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Western patients are increasingly travelling to developing countries for health care and developing countries are increasingly offering their skills and facilities to paying foreign customers. The potential and implications of this international trade in medical services is explored in this book through analysis of the market.

The addition of veliparib, a PARP inhibitor, to induction chemotherapy and maintenance therapy in women with advanced ovarian cancer significantly improved progression-free survival over induction chemotherapy alone without maintenance therapy. The improvement was especially notable in patients with mutated BRCA or homologous-recombination defects.

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson’s Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson’s disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal–lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

Background Fatigue is a common symptom of systemic autoimmune rheumatic disease (SARD). Patients with SARD have a protracted pre-clinical phase during which progressive immunologic derangements occur culminating in disease. In this study, we sought to determine when fatigue develops and whether its presence correlates with inflammatory factors or predicts disease progression. Methods Anti-nuclear antibody (ANA)-negative healthy controls (HCs) and ANA-positive participants with no criteria, at least one clinical criteria (undifferentiated connective tissue disease, UCTD), or meeting SARD classification criteria were recruited. Fatigue was assessed using a modified version of the FACIT-F questionnaire and the presence of fibromyalgia determined using a questionnaire based on the modified 2010 ACR criteria. Peripheral blood expression of five IFN-induced genes was quantified by NanoString and the levels of IL-1β, IL-6, or TNF-α by ELISA. Results Fatigue was as prevalent and severe in individuals lacking SARD criteria as it was in UCTD and SARD. Overall, ~ 1/3 of ANA + subjects met fibromyalgia criteria, with no differences between sub-groups. Although fatigue was more severe in these individuals, those lacking fibromyalgia remained significantly more fatigued than ANA − HC. However, even in these subjects, fatigue correlated with the widespread pain index and symptom severity scores on the fibromyalgia questionnaire. Fatigue was not associated with elevated cytokine levels in any of the ANA + sub-groups and did not predict imminent disease progression. Conclusions Fatigue is common in ANA + individuals lacking sufficient criteria for a SARD diagnosis, correlates with fibromyalgia-related symptoms, and is not associated with inflammation or predictive of disease progression.

A correction to this paper has been published: https://doi.org/10.1007/s00401-021-02309-z

IntroductionEuropean Alliance of Associations for Rheumatology (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) is a clinician-reported outcome (ClinRO) instrument, assessing Sjögren’s disease activity from the physician perspective. EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) is a patient-reported outcome (PRO) instrument, assessing patient-defined Sjögren’s symptom severity. Both instruments are commonly used as clinical trial endpoints and have been psychometrically validated. However, qualitative evidence supporting content validity and what constitutes a meaningful change is limited. Qualitative evidence supporting Physician/Patient Global Assessment of disease activity and symptom severity (PhGA/PaGA) items used within anchor-based analyses for ESSDAI/ESSPRI is also lacking.MethodsQualitative, semi-structured, telephone/video interviews were conducted with patients with Sjögren’s (n = 12) and physicians who specialise in Sjögren’s (n = 10). Interviews explored: appropriateness of ESSDAI domain weights and meaningful improvements on domain/total scores from the physician perspective, appropriateness of ESSPRI’s 2-week recall period from the patient/physician perspective, patients’ perspectives on meaningful improvements in ESSPRI total scores, and patients’/physicians’ interpretation of PhGA/PaGA items.ResultsMost ESSDAI domain weights were considered clinically appropriate. Generally, a one-category improvement in domain-level scores and a 3-point improvement in total ESSDAI scores were considered clinically meaningful. Most patients/physicians considered ESSPRI’s 2-week recall period appropriate, and patients considered a 1-to-2-point ESSPRI total score improvement meaningful. PhGA/PaGA items developed for use as ESSDAI/ESSPRI anchors were consistently interpreted.ConclusionsThe findings support use of ESSDAI and ESSPRI as Sjögren’s clinical trials endpoints, as well as in clinical practice and other research settings. Qualitative data exploring meaningful change supports existing minimal clinically important improvement (MCII) thresholds.Plain Language SummaryEuropean Alliance of Associations for Rheumatology (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) is an assessment used by physicians to measure how active Sjögren’s is in individuals with the condition. EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) is a questionnaire completed by individuals with Sjögren’s to assess the severity of their symptoms. It is important to show that ESSDAI and ESSPRI are considered appropriate by physicians and individuals with Sjögren’s, respectively, and that ESSPRI is well understood by individuals with Sjögren’s completing the questionnaire. Therefore, interviews were conducted with physicians who specialise in Sjögren’s to explore the appropriateness of ESSDAI, the level of improvement on the assessment that would be important to individuals with Sjögren’s, and the appropriateness of the ESSPRI recall period (i.e. whether it is acceptable to ask individuals to remember their symptoms over the past 2 weeks). Interviews were also conducted with individuals with Sjögren’s to explore their understanding and relevance of ESSPRI (including the 2-week recall period) and the level of improvement on the questionnaire that would be important to them. Most physicians and patients considered ESSDAI and ESSPRI appropriate, supporting their use in a range of settings including Sjögren’s clinical trials, clinical practice and other research settings. Most physicians reported that a 3-point improvement in ESSDAI total score would be meaningful to individuals with Sjögren’s. Individuals with Sjögren’s reported that a 1-to-2-point improvement in ESSPRI total score would be meaningful.

