Performance of CT With Adrenal-Washout Protocol in Heterogeneous Adrenal Nodules: A Multiinstitutional Study.

BACKGROUND. CT with adrenal-washout protocol (hereafter, adrenal-protocol CT) is commonly performed to distinguish adrenal adenomas from other adrenal tumors. However, the technique's utility among heterogeneous nodules is not well established, and the optimal method for placing ROIs in heterogeneous nodules is not clearly defined. OBJECTIVE. The purpose of our study was to determine the diagnostic performance of adrenal-protocol CT to distinguish adenomas from nonadenomas among heterogeneous adrenal nodules and to compare this performance among different methods for ROI placement. METHODS. This retrospective study included 164 patients (mean age, 59.1 years; 61 men, 103 women) with a total of 164 heterogeneous adrenal nodules evaluated using adrenal-protocol CT at seven institutions. All nodules had an available pathologic reference standard. A single investigator at each institution evaluated the CT images. ROIs were placed on portal venous phase images using four ROI methods: standard ROI, which refers to a single large ROI in the nodule's center; high ROI, a single ROI on the nodule's highest-attenuation area; low ROI, a single ROI the on nodule's lowest-attenuation area; and average ROI, the mean of the three ROIs on the nodule's superior, middle, and inferior thirds using the approach for the standard ROI. ROIs were then placed in identical locations on unenhanced and delayed phase images. Absolute washout was determined for all methods. RESULTS. The nodules comprised 82 adenomas and 82 nonadenomas (36 pheochromocytomas, 20 metastases, 12 adrenocortical carcinomas, and 14 nodules with other pathologies). The mean nodule size was 4.5 ± 2.8 (SD) cm (range, 1.6-23.0 cm). Unenhanced CT attenuation of 10 HU or less exhibited sensitivity and specificity for adenoma of 22.0% and 96.3% for standard-ROI, 11.0% and 98.8% for high-ROI, 58.5% and 84.1% for low-ROI, and 30.5% and 97.6% for average-ROI methods. Adrenal-protocol CT overall (unenhanced attenuation ≤ 10 HU or absolute washout of ≥ 60%) exhibited sensitivity and specificity for adenoma of 57.3% and 84.1% for the standard-ROI method, 63.4% and 51.2% for the high-ROI method, 68.3% and 62.2% for the low-ROI method, and 59.8% and 85.4% for the average-ROI method. CONCLUSION. Adrenal-protocol CT has poor diagnostic performance for distinguishing adenomas from nonadenomas among heterogeneous adrenal nodules regardless of the method used for ROI placement. CLINICAL IMPACT. Adrenal-protocol CT has limited utility in the evaluation of heterogeneous adrenal nodules.

The Impact of Morbidities Following Pediatric Cardiac Surgery on Family Functioning and Parent Quality of Life.

We previously selected and defined nine important post-operative morbidities linked to paediatric cardiac surgery, and prospectively measured their incidence following 3090 consecutive operations. Our aim was to study the impact of these morbidities on family functioning and parental quality of life over 6 months in a subset of cases. As part of a prospective case matched study in five of the ten children's cardiac centers in the UK, we compared outcomes for parents of children who had a 'single morbidity', 'multiple morbidities', 'extracorporeal life support (ECLS)' or 'no morbidity'. Outcomes were evaluated using the PedsQL Family impact module (FIM) at 6 weeks and 6 months post-surgery. Outcomes were modelled using mixed effects regression, with adjustment for case mix and clustering within centers. We recruited 340 patients with morbidity (60% of eligible patients) and 326 with no morbidity over 21 months. In comparison to the reference group of 'no morbidity', after adjustment for case mix, at 6 weeks parent health-related quality of life (HRQoL) and total FIM sores were lower (worse) only for ECLS (p < 0.005), although a higher proportion of parents in both the ECLS and multi-morbidity groups had low/very low scores (p < .05). At 6 months, parent outcomes had improved for all groups but parent HRQoL and total score for ECLS remained lower than the 'no morbidity' group (p < .05) and a higher proportion of families had low or very low scores in the ECLS (70%) group (p < .01). Post-operative morbidities impact parent HRQoL and aspects of family functioning early after surgery, with this impact lessening by 6 months. Families of children who experience post-operative morbidities should be offered timely psychological support.

Description of a Retrospective Cohort of Epithelial Ovarian Cancer Patients with Brain Metastases: Evaluation of the Role of PARP Inhibitors in this Setting.

