PARP Inhibitors in the Treatment of Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy in the western world, has been historically treated with surgery followed by chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most active new targeted therapies for the treatment of EOC. PARPis’ mechanism of action relies on their ability to interfere with DNA repair events leading ultimately to cell death, the biological concept known as synthetic lethality. Initially developed as maintenance therapy in patients with a response after platinum-based chemotherapy in a recurrent setting, PARPis are now approved as the frontline treatment strategy. The aim of this chapter is to examine PARPis’ antineoplastic activity and the clinical development studies that lead to their approval, as well as the safety and the management of adverse events associated with this new class of drugs. Lastly, the rational considerations for the use of PARPis in the frontline setting are discussed

Telehealth-Based Music Therapy Versus Cognitive Behavioral Therapy for Anxiety in Cancer Survivors: Rationale and Protocol for a Comparative Effectiveness Trial

Background: Cancer survivors represent one of the fastest growing populations in the United States. Unfortunately, nearly 1 in 3 survivors experience anxiety symptoms as a long-term consequence of cancer and its treatment. Characterized by restlessness, muscle tension, and worry, anxiety worsens the quality of life; impairs daily functioning; and is associated with poor sleep, depressed mood, and fatigue. Although pharmacological treatment options are available, polypharmacy has become a growing concern for cancer survivors. Music therapy (MT) and cognitive behavioral therapy (CBT) are evidence-based, nonpharmacological treatments that have demonstrated effectiveness in treating anxiety symptoms in cancer populations and can be adapted for remote delivery to increase access to mental health treatments. However, the comparative effectiveness of these 2 interventions delivered via telehealth is unknown. Objective: The aims of the Music Therapy Versus Cognitive Behavioral Therapy for Cancer-related Anxiety (MELODY) study are to determine the comparative effectiveness of telehealth-based MT versus telehealth-based CBT for anxiety and comorbid symptoms in cancer survivors and to identify patient-level factors associated with greater anxiety symptom reduction for MT and CBT. Methods: The MELODY study is a 2-arm, parallel-group randomized clinical trial that aims to compare the effectiveness of MT versus CBT for anxiety and comorbid symptoms. The trial will enroll 300 English- or Spanish-speaking survivors of any cancer type or stage who have experienced anxiety symptoms for at least 1 month. Participants will receive 7 weekly sessions of MT or CBT delivered remotely via Zoom (Zoom Video Communications, Inc) over 7 weeks. Validated instruments to assess anxiety (primary outcome), comorbid symptoms (fatigue, depression, insomnia, pain, and cognitive dysfunction), and health-related quality of life will be administered at baseline and at weeks 4, 8 (end of treatment), 16, and 26. Semistructured interviews will be conducted at week 8 with a subsample of 60 participants (30 per treatment arm) to understand individual experiences with the treatment sessions and their impact. Results: The first study participant was enrolled in February 2022. As of January 2023, 151 participants have been enrolled. The trial is expected to be completed by September 2024. Conclusions: This study is the first and largest randomized clinical trial to compare the short- and long-term effectiveness of remotely delivered MT and CBT for anxiety in cancer survivors. Limitations include the lack of usual care or placebo control groups and the lack of formal diagnostic assessments for psychiatric disorders among trial participants. The study findings will help guide treatment decisions for 2 evidence-based, scalable, and accessible interventions to promote mental well-being during cancer survivorship. International registered report identifier (irrid): DERR1-10.2196/46281

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Framing the difficulties resulting from implementing a Participatory Management Model in a public hospital

Objective: This study aims to address difficulties reported by the nursing team during the process of changing the management model in a public hospital in Brazil. Methods: This qualitative study used thematic content analysis as proposed by Bardin, and data were analyzed using the theoretical framework of Bolman and Deal. Results: The vertical implementation of Participatory Management contradicted its underlying philosophy and thereby negatively influenced employee acceptance of the change. The decentralized structure of the Participatory Management Model was implemented but shared decision-making was only partially utilized. Despite facilitation of the communication process within the unit, more significant difficulties arose from lack of communication inter-unit. Values and principals need to be shared by teams, however, that will happens only if managers restructure accountabilities changing job descriptions of all team members. Conclusion: Innovative management models that depart from the premise of decentralized decision-making and increased communication encourage accountability, increased motivation and satisfaction, and contribute to improving the quality of care. The contribution of the study is that it describes the complexity of implementing an innovative management model, examines dissent and intentionally acknowledges the difficulties faced by employees in the organization.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2008/03775-5

