Pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension in Cape Town, South Africa.

Background: Pulmonary endarterectomy (PEA) is the only definitive and potentially curative therapy for chronic thromboembolic pulmonary hypertension (CTEPH), associated with impressive improvements in symptoms and haemodynamics. However, it is only offered at a few centres in South Africa. The characteristics and outcomes of patients undergoing PEA in Cape Town have not been reported previously. Objectives: To assess the difference in World Health Organization functional class (WHO-FC) before and at least 6 weeks after surgery. Methods: We interrogated the adult cardiothoracic surgery database at the University of Cape Town between December 2005 and April 2021 for patients undergoing PEA at Groote Schuur Hospital and a private hospital. Results: A total of 32 patients underwent PEA, of whom 8 were excluded from the final analysis owing to incomplete data or a histological diagnosis other than CTEPH. The work-up of these patients for surgery was variable: all had a computed tomography pulmonary angiogram, 7 (29%) had a ventilation/perfusion scan, 5 (21%) underwent right heart catheterisation, and none had a pulmonary angiogram. The perioperative mortality was 4/24 (17%): 1 patient (4%) had a cardiac arrest on induction of anaesthesia, 2 patients (8%) died of postoperative pulmonary haemorrhage, and 1 patient (4%) died of septic complications in the intensive care unit. Among the survivors, the median (interquartile range) improvement in WHO-FC was 2 (1 - 3) classes (p=0.0004); 10/16 patients (63%) returned to a normal baseline (WHO-FC I). Conclusion: Even in a low-volume centre, PEA is associated with significant improvements in WHO-FC and a return to a normal baseline in survivors. Study synopsis: What the study adds. South African patients undergoing pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) have a marked improvement in functional status, with many returning to a normal functional baseline. However, the small number of patients included in this study indicates that PEA is probably underutilised. Pre- and postoperative assessment is inconsistent, despite availability of established guidelines.Implications of the findings. More patients should be referred to specialist centres for assessment for this potentially curative procedure. Use of guidelines to standardise investigations and monitoring of patients with CTEPH may improve patient selection for surgery.

Correction to: [89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

Missing Electronic Supplementary Materials.

[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

Digital vs traditional: Are diagnostic accuracy rates similar for glass slides vs whole slide images in a non-gynaecological external quality assurance setting?

INTRODUCTION: The Royal College of Pathologists of Australasia Quality Assurance Programs introduced virtual microscopy cases into its cytopathology non-gynaecological programme after a short pilot phase, to address the challenges of providing a purely glass slide-based external quality assurance programme to multiple participants both locally and internationally. The use of whole slide image (WSI) cases has facilitated a more robust programme in relation to standardised material and statistical analysis, with access to a wider variety of specimen types and diagnostic entities. METHOD: Diagnostic accuracy rates on 56 WSI were assessed against the reference diagnosis. A portion (12) of these WSI slides had been used in glass slide format in previous external quality assurance surveys, and the results of these were compared to the responses received as glass slide cases. RESULTS: Overall diagnostic accuracy for the 56 WSI cases was acceptable in comparison to the reference diagnosis. When these 12 cases were analysed individually, for seven of the 12 cases, virtual format was found to be not inferior to glass slides for diagnostic accuracy. For one case, accuracy using WSI for diagnosis was superior to glass format. CONCLUSION: Diagnostic accuracy, using WSI for cases in our external quality assurance programme is acceptable. As the use of digital microscopy in a large scale external quality assurance programme offers extensive advantages over a glass slide-based format, our results encourage future comparison of diagnostic accuracy for virtual compared to glass slide format at a point in time where pathologists are becoming increasingly familiar with virtual microscopy in everyday practice.

The aetiology, clinical presentation and treatment of patients with pulmonary hypertension in Cape Town: A preliminary report from the Groote Schuur Hospital Pulmonary Hypertension Registry.

BACKGROUND: There is a paucity of knowledge about pulmonary hypertension (PH) in sub-Saharan Africa and an urgent need for its investigation in this context. The impact of HIV infection in PH is also unknown. OBJECTIVES: To determine the aetiology, clinical presentation, severity and current management of PH at a tertiary-level hospital in Cape Town, South Africa (SA). METHODS: Demographic and clinical data, including from special investigations, were captured retrospectively for all patients referred to the Groote Schuur Hospital Pulmonary Hypertension Clinic between October 2015 and November 2017 (n=58) and entered into an online registry. Descriptive statistics were used to present the baseline data at enrolment. RESULTS: Patients were mainly young and female and almost half (48.3%) had severe symptoms according to World Health Organization classification. The main aetiologies were pulmonary arterial hypertension (PAH) and chronic thromboembolic PH. More than a fifth of the patients were HIV-positive, with nine patients presenting with HIV-associated PAH. The median time from initial presentation to referral to a specialist centre was 227 days (interquartile range: 72 - 625 days). Only a small number of patients were on PH-specific treatment at enrolment and a notable number never underwent right-heart catheterisation. CONCLUSION: PH diagnosis is often delayed and even at a tertiary institution with a dedicated clinic and access to special investigations, PH is suboptimally investigated and managed. Expansion of this registry to better understand the phenotype of this disease in SA can improve outcomes for these patients through awareness, early identification and effective management.