BACKGROUND: The incidence of brain metastases (BM) in patients with epithelial ovarian cancer (EOC) is low: 0.3-11%. The onset of BM has been regarded as a late event with limited treatment options and poor prognosis. This retrospective case series aims to explore the current management strategies with particular emphasis on the use of PARP inhibitors and outcomes, as well as identification of other prognostic indicators. METHODS: A total of 39 ovarian cancer patients with brain metastases were identified from eight cancer centres in the UK. Clinical characteristics, details of management, and survival data were collected. RESULTS: A total of 14/39 had BM as their first site of relapse. The majority (29 patients) received systemic treatments in addition to local radiotherapy (RT)/surgery. Nineteen patients had BRCA mutations (one somatic), one had a RAD51C mutation, and eighteen were BRCA wild type; one was unknown. A total of 14/39 patients received maintenance PARP inhibitors. As is well known, patients who received PARPi had consistently better outcomes. This was no different for those who received PARPi as part of the management of their BM. Platinum sensitivity and receiving more than one modality of therapy (e.g., radiation +/- chemotherapy and PARPi) for BM were also good prognostic indicators. Median PFS/OS for those treated with chemotherapy and either RT or surgery, then PARP inhibitor maintenance, have not been reached after a median of 33 months follow up. CONCLUSIONS: As with abdominal relapse, maintenance treatment with PARP inhibitors also has a valuable role in managing BMs in EOC patients.

Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: a multi-national observational study.

OBJECTIVE: Olaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022. METHODS: The Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with a BRCA1/2 mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network. RESULTS: The myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwent BRCA1/2 and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained a BRCA1/2 mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to be BRCA1/2 wild-type (n=510) than BRCA1/2 mutant (n=304). The distribution of GIS was bimodal, with BRCA1/2 mutant tumors having a higher mean score than BRCA1/2 wild-type tumors (61 vs 33, respectively, χ2 test p<0.0001). CONCLUSION: This is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specialization, and the NHS Genomic Laboratory Hub network.

Utility of a buccal swab point-of-care test for the IFNL4 genotype in the era of direct acting antivirals for hepatitis C virus.

BACKGROUND: The CC genotype of the IFNL4 gene is known to be associated with increased Hepatitis C (HCV) cure rates with interferon-based therapy and may contribute to cure with direct acting antivirals. The Genedrive® IFNL4 is a CE marked Point of Care (PoC) molecular diagnostic test, designed for in vitro diagnostic use to provide rapid, real-time detection of IFNL4 genotype status for SNP rs12979860. METHODS: 120 Participants were consented to a substudy comparing IFNL4 genotyping results from a buccal swab analysed on the Genedrive® platform with results generated using the Affymetix UK Biobank array considered to be the gold standard. RESULTS: Buccal swabs were taken from 120 participants for PoC IFNL4 testing and a whole blood sample for genetic sequencing. Whole blood genotyping vs. buccal swab PoC testing identified 40 (33%), 65 (54%), and 15 (13%) had CC, CT and TT IFNL4 genotype respectively. The Buccal swab PoC identified 38 (32%) CC, 64 (53%) CT and 18 (15%) TT IFNL4 genotype respectively. The sensitivity and specificity of the buccal swab test to detect CC vs non-CC was 90% (95% CI 76-97%) and 98% (95% CI 91-100%) respectively. CONCLUSIONS: The buccal swab test was better at correctly identifying non-CC genotypes than CC genotypes. The high specificity of the Genedrive® assay prevents CT/TT genotypes being mistaken for CC, and could avoid patients being identified as potentially 'good responders' to interferon-based therapy.

Assessing the Impact of Developments in Genetic Testing on Insurers' Risk Exposure.

Predictive genetic testing provides individuals with information about their future risk of developing health conditions. Theoretically, predictive genetic tests could have positive or negative impacts on the insurance industry. If genetic test results stimulate actions to reduce health risks, they may reduce costs to insurers. If disclosed to insurers, such information may allow them to better understand individual- and population-level risks and make insurance more affordable. However, if individuals who know they are at high genetic risk of becoming ill or dying are more likely to apply for insurance than those not at high risk, this may lead to an unanticipated increase in claims. It may be exacerbated if people at low genetic risk are less likely to apply for insurance compared to the general population. If this happened on a large scale it could make the insurance market unsustainable. Determining whether a genetic test could affect the insurance industry is complex and needs to be evaluated on a per-test basis. The Cambridge Centre for Health Services Research, a collaboration between RAND Europe and the University of Cambridge, developed a framework for evaluating the potential impacts on the UK insurance industry arising from predictive genetic tests. It considers the characteristics of genetic tests and behavioural aspects that influence their uptake. It is intended to provide a transparent approach for evaluating whether a specific condition for which a test is available could impact the insurance industry, currently or in the future, and understanding the key factors that influence this.