What works for whom in the management of diabetes in people living with dementia: a realist review

Background Dementia and diabetes mellitus are common long-term conditions and co-exist in a large number of older people. People living with dementia (PLWD) may be less able to manage their diabetes, putting them at increased risk of complications such as hypoglycaemia. The aim of this review was to identify key mechanisms within different interventions that are likely to improve diabetes outcomes in PLWD. Methods This is a realist review involving scoping of the literature and stakeholder interviews to develop theoretical explanations of how interventions might work, systematic searches of the evidence to test and develop the theories and their validation with a purposive sample of stakeholders. Twenty-six stakeholders — user/patient representatives, dementia care providers, clinicians specialising in diabetes or dementia and researchers — took part in interviews, and 24 participated in a consensus conference. Results We included 89 papers. Ten focused on PLWD and diabetes, and the remainder related to people with either dementia, diabetes or other long-term conditions. We identified six context-mechanism-outcome configurations which provide an explanatory account of how interventions might work to improve the management of diabetes in PLWD. This includes embedding positive attitudes towards PLWD, person-centred approaches to care planning, developing skills to provide tailored and flexible care, regular contact, family engagement and usability of assistive devices. An overarching contingency emerged concerning the synergy between an intervention strategy, the dementia trajectory and social and environmental factors, especially family involvement. Conclusions Evidence highlighted the need for personalised care, continuity and family-centred approaches, although there was limited evidence that this happens routinely. This review suggests there is a need for a flexible service model that prioritises quality of life, independence and patient and carer priorities. Future research on the management of diabetes in older people with complex health needs, including those with dementia, needs to look at how organisational structures and workforce development can be better aligned to their needs. Trial registration PROSPERO, CRD42015020625. Registered on 18 May 2015

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Supporting shared decision making for older people with multiple health and social care needs: a realist synthesis

Background: Health care systems are increasingly moving towards more integrated approaches. Shared decision making (SDM) is central to these models but may be complicated by the need to negotiate and communicate decisions between multiple providers, as well as patients and their family carers; particularly for older people with complex needs. The aim of this review was to provide a context relevant understanding of how interventions to facilitate SDM might work for older people with multiple health and care needs, and how they might be applied in integrated care models. Methods: Iterative, stakeholder driven, realist synthesis following RAMESES publication standards. It involved: 1) scoping literature and stakeholder interviews (n-13) to develop initial programme theory/ies, 2) systematic searches for evidence to test and develop the theories, and 3) validation of programme theory/ies with stakeholders (n=11). We searched PubMed, The Cochrane Library, Scopus, Google, Google Scholar, and undertook lateral searches. All types of evidence were included. Results: We included 88 papers; 29 focused on older people or people with complex needs. We identified four context-mechanism-outcome configurations that together provide an account of what needs to be in place for SDM to work for older people with complex needs. This includes: understanding and assessing patient and carer values and capacity to access and use care, organising systems to support and prioritise SDM, supporting and preparing patients and family carers to engage in SDM and a person-centred culture of which SDM is a part. Programmes likely to be successful in promoting SDM are those that allow older people to feel that they are respected and understood, and that engender confidence to engage in SDM. Conclusions: To embed SDM in practice requires a radical shift from a biomedical focus to a more person-centred ethos. Service providers will need support to change their professional behaviour and to better organise and deliver services. Face to face interactions, permission and space to discuss options, and continuity of patient-professional relationships are key in supporting older people with complex needs to engage in SDM. Future research needs to focus on inter-professional approaches to SDM and how families and carers are involved

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely