A novel cell line panel reveals non-genetic mediators of platinum resistance and phenotypic diversity in high grade serous ovarian cancer.

OBJECTIVES: Resistance to cancer therapy is an enduring challenge and accurate and reliable preclinical models are lacking. We interrogated this unmet need using high grade serous ovarian cancer (HGSC) as a disease model. METHODS: We created five in vitro and two in vivo platinum-resistant HGSC models and characterised the entire cell panel via whole genome sequencing, RNASeq and creation of intraperitoneal models. RESULTS: Mutational signature analysis indicated that platinum-resistant cell lines evolved from a pre-existing ancestral clone but a unifying mutational cause for drug resistance was not identified. However, cisplatin-resistant and carboplatin-resistant cells evolved recurrent changes in gene expression that significantly overlapped with independent samples obtained from multiple patients with relapsed HGSC. Gene Ontology Biological Pathways (GOBP) related to the tumour microenvironment, particularly the extracellular matrix, were repeatedly enriched in cisplatin-resistant cells, carboplatin-resistant cells and also in human resistant/refractory samples. The majority of significantly over-represented GOBP however, evolved uniquely in either cisplatin- or carboplatin-resistant cell lines resulting in diverse intraperitoneal behaviours that reflect different clinical manifestations of relapsed human HGSC. CONCLUSIONS: Our clinically relevant and usable models reveal a key role for non-genetic factors in the evolution of chemotherapy resistance. Biological pathways relevant to the extracellular matrix were repeatedly expressed by resistant cancer cells in multiple settings. This suggests that recurrent gene expression changes provide a fitness advantage during platinum therapy and also that cancer cell-intrinsic mechanisms influence the tumour microenvironment during the evolution of drug resistance. Candidate genes and pathways identified here could reveal therapeutic opportunities in platinum-resistant HGSC.

COVID-19 vaccine hesitancy and anti-vaxxers - supporting healthcare workers to navigate the unvaccinated: Reflections from clinical practice.

An important step in preparation for the fourth COVID-19 wave is to provide healthcare workers (HCWs) with skills to facilitate behaviour change in vaccine-hesitant patients. Convincing members of the public who are vaccine hesitant rather than anti-vaxxers should be the focus of our efforts. Our experience is that vaccine-hesitant individuals and anti-vaxxers are generally distinct cohorts, with differing reasons for their vaccine reluctance. If we are to truly address hesitancy, we must take time to understand the reasons for an individual's hesitancy. Developing a conceptual framework and skills for HCWs during encounters with unvaccinated individuals will be important not only for shifting some to get vaccinated, but also to manage the complex emotions that HCWs will undoubtedly be forced to confront during the fourth wave.

The mechanics of setting up a COVID-19 response: Experiences of the COVID-19 epidemic from Groote Schuur Hospital, Cape Town, South Africa.

The SARS-CoV-2 pandemic has challenged the provision of healthcare in ways that are unprecedented in our lifetime. Planning for the sheer numbers expected during the surge has required public hospitals to de-escalate all non-essential clinical services to focus on COVID-19. Western Cape Province was the initial epicentre of the COVID-19 epidemic in South Africa (SA), and the Cape Town metro was its hardest-hit geographical region. We describe how we constructed our COVID-19 hospital-wide clinical service at Groote Schuur Hospital, the University of Cape Town's tertiary-level teaching hospital. By describing the barriers and enablers, we hope to provide guidance rather than a blueprint for hospitals elsewhere in SA and in low-resource countries that face similar challenges now or during subsequent waves.

Clinical management of COVID-19: Experiences of the COVID-19 epidemic from Groote Schuur Hospital, Cape Town, South Africa.

The SARS-CoV-2 pandemic has presented clinicians with an enormous challenge in managing a respiratory virus that is not only capable of causing severe pneumonia and acute respiratory distress syndrome, but also multisystem disease. The extraordinary pace of clinical research, and particularly the surge in adaptive trials of new and repurposed treatments, have provided rapid answers to questions of whether such treatments work, and has resulted in corticosteroids taking centre stage in the management of hospitalised patients requiring oxygen support. Some treatment modalities, such as the role of anticoagulation to prevent and treat potential thromboembolic complications, remain controversial, as does the use of high-level oxygen support, outside of an intensive care unit setting. In this paper, we describe the clinical management of COVID-19 patients admitted to Groote Schuur Hospital, a major tertiary level hospital at the epicentre of South Africa's SARS-CoV-2 epidemic during its first 4 months.

Prolonged treatment of COVID-19 pneumonia with high-flow nasal oxygen: A story of oxygen and resilience.

The COVID-19 pandemic has placed significant strain on the oxygen delivery infrastructure of health facilities in resource-constrained health systems. In this case report, we describe a patient with severe COVID-19 pneumonia who was managed with high-flow nasal oxygen for 40 days, with an eventual successful outcome. We discuss the oxygen delivery infrastructure needed to offer this intervention, as well as the psychosocial impact on those undergoing treatment.

Population-based cohort study of surgical myotomy and pneumatic dilatation as primary interventions for oesophageal achalasia.

BACKGROUND: The aim of this national population-based cohort study was to compare rates of reintervention after surgical myotomy versus sequential pneumatic dilatation for the primary management of oesophageal achalasia. METHODS: Patients with oesophageal achalasia diagnosed between 2002 and 2012, and without an intervention in the preceding 5 years were identified from the Hospital Episode Statistics database. Patients were divided into two groups based on the primary treatment, and propensity score matching was used to compensate for differences in baseline characteristics. RESULTS: Some 14 705 patients were diagnosed with oesophageal achalasia, of whom 7487 (50·9 per cent) received interventional treatment: 1742 (23·3 per cent) surgical myotomy, 4534 (60·6 per cent) pneumatic dilatation and 1211 (16·2 per cent) endoscopic botulinum toxin injection. As age increased, the proportion of patients receiving myotomy decreased and the proportion undergoing dilatation increased. Patients who underwent surgical myotomy were younger (mean age 44·8 years versus 58·5 years among those who had pneumatic dilatation; P < 0·001), a greater proportion had a Charlson co-morbidity index score of 0 (90·1 versus 87·7 per cent; P = 0·003) and they were more commonly men (55·6 versus 51·8 per cent; P = 0·020). Following propensity score matching, the safety of the two initial treatment approaches was equivalent, with no difference in incidence of oesophageal perforation (1·3 and 1·4 per cent after myotomy and dilatation respectively; P = 0·750). However, dilatation was associated with increased need for reintervention (59·6 versus 13·8 per cent; P < 0·001) and frequency of reinterventions (mean 0·34 versus 0·06 per year; P < 0·001). CONCLUSION: Surgical myotomy was associated with a lower rate of reintervention and could be offered as primary treatment in patients with oesophageal achalasia who are fit for surgery. For those unfit for surgery, pneumatic dilatation may provide symptomatic relief with approximately 60 per cent of patients requiring reintervention.

Population-based cohort study of the management and survival of patients with early-stage oesophageal adenocarcinoma in England.

BACKGROUND: Until recently, oesophagectomy was the treatment of choice for early oesophageal cancer. Endoscopic treatment has been introduced relatively recently. This observational national database study aimed to describe how endoscopic therapy has been introduced in England and to examine the safety of this approach. METHODS: A population-based cohort study was undertaken of patients diagnosed with oesophageal adenocarcinoma between October 2007 and June 2009 using three linked national databases. Patients with early-stage disease (T1 tumours with no evidence of spread) were identified, along with the primary treatment modality where treatment intent was curative. Short-term outcomes after treatment and 5-year survival were evaluated. RESULTS: Of 5192 patients diagnosed with oesophageal adenocarcinoma, 306 (5·9 per cent) were considered to have early-stage disease before any treatment, of whom 239 (79·9 per cent of 299 patients with data on treatment intent) were managed with curative intent. Of 175 patients who had an oesophagectomy, 114 (65·1 (95 per cent c.i. 57·6 to 72·7) per cent) survived for 5 years. Among these, 47 (30·3 per cent of 155 patients with tissue results available) had their disease upstaged after pathological staging; this occurred more often in patients who did not have staging endoscopic ultrasonography before surgery. Of 41 patients who had an endoscopic resection, 27 (66 (95 per cent c.i. 49 to 80) per cent) survived for 5 years. Repeat endoscopic therapy was required by 23 (56 per cent) of these 41 patients. CONCLUSION: Between 2007 and 2009, oesophagectomy remained the initial treatment of choice (73·2 per cent) among patients with early-stage oesophageal cancer treated with curative intent; one in five patients were managed endoscopically, and this treatment was more common in elderly patients. Although the groups had different patient characteristics, 5-year survival rates were similar.