Balancing treatment efficacy, toxicity and complication risk in elderly patients with metastatic renal cell carcinoma.

The number of elderly patients with renal cell carcinoma is rising. Elderly patients differ from their younger counterparts in, among others, higher incidence of comorbidity and reduced organ function. Age influences outcome of surgery, and therefore has to be taken into account in elderly patients eligible for cytoreductive nephrectomy. Over the last decade several novel effective drugs have become available for the metastatic setting targeting angiogenesis and mammalian target of rapamycin. Immune checkpoint blockade with a programmed death 1 antibody has recently been shown to increase survival and further studies with immune checkpoint inhibitors are ongoing. In this review we summarize the available data on efficacy and toxicity of existing and emerging therapies for metastatic renal cell carcinoma in the elderly. Where possible, we provide evidence-based recommendations for treatment choices in elderly.

Cognitive coping and goal adjustment after first-time myocardial infarction: relationships with symptoms of depression.

The authors studied the relationships among cognitive coping strategies, goal adjustment processes (disengagement and reengagement), and depressive symptomatology in a sample of 139 patients who had experienced a first-time acute myocardial infarction between 3 and 12 months before data assessment. They assessed cognitive coping strategies, goal adjustment, and depressive symptoms by the Cognitive Emotion Regulation Questionnaire, the Goal Obstruction Questionnaire, and the Hospital Anxiety and Depression Scale, respectively. Main statistical methods were Pearson correlations and multiple regression analyses. Results show significant associations among the cognitive coping strategies of rumination, catastrophizing, and higher depressive symptoms, as well as among positive refocusing, goal reengagement, and lower depressive symptoms. This suggests that cognitive coping and goal reengagement strategies may be useful targets for intervention.

High yield and rapid growth of Neoparamoeba pemaquidensis in co-culture with a rainbow trout gill-derived cell line RTgill-W1.

Neoparamoeba pemaquidensis is an ubiquitous amphizoic marine protozoan and has been implicated as the causative agent for several diseases in marine organisms, most notably amoebic gill disease (AGD) in Atlantic salmon. Despite several reports on the pathology of AGD, relatively little is known about the protozoan and its relationship to host cells. In this study, an in vitro approach using monolayers of a rainbow trout gill cell line (RTgill-W1, ATCC CRL-2523) was used to rapidly grow large numbers of N. pemaquidensis (ATCC 50172) and investigate cell-pathogen interactions. Established cell lines derived from other tissues of rainbow trout and other fish species were also evaluated for amoeba growth support. The amoebae showed preference and highest yield when grown with RTgill-W1 over nine other tested fish cell lines. Amoeba yields could reach as high as 5 x 10(5) cells mL(-1) within 3 days of growth on the gill cell monolayers. The amoebae caused visible focal lesions in RTgill-W1 monolayers within 24 h of exposure and rapidly proliferated and spread with cytopathic effects destroying the neighbouring pavement-like cells within 48-72 h after initial exposure in media above 700 mOsm kg(-1). Disruption of the integrity of the gill cell monolayers could be noted within 30 min of exposure to the amoeba suspensions by changes in transepithelial resistance (TER) compared with control cell monolayers maintained in the exposure media. This was significantly different by 2 h (P < 0.05) compared with control cells and remained significantly different (P < 0.01) for the remaining 72 h that the TER was monitored. The RTgill-W1 cell line is thus a convenient model for growing N. pemaquidensis and for studying host-pathogen interactions in AGD.

Cell adhesion characteristics of a monocytic cell line derived from rainbow trout, Oncorhynchus mykiss.

