.42, p=0.015). CONCLUSIONS: Similar to fibroadenomas, phyllodes tumours show a high frequency of MED12 mutations, affirming the close biological relationship between these fibroepithelial neoplasms.

Role of macrophages and monocytes in hepatitis C virus infections.

A number of studies conducted over many years have shown that hepatitis C virus (HCV) can infect a variety of cell types. In vivo infection of monocytes, macrophages, and dendritic cells by HCV has been frequently shown by a number of researchers. These studies have demonstrated replication of HCV by detecting the presence of both negative genomic strands and a variety of non-structural HCV proteins in infected cells. In addition, analyses of genome sequences have also shown that different cell types can harbor different HCV variants. Investigators have also done preliminary studies of which cellular genes are affected by HCV infection, but there have not yet been a sufficient number of these studies to understand the effects of infection on these cells. Analyses of in vitro HCV replication have shown that monocytes, macrophages and dendritic cells can be infected by HCV from patient sera or plasma. These studies suggest that entry and cellular locations may vary between different cell types. Some studies suggest that macrophages may preferentially allow HCV genotype 1 to replicate, but macrophages do not appear to select particular hypervariable regions. Overall, these studies agree with a model where monocytes and macrophages act as an amplification system, in which these cells are infected and show few cytopathic effects, but continuously produce HCV. This allows them to produce virus over an extended time and allows its spread to other cell types.

Human cell types important for hepatitis C virus replication in vivo and in vitro: old assertions and current evidence.

Hepatitis C Virus (HCV) is a single stranded RNA virus which produces negative strand RNA as a replicative intermediate. We analyzed 75 RT-PCR studies that tested for negative strand HCV RNA in liver and other human tissues. 85% of the studies that investigated extrahepatic replication of HCV found one or more samples positive for replicative RNA. Studies using in situ hybridization, immunofluorescence, immunohistochemistry, and quasispecies analysis also demonstrated the presence of replicating HCV in various extrahepatic human tissues, and provide evidence that HCV replicates in macrophages, B cells, T cells, and other extrahepatic tissues. We also analyzed both short term and long term in vitro systems used to culture HCV. These systems vary in their purposes and methods, but long term culturing of HCV in B cells, T cells, and other cell types has been used to analyze replication. It is therefore now possible to study HIV-HCV co-infections and HCV replication in vitro.

An efficient chemical approach to bispecific antibodies and antibodies of high valency.

Irreversible chemical programming of monoclonal aldolase antibody (mAb) 38C2 has been accomplished with beta-lactam equipped mono- and bifunctional targeting modules, including a cyclic-RGD peptide linked to either the peptide (D-Lys(6))-LHRH or another cyclic RGD unit and a small-molecule integrin inhibitor SCS-873 conjugated to (D-Lys(6))LHRH. We also prepared monofunctional targeting modules containing either cyclic RGD or (D-Lys(6))-LHRH peptides. Binding of the chemically programmed antibodies to integrin receptors alpha(v)beta(3) and alpha(v)beta(5) and to the luteinizing hormone releasing hormone receptor were evaluated. The bifunctional and bivalent c-RGD/LHRH and SCS-783/LHRH, the monofunctional and tetravalent c-RGD/c-RGD, and the monofunctional bivalent c-RGD chemically programmed antibodies bound specifically to the isolated integrin receptor proteins as well as to integrins expressed on human melanoma M-21 cells. c-RGD/LHRH, SCS-783/LHRH, and LHRH chemically programmed antibodies bound specifically to the LHRH receptors expressed on human ovarian cancer cells. This approach provides an efficient, versatile, and economically viable route to high-valency therapeutic antibodies that target defined combinations of specific receptors. Additionally, this approach should be applicable to chemically programmed vaccines.

Aldehyde detection by chromogenic/fluorogenic oxime bond fragmentation.

Amination of 4-nitrophenol, umbelliferone and 4-methylumbelliferone gave the corresponding oxyamines 1-3. These oxyamines react with aldehydes and ketones to form oximes. In the case of aliphatic aldehydes and electron-poor aromatic aldehydes, the oximes undergo base-catalyzed fragmentation in aqueous buffer in the presence of bovine serum albumin to give the parent phenols, which is the acyclic analog of Kemp's elimination reaction of 5-nitrobenzisoxazole 28. The process can be used as a spectrophotometric assay for formaldehyde under aqueous neutral conditions.