Implementation of objective activity monitoring to supplement the interpretation of ambulatory esophageal PH investigations.

Conventional catheter-based systems used for ambulatory esophageal pH monitoring have been reported to affect patient behavior. As physical activity has been associated with gastroesophageal reflux disease (GERD), there is a risk that abnormal behavior will degrade the value of this diagnostic investigation and consequent management strategies. The aim of this study was to quantify the effect of conventional pH monitoring on behavior and to investigate the temporal association between activity and reflux. A total of 20 patients listed for 24 hours pH monitoring underwent activity monitoring using a lightweight ear-worn accelerometer (e-AR sensor, Imperial College London) 2 days prior to, and during their investigation. PH was measured and recorded using a conventional nasogastric catheter and waist-worn receiver. Daily activity levels, including subject-specific activity intensity quartiles, were calculated and compared. Physical activity was added to the standard pH output to supplement interpretation. Average patient activity levels decreased by 26.5% during pH monitoring (range -4.5 to 51.0%, P = 0.036). High-intensity activity decreased by 24.4% (range -4.0 to 75.6%, P = 0.036), and restful activity increased on average by 34% although this failed to reach statistical significance (-24.0 to 289.2%, P = 0.161). Some patients exhibited consistent associations between bouts of activity and acidic episodes. The results of this study support the previously reported reduction in activity during ambulatory esophageal pH monitoring, with the added reliability of objective data. In the absence of more pervasive pH monitoring systems (e.g. wireless), quantifying activity changes in the setting of activity-induced reflux might guide the physicians' interpretation of patient DeMeester scores resulting in more appropriate management of GERD.

Improvement over time in outcomes for patients undergoing endoscopic therapy for Barrett's oesophagus-related neoplasia: 6-year experience from the first 500 patients treated in the UK patient registry.

BACKGROUND: Barrett's oesophagus (BE) is a pre-malignant condition leading to oesophageal adenocarcinoma (OAC). Treatment of neoplasia at an early stage is desirable. Combined endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA) is an alternative to surgery for patients with BE-related neoplasia. METHODS: We examined prospective data from the UK registry of patients undergoing RFA/EMR for BE-related neoplasia from 2008 to 2013. Before RFA, visible lesions were removed by EMR. Thereafter, patients had RFA 3-monthly until all BE was ablated or cancer developed (endpoints). End of treatment biopsies were recommended at around 12 months from first RFA treatment or when endpoints were reached. Outcomes for clearance of dysplasia (CR-D) and BE (CR-IM) at end of treatment were assessed over two time periods (2008-2010 and 2011-2013). Durability of successful treatment and progression to OAC were also evaluated. RESULTS: 508 patients have completed treatment. CR-D and CR-IM improved significantly between the former and later time periods, from 77% and 56% to 92% and 83%, respectively (p<0.0001). EMR for visible lesions prior to RFA increased from 48% to 60% (p=0.013). Rescue EMR after RFA decreased from 13% to 2% (p<0.0001). Progression to OAC at 12 months is not significantly different (3.6% vs 2.1%, p=0.51). CONCLUSIONS: Clinical outcomes for BE neoplasia have improved significantly over the past 6 years with improved lesion recognition and aggressive resection of visible lesions before RFA. Despite advances in technique, the rate of cancer progression remains 2-4% at 1 year in these high-risk patients. TRIAL REGISTRATION NUMBER: ISRCTN93069556.

The neurobiology of HIV dementia: implications for practice in South Africa.