Developing a taxonomy of care coordination for people living with rare conditions: a qualitative study.

BACKGROUND: Improving care coordination is particularly important for individuals with rare conditions (who may experience multiple inputs into their care, across different providers and settings). To develop and evaluate strategies to potentially improve care coordination, it is necessary to develop a method for organising different ways of coordinating care for rare conditions. Developing a taxonomy would help to describe different ways of coordinating care and in turn facilitate development and evaluation of pre-existing and new models of care coordination for rare conditions. To the authors' knowledge, no studies have previously developed taxonomies of care coordination for rare conditions. This research aimed to develop and refine a care coordination taxonomy for people with rare conditions. METHODS: This study had a qualitative design and was conducted in the United Kingdom. To develop a taxonomy, six stages of taxonomy development were followed. We conducted interviews (n = 30 health care professionals/charity representatives/commissioners) and focus groups (n = 4 focus groups, 22 patients/carers with rare/ultra-rare/undiagnosed conditions). Interviews and focus groups were audio-recorded with consent, and professionally transcribed. Findings were analysed using thematic analysis. Themes were used to develop a taxonomy, and to identify which types of coordination may work best in which situations. To refine the taxonomy, we conducted two workshops (n = 12 patients and carers group; n = 15 professional stakeholder group). RESULTS: Our taxonomy has six domains, each with different options. The six domains are: (1) Ways of organising care (local, hybrid, national), (2) Ways of organising those involved in care (collaboration between many or all individuals, collaboration between some individuals, a lack of collaborative approach), (3) Responsibility for coordination (administrative support, formal roles and responsibilities, supportive roles and no responsibility), (4) How often appointments and coordination take place (regular, on demand, hybrid), (5) Access to records (full or filtered access), and (6) Mode of care coordination (face-to-face, digital, telephone). CONCLUSIONS: Findings indicate that there are different ways of coordinating care across the six domains outlined in our taxonomy. This may help to facilitate the development and evaluation of existing and new models of care coordination for people living with rare conditions.

Isolated Penile Calciphylaxis Diagnosed by Ultrasound Imaging in a New Dialysis Patient: A Case Report.

RATIONALE: The recognition of calciphylaxis often eludes practitioners because of its multiple ambiguous presentations. It classically targets areas of the body dense with adipose tissue. A heightened suspicion for the disorder is therefore required in the case of penile calciphylaxis, given its unconventional location. The diagnosis of calciphylaxis is also challenging as the gold standard for diagnosis is biopsy which can often yield equivocal results. Unfortunately, in penile calciphylaxis, the utility of biopsies is further debated due to their potential to precipitate new lesions and their decreased sensitivity due to the limited depth of tissue that can be sampled. For these reasons, it is important that practitioners recognize other accessible and accurate investigative tools which can aid in their diagnosis. PRESENTING CONCERNS OF THE PATIENT: We present the case of a 49-year-old man who presented to the emergency room with penile pain in the context of known chronic kidney disease secondary to diabetic nephropathy. The pain had been present for about a week, was exquisitely tender, and was initially associated with a faint violaceous lesion. This gentleman had just recently initiated peritoneal dialysis and had no other lesions on his body. DIAGNOSIS: His pain was determined by ultrasound and plain radiograph to be secondary to calciphylaxis after two biopsies were nondiagnostic. INTERVENTIONS: The patient had already made changes to his diet to reduce phosphate and calcium intake, and had been on phosphate-lowering therapy with both calcium and phosphate being within their respective target range. Following his diagnosis, this patient was promptly converted from peritoneal dialysis to hemodialysis with sodium thiosulphate and initiated hyperbaric oxygen therapy. This patient continues to be followed by nephrology and urology specialists.