In experiments investigating the adhesive properties of the rainbow trout splenic monocyte-like cell line RTS11 it was found that the cells bound with low affinity to plates coated with bovine serum albumin (BSA) but that phorbol ester-induced activation/differentiation greatly increased adhesion to BSA. Similarly, pre-exposure to 500 microM MnCl(2) at time of plating, increased RTS11 adhesion to BSA coated plates, in agreement with the reported ability of divalent cations such as Mn(2+) to activate integrins. Integrins are a diverse family of heterodimeric cell surface glycoproteins that have been shown to mediate cell-cell and cell-extracellular matrix adhesion. Transcripts of the beta(2)-integrin CD18 were detected by PCR in RTS11 but not in RTG-2 cells, a fibroblastic lineage derived from rainbow trout gonads. These results suggest that differentiated RTS11 express molecules related to members of the beta(2)-integrin subfamily such as the macrophage lineage marker Mac-1 (CD11b/CD18) and/or p150,95 (CD11c/CD18) and possibly as well alpha(4)beta(1) of the beta(1)-integrin subfamily.

Is personality a determinant of patient satisfaction with hospital care?

OBJECTIVE: We investigated to what extent personality is associated with patient satisfaction with hospital care. A sizeable association with personality would render patient satisfaction invalid as an indicator of hospital care quality. DESIGN: Overall satisfaction and satisfaction with aspects of care were regressed on the Big Five dimensions of personality, controlled for patient characteristics as possible explanatory variables of observed associations. PARTICIPANTS: A total of 237 recently discharged inpatients aged 18-84 years (M = 50, SD = 17 years), 57% female, who were hospitalized for an average of 8 days. INSTRUMENTS: The Satisfaction with Hospital Care Questionnaire addressing 12 aspects of care ranging from admission procedures to discharge and aftercare and the Five-Factor Personality Inventory assessing a person's standing on Extraversion, Agreeableness, Conscientiousness, Emotional stability, and Autonomy. RESULTS: Agreeableness significantly predicted patient satisfaction in about half of the scales. After controlling for shared variance with age and educational level, the unique contribution of Agreeableness shrank to a maximum of 3-5% explained variance. When one outlier was dropped from the analysis, the contribution of Agreeableness was no longer statistically significant. CONCLUSION: Patient satisfaction seems only marginally associated with personality, at least at the level of the broad Big Five dimensions.

An intervention programme using the ASE-model aimed at enhancing adherence in adolescents with asthma.

A randomised controlled trial, involving 112 adolescents with asthma, and a 2-year follow-up was conducted to assess the impact of an intervention programme aimed at enhancing adherence to asthma medication. This programme had a duration of 1 year and consisted of an experimental group which received usual care from a paediatrician, but additionally attended individual and group sessions with an asthma nurse, and a control group which received usual care only. The programme aimed at enhancing adherence by stimulating a positive attitude, increasing feelings of social support, and enhancing self-efficacy. At baseline, and after 12-month (T1) and 24-month (T2) follow-up, the participants filled in questionnaires which were based on the concepts of the ASE-model. Adherence was assessed by self-report (range: 1-10) at the same points in time. After 12 months, 97 adolescents (87%) were available for follow-up, decreasing to 86 adolescents (77%) after 24 months. No statistically significant differences were found between the control and the experimental group, except for one. At T2, self-reported adherence appeared to be statistically significantly higher in the experimental group. In conclusion, there seems to have been no substantial effect of the intervention programme.

The protein kinase YakA regulates g-protein-linked signaling responses during growth and development of Dictyostelium.

A genetic screen for Dictyostelium mutants that phenotypically resemble cells lacking the G-protein beta-subunit yielded the protein kinase YakA. Like gbeta-null cells, yakA-null cells fail to enter development and display slow growth on bacterial lawns. We created a temperature-sensitive yakA mutant and showed that YakA activity is required not only at the onset but also during development. The yakA-null cells have strong defects in folic acid-induced responses, such as actin polymerization and cGMP accumulation, indicating that they play a role in G-protein-mediated signaling responses. We propose that YakA acts downstream of G-proteins, because cAMP receptors still couple to G-proteins in the yakA mutant. In addition, the previously observed growth arrest induced by overexpression of YakA also occurs in gbeta mutants. We localized YakA-GFP to the cytosol suggesting that YakA may be a functional homolog of its mammalian counterparts Dyrk2 and Dyrk3, a subclass of dual-specificity Yak-related kinases (Dyrk) with unknown function.

Improving the assessment of (in)patients' satisfaction with hospital care.