In this review, the neuropathogenesis of HIV dementia (HIV-D) is discussed in the context of the local epidemic. HIV-D continues to be prevalent in the era of highly active anti-retroviral therapy. HIV neuro-invasion into the central nervous system may result in the development of separate HIV genotypes in an individual through compartmentalisation. The blood brain barrier continues to limit penetration of anti-retroviral drugs into the cerebrospinal fluid. Individuals with active neuro-inflammation appear to respond well to HAART. In some cases low grade neuro-degeneration persists with consequent clinical deterioration. In South Africa, the emergence of a sub-epidemic of HIV-D is being driven by various factors, including the incomplete coverage of HAART to all who need it, the late stage presentation of people living with HIV/AIDS (PLWHA) and a co-occurring methamphetamine epidemic. Differences in viral subtype do not appear to confer protection against HIV-D. Implications for PLWHA who are at risk for HIV-D in South Africa are explored, with a view to providing suggestions for improving practice and research into this area.

Images of the terminal ileum are more convincing than cecal images for verifying the extent of colonoscopy.

BACKGROUND AND STUDY AIMS: Independent verification of colonoscopy completion is important for quality assurance. Cecal photographs aimed at showing key landmarks, including the ileocecal valve (ICV) and appendiceal orifice are the currently recommended standard, but are often perceived as unreliable. Images of the terminal ileum demonstrating villi may provide more robust evidence of completion. We sought to prospectively evaluate the ease of routine intubation of the terminal ileum and to compare the effectiveness of terminal ileum and cecal photographs in convincing independent reviewers that total colonoscopy had been accomplished. PATIENTS AND METHODS: A prospective, observational study evaluated 216 consecutively completed colonoscopies performed in routine clinical practice. Cecal and terminal ileum photographs were evaluated and scored by independent reviewers. Frequency of terminal ileum intubation, time required, and safety parameters were recorded. RESULTS: The terminal ileum was intubated and photographed in 188/216 (87%) of cases. Median time taken to intubate, or attempt to intubate the terminal ileum was 1 min 24 s, and was achieved without complications or requirement for additional sedation. Terminal ileum images were significantly more likely to be considered convincing than cecal images ( P<0.0001 for all reviewers). There was excellent interobserver agreement amongst the opinion of reviewers regarding terminal ileum photographs (kappa=0.91). CONCLUSION: Terminal ileum intubation is achievable rapidly and safely in the majority of patients undergoing colonoscopy. Terminal ileum images provide more convincing evidence of complete examination of the colon than cecal images, even when attempts to capture images specifically of the ICV and appendiceal orifice are made.

What is the most reliable imaging modality for small colonic polyp characterization? Study of white-light, autofluorescence, and narrow-band imaging.

BACKGROUND AND STUDY AIMS: In vivo optical diagnosis of small colorectal polyps has potential clinical and cost advantages, but requires accuracy and high interobserver agreement for clinically acceptability. We aimed to assess interobserver variability and diagnostic performance of endoscopic imaging modalities in characterizing small colonic polyps. METHODS: High quality still images of 80 polyps < 1 cm were recorded using white-light endoscopy (WLE), autofluorescence imaging (AFI) and narrow-band imaging with and without magnification (NBI and NBImag). All images were assessed for quality, prediction of polyp histology, and vascular pattern intensity (with NBI) by nine experienced colonoscopists (four experts in advanced imaging) from five UK centers. Interobserver agreement (kappa statistic), sensitivity, specificity, and accuracy were calculated compared with histopathological findings. RESULTS: Interobserver agreement for predicting polyp histology using NBImag was significantly better for experts (κ = 0.63, substantial) compared with nonexperts (κ = 0.30, fair; P < 0.001), and was moderate for all colonoscopists with WLE, AFI and NBI. Interobserver agreement for vascular pattern intensity using NBI was 0.69 (substantial) for experts and 0.57 (good) for nonexperts. NBImag had higher sensitivity than WLE (experts, 0.93 vs. 0.68, P < 0.001; nonexperts, 0.90 vs. 0.52, P < 0.001) and higher overall accuracy (experts, 0.76 vs. 0.64, P = 0.003; nonexperts 0.61 vs. 0.40, P < 0.001). AFI had worse accuracy than WLE for both expert colonoscopists (0.53 vs. 0.64, P = 0.02) and nonexperts (0.32 vs. 0.40, P = 0.04). CONCLUSIONS: Of the imaging modalities tested, NBImag appeared to have the best overall accuracy and interobserver agreement, although not adequate for in vivo diagnosis. NBI and AFI did not have better sensitivity, specificity, or accuracy compared with WLE.

Implications of eosinophilia in the normal duodenal biopsy - an association with allergy and functional dyspepsia.

BACKGROUND: Allergy and functional gastrointestinal disorders have been associated with eosinophilia in duodenal mucosa. AIM: To assess the prevalence of eosinophilia in duodenal biopsies of patients attending for oesophogastroduodenoscopy and delineate associated clinical conditions. METHODS: A total of 155 patients (mean age 55 years, 59% women) with normal duodenal biopsies were randomly selected for audit from histopathology files. Eosinophil counts in five high power fields (HPFs) were assessed. Records were analysed for symptoms, diagnosis and medications; patients were divided into five groups based on upper gastrointestinal (UGI) symptom profiles, including a control group of those without predominant UGI symptoms. The prevalence of duodenal eosinophilia (defined as >22/5HPFs a priori) was calculated. RESULTS: In the control group, the mean duodenal eosinophil count was 15/5HPFs; prevalence of duodenal eosinophilia was 22.5%. In postprandial distress syndrome (PDS), both mean eosinophil counts (20.2/5HPF, P < 0.04) and prevalence of duodenal eosinophilia (47.3%, P < 0.04) were significantly higher. Duodenal eosinophilia was significantly associated with allergy (OR 5.04, 95% CI 2.12-11.95, P < 0.001). There was no association with irritable bowel syndrome or medications. CONCLUSIONS: Subtle duodenal eosinophilia is relatively common in routine oesophogastroduodenoscopy and previously overlooked; it is associated with allergy and may indicate a hypersensitivity mechanism in some patients with PDS including early satiety.

Homeopathic prescribing for chronic conditions in equine veterinary practice in the UK.

Twelve Faculty of Homeopathy veterinarians recorded data systematically at 777 consecutive homeopathic appointments for horses over a period of 12 months. A spreadsheet enabled the recording of information, which included the date of appointment; horse and owner identity (anonymised); sex of horse; main medical problem treated; whether the condition was chronic or acute; whether the appointment was new or a follow-up; owner-assessed clinical outcome on a seven-point scale, ranging from -3 to +3, compared with the first appointment; homeopathic medicine(s) prescribed; and whether any conventional or other complementary/alternative medicine (CAM) was being used concurrently to treat the condition. Data from 289 horses comprised a total of 305 individual conditions identified as chronic in nature, of which 234 had a follow-up assessment. At the final appointment for chronic cases during the study period, 4.3 per cent were receiving conventional medication and 17.1 per cent were being given another CAM treatment in addition to homeopathy. The eight chronic conditions most frequently treated with homeopathy were: arthritis, headshaking, laminitis, chronic obstructive pulmonary disease, sweet itch, dermatitis, sarcoidosis and Cushing's syndrome.

Pilot study of the effect of individualised homeopathy on the pruritus associated with atopic dermatitis in dogs.

Twenty dogs with confirmed atopic dermatitis were treated with homeopathy. In the first phase of this pilot study, all of the dogs were treated by a veterinary homeopath with individualised remedies prescribed on the basis of the dog's cutaneous signs and constitutional characteristics. The response to treatment was assessed by scoring the severity of pruritus from 0 to 10 on a validated scale. The dogs were evaluated at monthly intervals for at least two months. In 15 cases, the owners reported no improvement following homeopathic treatment. In the other five cases, the owners believed that the homeopathic treatment was associated with a substantial improvement, and reported reductions in pruritus scores ranging from 64 to 100 per cent. These five dogs were selected for the second phase of the study, in which homeopathic remedies were tested against placebos in a randomised and blinded trial. In one of these dogs, atopic dermatitis resolved completely and so this dog could not participate in phase 2; another dog was euthanased because of status epilepticus before phase 2 could be started. In the remaining three cases, the owners correctly distinguished between the placebo and homeopathic remedies, and reported reductions in the pruritus score of 0, 0.2 and 0.8 following placebo treatment and 4.3, 2.4 and 3.0, respectively, following the remedy.

Antibiotic-resistant Campylobacter: an increasing problem.

The case is described of a 27-year-old woman who presented with an acute diarrhoeal illness. She was initially poorly responsive to antibiotics and developed lymphocytic ascites. Diagnosis was difficult to establish, and peritoneal tuberculosis was considered to be the most likely cause of her symptoms. Serological tests eventually confirmed Campylobacter jejuni infection. Campylobacter is one of the most common bacterial diarrhoeal infections, and complications, except for colitis, are rare except in specific disease states--for example, patients with cirrhosis or undergoing peritoneal dialysis. Antibiotic resistance is an increasing problem, and this may potentially lead to a greater incidence of complications in the future.

Outcomes from homeopathic prescribing in veterinary practice: a prospective, research-targeted, pilot study.

BACKGROUND AND AIMS: Targeted research development in veterinary homeopathy is properly informed by the systematic collection and analysis of relevant clinical data obtained by its practitioners. We organised a pilot data collection study, in which 8 Faculty of Homeopathy veterinarians collected practice-based clinical and outcomes data over a 6-month period. METHODS: A specifically designed Excel spreadsheet enabled recording of consecutive clinical appointments under the following headings: date; identity of patient and owner (anonymised); age, sex and species of patient; medical condition/complaint treated; whether confirmed diagnosis, chronic or acute, new or follow-up case; owner-assessed outcome (7-point Likert scale: -3 to +3) compared with first appointment; homeopathic medicine/s prescribed; other medication/s for the condition/complaint. Spreadsheets were submitted monthly by e-mail to the project organisers for data checking, synthesis and analysis. RESULTS: Practitioners submitted data regularly and punctually, and most data cells were completed. 767 individual patients were treated (547 dogs, 155 cats, 50 horses, 5 rabbits, 4 guinea-pigs, 2 birds, 2 goats, 1 cow, and 1 tortoise). Outcome from two or more homeopathic appointments per patient condition was obtained in 539 cases (79.8% showing improvement, 6.1% deterioration, 11.7% no change; outcome not recorded in 2.4% of follow-ups). Strongly positive outcomes (scores of +2 or +3) were achieved in: arthritis and epilepsy in dogs and, in smaller numbers, in atopic dermatitis, gingivitis and hyperthyroidism in cats. CONCLUSIONS: Systematic recording of data by veterinarians in clinical practice is feasible and capable of informing future research in veterinary homeopathy. A refined version of the spreadsheet can be used in larger-scale research-targeted veterinary data collection.

Decline in admission rates for acute appendicitis in England.

BACKGROUND: The incidence of acute appendicitis declined in western countries between the 1930s and the early 1990s. The aim of this study was to determine time trends in hospital admissions for acute appendicitis in England between 1989-1990 and 1999-2000, and in population mortality rates for appendicitis from 1979 to 1999. METHODS: : Hospital Episode Statistics for admissions were obtained from the Department of Health and mortality data from the Office for National Statistics. RESULTS: Between 1989-1990 and 1999-2000, age-standardized hospital admission rates for acute appendicitis decreased by 12.5 per cent in male patients and by 18.8 per cent in female patients. The proportions of admissions that resulted in operation remained stable. Admission rates for non-specific mesenteric lymphadenitis fell. Admission rates for abdominal pain increased between 1989-1990 and 1995-1996, at which time the International Classification of Diseases codes changed. Between 1995-1996 and 1999-2000, admission rates for abdominal pain declined. Analysis of age-specific admission rates for acute appendicitis and abdominal pain from 1989-1990 to 1995-1996 showed that the decline in acute appendicitis could not be accounted for by a change in diagnostic practice. Mortality rates for acute appendicitis remained stable over the study period. CONCLUSION: Admission rates for acute appendicitis declined over the study period. This decline cannot be explained by reclassification.