OUTCOMES: At the time of publication there has been no amputation of the appendage although there has been presumably permanent loss of function. TEACHING POINTS: This case should reinforce the high index of suspicion needed to make a timely diagnosis of calciphylaxis, and the broad variety of ways in which the disorder may present. The findings advocate for the utility of alternative diagnostic modalities, including imaging with plain radiograph and ultrasound, for calciphylaxis diagnosis. JUSTIFICATION: Les multiples présentations cliniques de la calciphylaxie, une affection qui cible habituellement des régions du corps denses en tissu adipeux, font en sorte que sa détection échappe fréquemment aux praticiens. La calciphylaxie pénienne, en raison de son emplacement inhabituel, devrait faire l'objet d'une suspicion clinique accrue. La calciphylaxie est en outre difficile à diagnostiquer puisque la biopsie, l'étalon-or pour sa détection, mène souvent à des résultats équivoques. Dans le cas de la calciphylaxie pénienne, la pertinence de la biopsie fait d'autant plus débat puisqu'elle est susceptible de précipiter de nouvelles lésions et qu'elle présente une sensibilité réduite compte tenu de la profondeur limitée des tissus pouvant être obtenus. Il est donc important que les praticiens connaissent d'autres outils d'investigation accessibles et plus précis pouvant les aider dans leur diagnostic. PRÉSENTATION DU CAS: Nous présentons le cas d'un homme de 49 ans s'étant présenté aux urgences avec une douleur au pénis. Le patient était connu pour une insuffisance rénale chronique découlant d'une néphropathie diabétique. La douleur, initialement associée à une lésion légèrement violacée, était présente depuis environ une semaine et le membre était extrêmement sensible. Le patient venait tout juste d'amorcer des traitements de dialyze péritonéale et ne présentait aucune autre lésion sur le corps. DIAGNOSTIC: Après deux biopsies non diagnostiques, une échographie et une radiographie standard ont permis d'associer la douleur à la calciphylaxie. INTERVENTIONS: Le patient avait déjà apporté des changements à son alimentation afin de réduire son apport en phosphore et en calcium, et recevait déjà un traitement de chélateur de phosphate. Les taux de calcium et de phosphore se situaient dans leur plage cible respective. À la suite du diagnostic, le patient est rapidement passé de la dialyze péritonéale à l'hémodialyse, a été traité avec du thiosulfate de sodium et a entrepris une oxygénothérapie hyperbare. Le patient continue d'être suivi par des spécialistes en néphrologie et en urologie. RÉSULTATS: Au moment de la publication, le patient n'avait toujours pas subi d'amputation, malgré une vraisemblable perte de fonction permanente. ENSEIGNEMENTS TIRÉS: Ce cas devrait renforcer l'indice élevé de suspicion qui est nécessaire pour poser rapidement un diagnostic de calciphylaxie, en plus de montrer les très nombreuses présentations cliniques de ce trouble. Ces résultats plaident en faveur de modalités alternatives pour le diagnostic de la calciphylaxie, notamment le recours à l'échographie et à la radiographie standard.

Retrospective analysis of real-world treatment patterns and clinical outcomes in patients with advanced non-small cell lung cancer starting first-line systemic therapy in the United Kingdom.

BACKGROUND: The treatment landscape for advanced non-small cell lung cancer (aNSCLC) has evolved rapidly since immuno-oncology (IO) therapies were introduced. This study used recent data to assess real-world treatment patterns and clinical outcomes in aNSCLC in the United Kingdom. METHODS: Electronic prescribing records of treatment-naive patients starting first-line (1 L) treatment for aNSCLC between June 2016 and March 2018 (follow-up until December 2018) in the United Kingdom were assessed retrospectively. Patient characteristics and treatment patterns were analyzed descriptively. Outcomes assessed included overall survival (OS), time to treatment discontinuation, time to next treatment, and real-world tumor response. RESULTS: In all, 1003 patients were evaluated (median age, 68 years [range, 28-93 years]; 53.9% male). Use of 1 L IO monotherapy (0-25.9%) and targeted therapy (11.8-15.9%) increased during the study period, but chemotherapy remained the most common 1 L treatment at all time points (88.2-58.2%). Median OS was 9.5 months (95% CI, 8.8-10.7 months) for all patients, 8.1 months (95% CI, 7.4-8.9 months) with chemotherapy, 14.0 months (95% CI, 10.7-20.6 months) with IO monotherapy, and 20.2 months (95% CI, 16.0-30.5 months) with targeted therapy. In the 28.6% of patients who received second-line treatment, IO monotherapy was the most common drug class (used in 51.6%). CONCLUSIONS: Although use of 1 L IO monotherapy for aNSCLC increased in the United Kingdom during the study period, most patients received 1 L chemotherapy. An OS benefit for first-line IO monotherapy vs chemotherapy was observed but was numerically smaller than that reported in clinical trials. Targeted therapy was associated with the longest OS, highlighting the need for improved treatment options for tumors lacking targetable mutations.

Real world SOF/VEL/VOX retreatment outcomes and viral resistance analysis for HCV patients with prior failure to DAA therapy.

Sustained viral response (SVR) rates for direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection routinely exceed 95%. However, a small number of patients require retreatment. Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is a potent DAA combination primarily used for the retreatment of patients who failed by DAA therapies. Here we evaluate retreatment outcomes and the effects of resistance-associated substitutions (RAS) in a real-world cohort, including a large number of genotype (GT)3 infected patients. 144 patients from the UK were retreated with SOF/VEL/VOX following virologic failure with first-line DAA treatment regimens. Full-length HCV genome sequencing was performed prior to retreatment with SOF/VEL/VOX. HCV subtypes were assigned and RAS relevant to each genotype were identified. GT1a and GT3a each made up 38% (GT1a n = 55, GT3a n = 54) of the cohort. 40% (n = 58) of patients had liver cirrhosis of whom 7% (n = 4) were decompensated, 10% (n = 14) had hepatocellular carcinoma (HCC) and 8% (n = 12) had received a liver transplant prior to retreatment. The overall retreatment SVR12 rate was 90% (129/144). On univariate analysis, GT3 infection (50/62; SVR = 81%, p = .009), cirrhosis (47/58; SVR = 81%, p = .01) and prior treatment with SOF/VEL (12/17; SVR = 71%, p = .02) or SOF+DCV (14/19; SVR = 74%, p = .012) were significantly associated with retreatment failure, but existence of pre-retreatment RAS was not when viral genotype was taken into account. Retreatment with SOF/VEL/VOX is very successful for non-GT3-infected patients. However, for GT3-infected patients, particularly those with cirrhosis and failed by initial SOF/VEL treatment, SVR rates were significantly lower and alternative retreatment regimens should be considered.

How are patients with rare diseases and their carers in the UK impacted by the way care is coordinated? An exploratory qualitative interview study.

BACKGROUND: Care coordination is considered important for patients with rare conditions, yet research addressing the impact of care coordination is limited. This study aimed to explore how care coordination (or lack of) impacts on patients and carers. Semi-structured interviews were conducted with 15 patients and carers/parents in the UK, representing a range of rare conditions (including undiagnosed conditions). Transcripts were analysed thematically in an iterative process. RESULTS: Participants described a range of experiences and views in relation to care coordination. Reports of uncoordinated care emerged: appointments were uncoordinated, communication between key stakeholders was ineffective, patients and carers were required to coordinate their own care, and care was not coordinated to meet the changing needs of patients in different scenarios. As a result, participants experienced an additional burden and barriers/delays to accessing care. The impacts described by patients and carers, either attributed to or exacerbated by uncoordinated care, included: impact on physical health (including fatigue), financial impact (including loss of earnings and travel costs), and psychosocial impact (including disruption to school, work and emotional burden). Overall data highlight the importance of flexible care, which meets individual needs throughout patients'/carers' journeys. Specifically, study participants suggested that the impacts may be addressed by: having support from a professional to coordinate care, changing the approach of clinics and appointments (where they take place, which professionals/services are available and how they are scheduled), and improving communication through the use of technology, care plans, accessible points of contact and multi-disciplinary team working. CONCLUSION: This study provides further evidence of impacts of uncoordinated care; these may be complex and influenced by a number of factors. Approaches to coordination which improve access to care and lessen the time and burden placed on patients and carers may be particularly beneficial. Findings should influence future service developments (and the evaluation of such developments). This will be achieved, in the first instance, by informing the CONCORD Study in the UK.

Health-related quality of life of alcohol use disorder with co-occurring conditions in the US population.

BACKGROUND: Alcohol use disorder (AUD) commonly co-occurs with other health conditions or other substance use, complicating our understanding of the health-related quality of life (HRQoL) of AUD. We described the HRQoL of alcohol use disorder in the presence of co-occurring conditions and identified the contribution of each. METHODS: Secondary analysis of National Epidemiologic Survey on Alcohol and Related Conditions III data, consisting of 36,309 non-institutionalized US adults; descriptive and regression analysis. HRQoL measured via the SF-6D; AUD via the Alcohol Use Disorder and Associated Disabilities Interview Schedule (AUDADIS-5); physical, mental health, and substance use disorders/conditions as reported or assessed via AUDADIS-5. RESULTS: AUD was independently associated with lower HRQoL for individuals experiencing co-occurring conditions. Compared to no AUD, past year AUD reduced SF-6D score by 0.0304 (SE = 0.0027) and prior-to-past-year AUD reduced SF-6D by 0.0163 (SE = 0.0023). AUD's co-occurring conditions were independently associated with lower HRQoL, beyond the reduction from AUD: any co-occurring physical health condition was associated with a 0.062 point reduction in SF-6D score (SE = 0.0023), any mental health condition with a 0.084 point reduction (SE = 0.0025), and any substance use disorder with a 0.038 point reduction (SE = 0.0023). CONCLUSIONS: AUD's association with diminished HRQoL may be explained in large part by the presence of co-occurring conditions among individuals reporting AUD, as these co-occurring conditions are associated with substantial decrements in HRQoL-often eclipsing the magnitude of the decrements associated with AUD alone. Alcohol use interventions endeavoring to improve HRQoL should consider the entirety of an individual to design patient-centered care.

Morbidities After Cardiac Surgery: Impact on Children's Quality of Life and Parents' Mental Health.

BACKGROUND: Most children now survive cardiac surgery, and the focus of quality improvement initiatives has shifted toward more complex outcome measures. The aim of this investigation was to study the impact of early postoperative morbidities on parent-reported patient quality of life and parental anxiety or depression over 6 months. METHODS: This prospective case-matched cohort study was conducted in 5 UK children's cardiac centers. Measures of impact for patient categories of "single morbidity," "multiple morbidities," and "extracorporeal life support (ECLS)" were compared with "no morbidity." The measures used were the Pediatric Quality of Life Inventory (PedsQL) and the 4-item Patient Health Questionnaire (PHQ-4) at 6 weeks and 6 months postoperatively. The study modeled the outcomes using mixed effects regression, adjusting for case mix and clustering within centers. RESULTS: The study included 666 patients who underwent operation at a median age of 81 days (interquartile range, 10 to 325 days). At 6-week follow-up, significant adjusted differences to the reference group with no morbidity were found for total PedsQL scores, which were lower in patients with ECLS (P = .01), multiple morbidities (P < .001), and a single morbidity (P = .04), as well as the proportion of parents with anxiety and depression, which were higher in the group with multiple morbidities (P = .04 and P = .01, respectively). At 6 months, measures had improved in all morbidity groups. The only significant adjusted difference in the reference group was for physical PedsQL scores in ECLS (P = .04) and multiple morbidities (P < .01). CONCLUSIONS: Patient and parent well-being are strongly influenced by postoperative morbidities early after surgery, with improvement by 6 months. Family psychological support and holistic rehabilitation are vital for children who experience postoperative morbidities.

Super giant basal cell carcinoma in an autistic patient: A case report.

Basal cell carcinoma is the most common skin cancer in the world and is generally treated when small in size with an excellent prognosis. Rarely, basal cell carcinoma will grow to be larger than 5 cm, at which point they are termed giant basal cell carcinoma. Giant basal cell carcinoma comprises only 0.5% of all basal cell carcinoma, but is associated with impaired quality of life and increased risk of metastasis. When a basal cell carcinoma grows to over 20 cm in size, it is termed super giant basal cell carcinoma. Here, we report a case of both a super-giant basal cell carcinoma and a giant basal cell carcinoma developing over 10-12 years on the upper back and anterior chest wall of an autistic male. Generally, this presentation is associated with neglect on the part of the patient. This case report demonstrates a super-giant basal cell carcinoma developing secondary to patient neglect in the context of comorbid mental illness.

Defining Coordinated Care for People with Rare Conditions: A Scoping Review.

INTRODUCTION: To coordinate care effectively for rare conditions, we need to understand what coordinated care means. This review aimed to define coordinated care and identify components of coordinated care within the context of rare diseases; by drawing on evidence from chronic conditions. METHODS: A systematic scoping review. We included reviews that reported or defined and outlined components of coordinated care for chronic or rare conditions. Thematic analysis was used to develop a definition and identify components or care coordination. Stakeholder consultations (three focus groups with patients, carers and healthcare professionals with experience of rare conditions) were held to further explore the relevance of review findings for rare conditions. RESULTS: We included 154 reviews (n = 139 specific to common chronic conditions, n = 3 specific to rare conditions, n = 12 both common/rare conditions). A definition of coordination was developed. Components were identified and categorised by those that: may need to be coordinated, inform how to coordinate care, have multiple roles, or that contextualise coordination. CONCLUSIONS: Coordinated care is multi-faceted and has both generic and context-specific components. Findings outline many ways in which care may be coordinated for both rare and common chronic conditions. Findings can help to develop and eventually test different ways of coordinating care for people with rare and common chronic conditions.

