Understanding the journeys of patients with an asthma exacerbation requiring urgent therapy at a primary care clinic.

BACKGROUND: Asthma is a significant health issue in primary care. We examined the journeys of patients with asthma exacerbations requiring urgent therapy at a primary care clinic in Singapore. METHODS: Face-to-face semi-structured interviews were conducted with patients who received urgent therapy for asthma exacerbation at a primary care clinic. Data collected was used to construct themes. RESULTS: Fifteen multi-ethnic adult patients were recruited. Participants cited treatment cost, underuse of preventer medication, difficulties attending routine asthma care due to work, and stigma as barriers to asthma control. Reasons for delay in seeking urgent care for asthma were: inability to access medical care out of hours, competing priorities, perception that an exacerbation was 'not serious enough', difficulty recognizing symptoms of asthma exacerbation, and being tired or despondent. Participants were triggered to seek care due to failure of reliever inhalers, duration of symptoms, sleep disturbance, inability to work, or advice from others. During an exacerbation, participants often initiated other self-management measures besides using reliever medication. This included over-the-counter medications and non-pharmacological interventions (e.g. drinking water). Of the 15 patients interviewed, only one stepped up preventer inhaler adequately, according to their Asthma Action Plan (AAP). CONCLUSIONS: In caring for patients with asthma, primary care providers should address patients' asthma self-management skills, such as recognizing symptoms of asthma exacerbations and regular preventer use, and provide clear instructions on how to respond to asthma symptoms (AAP). Minimizing direct (medication and consultation fees) and indirect costs (loss of earnings and adverse impact on employment prospects) are also important considerations.

Which Aspect of Patient-Provider Relationship Affects Acceptance and Adherence of Insulin Therapy in Type 2 Diabetes Mellitus? A Qualitative Study in Primary Care.

PURPOSE: In type 2 diabetes mellitus (T2DM), insulin therapy is often recommended to achieve the optimal control of disease, thereby preventing the onset and progression of diabetes-related complications. Despite knowing about the benefits, it has been reported that 71% of patients refuse insulin and the adherence rate ranges from 30 to 80%. Patient-provider relationship (PPR) may affect such insulin-related behaviours, but little is known about which aspect of PPR affects this. This study aimed to explore the key aspect of the patient-provider relationship that affects the initial insulin acceptance and continued adherence. PATIENTS AND METHODS: We used the grounded theory approach in this qualitative research. The study was conducted at two primary care clinics between September 2019 and January 2021. Patients with T2DM on basal or premixed insulin were recruited using maximum variation sampling. Data were collected using semi-structured in-depth interviews and transcribed verbatim for analysis using constant comparison and synthesis. RESULTS: Twenty-one participants with different levels of diabetes control and adherence were recruited. Four themes that emerged were 1) patient-provider interaction, 2) addressing the psychological fears, 3) gaining confidence in handling insulin equipment and 4) follow-up after insulin initiation. Among the subthemes, trust in doctors, provider's communication skills, patient-centred decision-making and continuity of care positively influenced insulin acceptance and adherence. Conversely, fear of being judged by the provider hindered open communication around non-adherence. Various aspects of interaction with nurses helped in alleviating patient's fear of injection and gaining confidence with the insulin equipment. CONCLUSION: Many aspects of PPR affect insulin acceptance and adherence. Among these, gaining patients' trust, effective patient-provider communication, patient-centred decision-making, and ensuring continuity of care improve both insulin acceptance and treatment adherence. Various interactions with nurses help in addressing fears surrounding injection and gaining acceptance towards insulin therapy. Patients' fear of being blamed or judged by the provider negatively affects open communication around non-adherence.

Assessing the mechanisms contributing to self-care behaviours in young and usual-onset diabetes.

Context: Young-onset diabetes (YOD) (age of onset 21-39 years) is associated with a poorer metabolic profile and a higher risk of complications, and poor self-care behaviours play a significant role. However, few studies have comprehensively examined the mechanisms (self-efficacy, dietary barriers, illness perceptions, knowledge, diabetes-related distress) that may contribute to poor self-care behaviours in YOD. Objectives: Our study aims to compare these mechanisms and self-care behaviours between participants with YOD and usualonset diabetes (age of onset 40-59 years). Study design: A cross-sectional survey was conducted in primary care clinics in participants with YOD or UOD, and type 2 diabetes for 10 years or less. Survey tools included the Diabetes Empowerment Scale short-form (DES-SF), dietary barriers of the Personal Diabetes Questionnaire (PDQ-DB), Brief Illness Perceptions Questionnaire (BIPQ), revised Michigan Diabetes Knowledge Test (DKT), diabetes distress scale (DDS), Summary of Diabetes Self-care Activities (SDSCA), International Physical Activity Questionnaire (IPAQ-SF) and medication adherence report scale (MARS-5), and means of both groups were compared using independent T-tests and effect sizes were analysed (Cohen's d). Results: 97 participants with YOD and 312 with UOD completed the survey. Compared with UOD, participants with YOD reported a lower adherence to a specific diet (d=0.45), with no significant differences in levels of physical activity or medication adherence. Participants with YOD experienced greater diabetes-related distress (d=0.35), especially with emotional (d=0.37), regimen-related (d=0.43) and interpersonal (d=0.39) distress. At the same time, perception of self-efficacy was significantly lower (d=0.27) and more dietary barriers were perceived (d=0.76). Participants with YOD also perceived that diabetes affected their lives more severely (consequence) (d=0.26), had a larger effect on their emotions (emotional representation) (d=0.28), will last longer (timeline) (d=0.37), and perceived that treatment was less likely help their diabetes (treatment control) (d=0.26). Conclusions: Participants with YOD experienced greater diabetes-related distress, lower self-efficacy and reported lower dietary adherence with more dietary barriers than those with UOD. Patients with YOD have distinctly different issues from UOD, and in providing care for YOD, clinicians should actively seek to identify and address these issues.

Structured Training for Laparoscopic Appendectomy for Residents (STAR Trial)-A Randomized Pilot Study.

OBJECTIVE: Laparoscopic appendectomy is a common operation that is frequently performed by junior surgical residents. We investigated the effect of a structured training program on the proficiency of junior residents in acquiring skills necessary in this operation. DESIGN AND PARTICIPANTS: This is a randomized pilot trial. Between December 2014 and July 2018, twenty junior residents were recruited for this study. 11 were randomized to receive a structured training program of supervised, task-specific training. Each resident subsequently performed ten cases of laparoscopic appendectomy with their performance assessed for the last 5. The GOALS scale was used as the primary endpoint. Secondary endpoints were perioperative outcomes. The effect of intervention on these outcomes were evaluated assuming a linear mixed effect multi-level model. The study was single-blinded as the assessors did not know which group each resident belonged to. RESULTS: There were no statistically significant differences in the total GOALS score or any of its individual domains. After adjusting for the number of operations done within the trial, the mean difference between the total GOALS score was 0.07 (95% CI -0.76 to 0.90, P=0.866). Blood loss, hospital stay and postoperative complication rates were similar. There was suggestion of a shorter operative time (effect estimate -9.03, 95% CI -19.56 to 1.50) in the intervention arm although statistical significance was not achieved. No avoidable adverse events due to this study were recorded. CONCLUSION: Structured training program did not significantly improve surgical performance and outcomes in laparoscopic appendectomy in this pilot trial. Despite these findings, residents can still potentially mount their learning curves in laparoscopy earlier in a safe environment with such a program which is especially important in the era of minimally invasive surgery.

Study protocol: phase 1 dose escalating study of Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) with oxaliplatin in peritoneal metastasis.

BACKGROUND: Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is a novel laparoscopic intraperitoneal chemotherapy technique, with advantages such as homogeneous distribution of aerosol and deeper tissue penetration. Thus far, PIPAC oxaliplatin has been administered at an arbitrary dose of 92 mg/m2. AIM: We aim to determine the dose-related safety profile and tolerability of PIPAC oxaliplatin using an evidence-based approach. The secondary aim is to evaluate clinic-pathologic response and the pharmacokinetic profile. METHODS: This is a phase I 3+3 dose escalation study for gastric and colorectal cancer with predominant peritoneal metastasis starting at a dose of 45 mg/m2. Safety is assessed according to Clavien-Dindo Classification and Common Terminology Criteria for Adverse Events (version 4.0). Clinico-pathologic response is assessed using the Peritoneal Regression Grading Score, Peritoneal Cancer Index, and Response Evaluation Criteria In Solid Tumour criteria (version 1.1). Pharmacokinetic analysis is performed using Inductively Coupled Plasma-Mass Spectrometry assay. This trial is registered on ClinicalTrials.gov (NCT03172416). CONCLUSIONS: This phase I study can provide the scientific basis to identify the optimal dose for PIPAC with oxaliplatin such that the benefits of this novel and promising intraperitoneal chemotherapy delivery technique can be maximized.

Extensive peritoneal lavage after curative gastrectomy for gastric cancer (EXPEL): study protocol of an international multicentre randomised controlled trial.

Peritoneal recurrence after gastrectomy for gastric cancer is common and the prognosis is dismal. Recent evidence suggests that extensive peritoneal lavage with large volume of normal saline after surgery before abdominal closure can reduce the risk of peritoneal recurrence and improve overall survival. This study aims to evaluate the benefit of extensive intraoperative peritoneal lavage. This is a prospective, open-label, multicentre randomised controlled trial involving 15 international centres in China, Korea, Japan, Malaysia and Singapore. Patients with cT3/4 stomach cancer undergoing curative resection are randomised to either extensive peritoneal lavage (10 l of saline) or standard lavage (≤2 l of saline). The primary outcome is overall survival and secondary outcomes include disease-free survival and peritoneal recurrence. The minimum sample size is 600 subjects with 300 per arm completing 3 years follow-up. The data will be analysed on an intention-to-treat basis, assuming a two-sided test with a 5% level of significance.

PRL3-zumab, a first-in-class humanized antibody for cancer therapy.

Novel, tumor-specific drugs are urgently needed for a breakthrough in cancer therapy. Herein, we generated a first-in-class humanized antibody (PRL3-zumab) against PRL-3, an intracellular tumor-associated phosphatase upregulated in multiple human cancers, for unconventional cancer immunotherapies. We focused on gastric cancer (GC), wherein elevated PRL-3 mRNA levels significantly correlated with shortened overall survival of GC patients. PRL-3 protein was overexpressed in 85% of fresh-frozen clinical gastric tumor samples examined but not in patient-matched normal gastric tissues. Using human GC cell lines, we demonstrated that PRL3-zumab specifically blocked PRL-3+, but not PRL-3-, orthotopic gastric tumors. In this setting, PRL3-zumab had better therapeutic efficacy as a monotherapy, rather than simultaneous combination with 5-fluorouracil or 5-fluorouracil alone. PRL3-zumab could also prevent PRL-3+ tumor recurrence. Mechanistically, we found that intracellular PRL-3 antigens could be externalized to become "extracellular oncotargets" that serve as bait for PRL3-zumab binding to potentially bridge and recruit immunocytes into tumor microenvironments for killing effects on cancer cells. In summary, our results document a comprehensive cancer therapeutic approach to specific antibody-targeted therapy against the PRL-3 oncotarget as a case study for developing antibodies against other intracellular targets in drug discovery.

Prevalence of KRAS, BRAF, PI3K and EGFR mutations among Asian patients with metastatic colorectal cancer.

Mutations in oncogenes along the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the resistance to cetuximab in patients with metastatic colorectal cancer (mCRC). However, the relative significance of these mutations based on their frequencies of occurrence in the Singaporean population remains unclear. In the present study, the prevalence of Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF), phosphoinositide 3-kinase (PI3K) and EGFR somatic mutations were determined among Singaporean patients with mCRC. DNA extracted from 45 pairs of surgically resected tumor and normal mucosa samples was subjected to direct sequencing or restriction fragment length polymorphism. Associations of the genetic mutations with various clinicopathological parameters were further explored. Mutations in either codon 12 or 13 of KRAS were confirmed as prominent phenomena among the included Singaporean mCRC patients, at a prevalence comparable with that of Caucasian and patients of other Asian ethnicities [33.3% (90% confidence interval, 21.8-44.9%)]. KRAS mutation was not associated with clinicopathological features, including age, gender and ethnicity of patients, or the tumor site, differentiation and mucinous status. Conversely, the prevalence of BRAF (0%), PI3K (2.2%) and EGFR (0%) mutations were low. The results of the present study indicate that KRAS mutations are prevalent among the studied population, and confirm the low prevalence of BRAF, PI3K and EGFR mutations. KRAS should be prioritized as an investigational gene for future studies of predictive biomarkers of cetuximab response among Singaporean patients with mCRC.

IL-1beta signals through the EGF receptor and activates Egr-1 through MMP-ADAM.

The immediate-early gene Egr-1 controls the inducible expression of many genes implicated in the pathogenesis of a range of vascular disorders, yet our understanding of the mechanisms controlling the rapid expression of this prototypic zinc finger transcription factor is poor. Here we show that Egr-1 expression induced by IL-1beta is dependent on metalloproteinases (MMP) and a disintegrin and a metalloproteinase (ADAM). Pharmacologic MMP/ADAM inhibitors and siRNA knockdown prevent IL-1beta induction of Egr-1. Further, IL-1beta activates Egr-1 via the epidermal growth factor receptor (EGFR). This is blocked by EGFR tyrosine kinase inhibition and EGFR knockdown. IL-1beta induction of Egr-1 expression is reduced in murine embryonic fibroblasts (mEFs) deficient in ADAM17 despite unbiased expression of EGFR and IL-1RI in ADAM17-deficient and wild-type mEFs. Finally, we show that IL-1beta-inducible wound repair after mechanical injury requires both EGFR and MMP/ADAM. This study reports for the first time that Egr-1 induction by IL-1beta involves EGFR and MMP/ADAM-dependent EGFR phosphorylation.