BACKGROUND: A self-report questionnaire is the most widely used method to assess (in)patients' satisfaction with (hospital) care. However, problems like nonresponse, missing values, and skewed score distributions may threaten the representativeness, validity, and reliability of results. We investigated which of alternative item-response formats maximizes desired outcomes. DESIGN: Five formats were compared on the basis of sample characteristics, psychometric properties at the scale and item levels, and patients' opinions of the questionnaire. SUBJECTS: Consecutively discharged patients (n=784) were sampled, of which a representative (sex, age, length of hospital stay) subsample of 514 (65%) responded. MEASURES: A 54-item satisfaction questionnaire addressing 12 aspects of care was used. Patients responded using either a 10-step evaluation scale ranging from "very poor" to "excellent" (E10), a 5-step evaluation scale ranging from "poor" to "excellent" (E5), or a 5-step satisfaction scale ranging from "dissatisfied" to "very satisfied" (S5). The 5-step scales were administered with response options presented as either boxed scale steps to be marked or words to be circled. RESULTS: E5 scales yielded lower means than S5 scales. However, at the item level, the S5 scale showed better construct validity, more variability, and less peaked score distributions. Circling words yielded fewer missing item scores than marking boxes. The E5 scale showed more desirable score distributions than the E10 scale, but construct validity and reliability were lower. CONCLUSIONS: No large differences among formats were found. However, if individual items are important carriers of information, a (5-step) satisfaction response scale, with response options presented in words next to each item, appears to be the optimal format.

Differential developmental expression and cell type specificity of Dictyostelium catalases and their response to oxidative stress and UV-light.

Cells of Dictyostelium discoideum are highly resistant to DNA damaging agents such as UV-light, gamma-radiation and chemicals. The genes encoding nucleotide excision repair (NER) and base excision repair (BER) enzymes are rapidly upregulated in response to UV-irradiation and DNA-damaging chemicals, suggesting that this is at least partially responsible for the resistance of this organism to these agents. Although Dictyostelium is also unusually resistant to high concentrations of H(2)O(2), little is known about the response of this organism to oxidative stress. To determine if transcriptional upregulation is a common mechanism for responding to DNA-damaging agents, we have studied the Dictyostelium catalase and Cu/Zn superoxide dismutase antioxidant enzymes. We show that there are two catalase genes and that each is differentially regulated both temporally and spatially during multicellular development. The catA gene is expressed throughout growth and development and its corresponding enzyme is maintained at a steady level. In contrast, the catB gene encodes a larger protein and is only expressed during the final stages of morphogenesis. Cell type fractionation showed that the CatB enzyme is exclusively localized to the prespore cells and the CatA enzyme is found exclusively in the prestalk cells. Each enzyme has a different subcellular localization. The unique developmental timing and cell type distribution suggest that the role for catB in cell differentiation is to protect the dormant spores from oxidative damage. We found that exposure to H(2)O(2) does not result in the induction of the catalase, superoxide dismutase, NER or BER mRNAs. A mutant with greatly reduced levels of catA mRNA and enzyme has greatly increased sensitivity to H(2)O(2) but normal sensitivity to UV. These results indicate that the natural resistance to oxidative stress is not due to an ability to rapidly raise the level of antioxidant or DNA repair enzymes and that the response to UV-light is independent from the response to reactive oxygen compounds.

Molecular basis of localized responses during chemotaxis in amoebae and leukocytes.

Free-living amoebae as well as mammalian leukocytes sense chemoattractants with seven helix receptors linked to G-proteins. The cells respond by extending pseudopods and moving in the direction of the highest concentration. Recent studies using GFP-tagged proteins in Dictyostelium have shown that the directional response becomes sharply localized downstream of the receptors and G-proteins but upstream of the actin cytoskeleton. These studies together with the isolation novel genes by insertional mutagenesis in Dictyostelium are leading to a new understanding of chemotaxis in eucaryotic cells.

Adherence-related behavior in adolescents with asthma: results from focus group interviews.

Focus group interviews were conducted with 14 adolescents with asthma to explore self-management behavior, in particular with regard to adherence behavior. In addition, the adolescents discussed their feelings about having asthma, gave insight into how they evaluate the provided health care, and made recommendations for healthcare providers and for the development of patient education materials. The majority of participants did not take their prophylactic asthma medication regularly, and were rather late in starting to use their bronchodilator. They were sometimes fed up with having asthma. Moreover, the majority of participants were not always frank in telling their pediatrician how they managed their asthma. Finally, they found it essential that information about asthma should be given personally and not by means of leaflets, and recommended that healthcare providers should use audio-visual aids to illustrate what they are explaining. The results of the focus group interviews have been used for the development of an intervention program which aims at enhancing adherence in adolescents with asthma.

Two ras genes in Dictyostelium minutum show high sequence homology, but different developmental regulation from Dictyostelium discoideum rasD and rasG genes.

The social amoeba Dictyostelium discoideum expresses five ras genes at different stages of development. One of them, DdrasD is expressed during postaggregative development and transcription is induced by extracellular cAMP. A homologue of DdrasD, the DdrasG gene, is expressed exclusively during vegetative growth. We cloned two ras homologues Dmras1 and Dmras2 from the primitive species D. minutum, which show high homology to DdrasD and DdrasG and less homology to the other Ddras genes. In contrast to the DdrasD and DdrasG genes, both the Dmras1 and Dmras2 genes are expressed during the entire course of development. The expression levels are low during growth, increase at the onset of starvation and do not decrease until fruiting bodies have formed. Expression of neither Dmras1 or Dmras2 is regulated by cAMP. So even though the high degree of homology between the ras genes of different species suggests conservation of function, this function is apparently not associated with a specific developmental stage.

Adenylyl cyclase G, an osmosensor controlling germination of Dictyostelium spores.

Dictyostelium cells express a G-protein-coupled adenylyl cyclase, ACA, during aggregation and an atypical adenylyl cyclase, ACG, in mature spores. The ACG gene was disrupted by homologous recombination. acg- cells developed into normal fruiting bodies with viable spores, but spore germination was no longer inhibited by high osmolarity, a fairly universal constraint for spore and seed germination. ACG activity, measured in aca-/ACG cells, was strongly stimulated by high osmolarity with optimal stimulation occurring at 200 milliosmolar. RdeC mutants, which display unrestrained protein kinase A (PKA) activity and a cell line, which overexpresses PKA under a prespore specific promoter, germinate very poorly, both at high and low osmolarity. These data indicate that ACG is an osmosensor controlling spore germination through activation of protein kinase A.

MRI findings in children with neurofibromatosis type 1: a prospective study.

To determine the frequency and nature of MRI lesions in children with neurofibromatosis type I (NF1), 50 patients aged 8 to 16 years were evaluated prospectively with cranial MRI. Forty-one children were asymptomatic with respect to central nervous system pathology, and 50% were macrocephalic. Sixteen patients (32%) had normal MRI examinations. Thirty-two patients (64%) had high intensity lesions on T2-weighted images and 16 patients (32%) had hyperintense lesions on T1-weighted images. Seven patients (14%) had ventricular dilatation (associated with increased intracranial pressure in 2) and 11 patients (22%) had optic pathway lesions (optic glioma in 7). MRI was superior to CT in differentiating optic sheath thickening and optic nerve tortuosity from optic glioma in four patients. An intracranial tumour (ependymoma) and sphenoid wing dysplasia were evident in individual patients. Findings previously unreported in NF1 included an aqueductal web resulting in hydrocephalus, intraocular neurofibroma resulting in retinal detachment, and asymptomatic enlargement of the septum pellucidum. T1 and T2 signal abnormalities in isolation were not associated with neurological deficits or the occurrence of macrocephaly, and all lesions that required intervention were suspected clinically. Macrocephaly in the absence of increased intracranial pressure or accelerated head growth is not an indication for neuroimaging in children with NF1. However, the majority of children (68%) had disease-specific abnormalities and thus MRI may provide a useful adjunct to clinical evaluation in the diagnosis of equivocal cases.

Regulation of Dictyostelium adenylylcyclases by morphogen-induced modulation of cytosolic pH or Ca2+ levels.

Inhibition of cAMP production and consequent inactivation of protein kinase A (PKA) by the putative morphogen ammonia has been suggested to block culmination and stalk cell differentiation in Dictyostelium. Since other weak bases mimic and weak acids act oppositely to ammonia, its effects were attributed to cytosolic or vesicular alkalinization; the latter resulting in impaired Ca2+ sequestration. We investigated whether weak bases and acids modulate the activity of the two Dictyostelium adenylylcyclases ACA and ACG in a manner consistent with their effects on development. It appeared that ammonia inhibits both ACG activity and ACA activation only transiently and does not significantly affect cAMP levels in slugs. Surprisingly, weak acids inhibit both ACA and ACG permanently, but do not affect secretion of cAMP as was suggested earlier. The effects of weak acids, which reduce cytosolic pH, are consistent with the pH dependence of ACA and ACG. In lysates, basal and GTP gamma S-stimulated ACA activity as well as ACG activity are optimal at pH 8 and are virtually absent below pH 7. ACG activity in cell lysates is completely insensitive to Ca2+, while GTP gamma S-stimulated ACA activity is maximally 50% reduced by supraphysiological Ca2+ concentrations. The observation that weak acids strongly inhibit ACA and ACG while promoting a PKA-dependent process such as stalk cell differentiation suggests that in Dictyostelium PKA can be activated in the absence of cAMP production.