Does time taken by paediatric critical care transport teams to reach the bedside of critically ill children affect survival? A retrospective cohort study from England and Wales.

BACKGROUND: Reaching the bedside of a critically ill child within three hours of agreeing the child requires intensive care is a key target for Paediatric Critical Care Transport teams (PCCTs) to achieve in the United Kingdom. Whilst timely access to specialist care is necessary for these children, it is unknown to what extent time taken for the PCCT to arrive at the bedside affects clinical outcome. METHODS: Data from transports of critically ill children who were admitted to Paediatric Intensive Care Units (PICUs) in England and Wales from 1 January 2014 to 31 December 2016 were extracted from the Paediatric Intensive Care Audit Network (PICANet) and linked with adult critical care data and Office for National Statistics mortality data. Logistic regression models, adjusted for pre-specified confounders, were fitted to investigate the impact of time-to-bedside on mortality within 30 days of admission and other key time points. Negative binomial models were used to investigate the impact of time-to-bedside on PICU length of stay and duration of invasive ventilation. RESULTS: There were 9116 children transported during the study period, and 645 (7.1%) died within 30 days of PICU admission. There was no evidence that 30-day mortality changed as time-to-bedside increased. A similar relationship was seen for mortality at other pre-selected time points. In children who waited longer for a team to arrive, there was limited evidence of a small increase in PICU length of stay (expected number of days increased from: 7.17 to 7.58). CONCLUSION: There is no evidence that reducing the time-to-bedside target for PCCTs will improve the survival of critically ill children. A shorter time to bedside may be associated with a small reduction in PICU length of stay.

Costs of postoperative morbidity following paediatric cardiac surgery: observational study.

OBJECTIVE: Early mortality rates for paediatric cardiac surgery have fallen due to advancements in care. Alternative indicators of care quality are needed. Postoperative morbidities are of particular interest. However, while health impacts have been reported, associated costs are unknown. Our objective was to calculate the costs of postoperative morbidities following paediatric cardiac surgery. DESIGN: Two methods of data collection were integrated into the main study: (1) case-matched cohort study of children with and without predetermined morbidities; (2) incidence rates of morbidity, measured prospectively. SETTING: Five specialist paediatric cardiac surgery centres, accounting for half of UK patients. PATIENTS: Cohort study included 666 children (340 with morbidities). Incidence rates were measured in 3090 consecutive procedures. METHODS: Risk-adjusted regression modelling to determine marginal effects of morbidities on per-patient costs. Calculation of costs for hospital providers according to incidence rates. Extrapolation using mandatory audit data to report annual financial burden for the health service. OUTCOME MEASURES: Impact of postoperative morbidities on per-patient costs, hospital costs and UK health service costs. RESULTS: Seven of the 10 morbidity categories resulted in significant costs, with mean (95% CI) additional costs ranging from £7483 (£3-£17 289) to £66 784 (£40 609-£103 539) per patient. On average all morbidities combined increased hospital costs by 22.3%. Total burden to the UK health service exceeded £21 million each year. CONCLUSION: Postoperative morbidities are associated with a significant financial burden. Our findings could aid clinical teams and hospital providers to account for costs and contextualise quality improvement initiatives.

Real world outcomes in platinum sensitive relapsed ovarian, fallopian tube, or peritoneal cancer treated in routine clinical practice in the United Kingdom prior to poly-ADP ribose polymerase inhibitors.

INTRODUCTION: The introduction of poly-ADP ribose polymerase inhibitors in ovarian cancer has demonstrated significantly improved progression free survival in four randomized controlled clinical trials in patients with platinum sensitive relapsed ovarian cancer. While overall survival data remain immature, this real world evidence study sets a baseline for future evaluation of poly-ADP ribose polymerase inhibitors. METHODS: A retrospective chart review was undertaken to investigate real world survival outcomes across 13 National Health Service Trusts in England, Wales, and Scotland. Patients were included if they had platinum sensitive relapsed high grade serous ovarian cancer and had responded to secondline platinum based chemotherapy. Clinical data were collected retrospectively from electronic prescribing records and chart notes. The index date for overall survival analysis was defined as the later of (1) day 1 of the final secondline platinum based treatment or (2) date of response to secondline treatment. The primary objective was overall survival from the index date. Secondary objectives included progression free survival and overall survival by subsequent line of treatment. BRCA mutation status was collected where available. Quality of life questionnaires were not assessed within this study. RESULTS: 233 patients were identified who met the study inclusion criteria. Patient characteristics were consistent with other published data, with a median age of 61 years (range 35-85). Sensitivity analysis of the primary objective demonstrated that the earliest point poly-ADP ribose polymerase inhibitors may be initiated (following completion of secondline chemotherapy) is associated with a median overall survival of 19.8 months. Secondline median overall survival and progression free survival from the index date were 19.3±2.4 months and 7.3±1.2 months, respectively. 144 patients were treated with thirdline chemotherapy with median overall survival and progression free survival from the index date (either date of last cycle of thirdline treatment or date of response to thirdline treatment) of 8.3±2.6 and 4.4±1.8 months, respectively. CONCLUSION: Overall survival was shown to be shorter in this real world study compared with randomized clinical trials, and underlines the differences in clinical outcomes of patients in a real life setting. This baseline real world study has demonstrated poor survival outcomes in this patient group prior to availability of poly-ADP ribose polymerase inhibitors.

Interferon lambda 4 impacts the genetic diversity of hepatitis C virus.

Hepatitis C virus (HCV) is a highly variable pathogen that frequently establishes chronic infection. This genetic variability is affected by the adaptive immune response but the contribution of other host factors is unclear. Here, we examined the role played by interferon lambda-4 (IFN-λ4) on HCV diversity; IFN-λ4 plays a crucial role in spontaneous clearance or establishment of chronicity following acute infection. We performed viral genome-wide association studies using human and viral data from 485 patients of white ancestry infected with HCV genotype 3a. We demonstrate that combinations of host genetic variants, which determine IFN-λ4 protein production and activity, influence amino acid variation across the viral polyprotein - not restricted to specific viral proteins or HLA restricted epitopes - and modulate viral load. We also observed an association with viral di-nucleotide proportions. These results support a direct role for IFN-λ4 in exerting selective pressure across the viral genome, possibly by a novel mechanism.

What are the important morbidities associated with paediatric cardiac surgery? A mixed methods study.

OBJECTIVES: Given the current excellent early mortality rates for paediatric cardiac surgery, stakeholders believe that this important safety outcome should be supplemented by a wider range of measures. Our objectives were to prospectively measure the incidence of morbidities following paediatric cardiac surgery and to evaluate their clinical and health-economic impact over 6 months. DESIGN: The design was a prospective, multicentre, multidisciplinary mixed methods study. SETTING: The setting was 5 of the 10 paediatric cardiac surgery centres in the UK with 21 months recruitment. PARTICIPANTS: Included were 3090 paediatric cardiac surgeries, of which 666 patients were recruited to an impact substudy. RESULTS: Families and clinicians prioritised:Acute neurological event, unplanned re-intervention, feeding problems, renal replacement therapy, major adverse events, extracorporeal life support, necrotising enterocolitis, postsurgical infection and prolonged pleural effusion or chylothorax.Among 3090 consecutive surgeries, there were 675 (21.8%) with at least one of these morbidities. Independent risk factors for morbidity included neonatal age, complex heart disease and prolonged cardiopulmonary bypass (p<0.001). Among patients with morbidity, 6-month survival was 88.2% (95% CI 85.4 to 90.6) compared with 99.3% (95% CI 98.9 to 99.6) with none of the morbidities (p<0.001). The impact substudy in 340 children with morbidity and 326 control children with no morbidity indicated that morbidity-related impairment in quality of life improved between 6 weeks and 6 months. When compared with children with no morbidities, those with morbidity experienced a median of 13 (95% CI 10.2 to 15.8, p<0.001) fewer days at home by 6 months, and an adjusted incremental cost of £21 292 (95% CI £17 694 to £32 423, p<0.001). CONCLUSIONS: Evaluation of postoperative morbidity is more complicated than measuring early mortality. However, tracking morbidity after paediatric cardiac surgery over 6 months offers stakeholders important data that are of value to parents and will be useful in driving future quality improvement.