IntroductionSjögren’s Syndrome Symptom Diary (SSSD) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) are patient-reported outcome (PRO) instruments assessing Sjögren’s symptoms. Original SSSD items have demonstrated content validity, however qualitative evidence supporting the updated ‘tiredness’ item and two new supplementary items is lacking. Although well established and validated in other rheumatic diseases, there is no qualitative evidence supporting content validity of FACIT-F in Sjögren’s. This study addressed these evidence gaps to support use of SSSD and FACIT-F as clinical trial endpoints, in clinical practice and in other research settings.MethodsQualitative, semi-structured telephone interviews were conducted with patients with Sjögren’s (n = 12) and expert Sjögren’s physicians (n = 10). Patient interviews explored content validity (e.g., understanding and relevance) of the new and updated SSSD items, perceptions of item and total score meaningful change on SSSD, and understanding and relevance of FACIT-F items. Physician interviews explored opinions on various SSSD scoring approaches.ResultsThe new and updated SSSD items and FACIT-F demonstrated good content validity. Most patients considered a two-point improvement on most SSSD items meaningful, as well as a one- or two-point total score improvement. Most physicians reported tracking changes in patient responses to individual items as the most appropriate SSSD scoring approach.ConclusionsSSSD and FACIT-F are content valid in a Sjögren’s population, meeting an important criterion to support their use as clinical trial endpoints, but also their use in clinical practice and other research settings. Qualitative data exploring meaningful change will be valuable in supporting psychometrically derived responder definitions.Plain Language SummarySjögren’s Syndrome Symptom Diary (SSSD) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) are questionnaires completed by individuals with Sjögren’s to assess the severity of their symptoms. It is important to show that these questionnaires are well understood and relevant to the individuals who complete them. Therefore, interviews were conducted with individuals with Sjögren’s to explore their understanding and relevance of new and updated SSSD questions. Similarly, the interviews explored whether the FACIT-F questionnaire was well understood and relevant to individuals with Sjögren’s, as this has not been explored before. Interviews were also conducted with expert Sjögren’s physicians to explore the best approach to scoring SSSD (e.g., calculating a total score or looking at scores on individual items). The new and updated SSSD questions and the FACIT-F questionnaire were well understood and considered relevant by most individuals with Sjögren’s. This suggests these questionnaires are appropriate for use in Sjögren’s clinical trials, clinical practice, and other research settings. Most individuals with Sjögren’s considered an improvement of two points on individual SSSD questions to be important, as well as a one- or two-point improvement in their total SSSD score. Most physicians agreed on the best approach to scoring SSSD.

. Mature results from GOG158 have clearly established carboplatin and paclitaxel as an effective and well tolerated standard regimen, providing a basis for the reference arm in GOG0182‐ICON5, an ongoing multiarmed phase III trial of the Gynecologic Cancer InterGroup (GCIG) evaluating the incorporation of newer cytotoxic agents. Results from GOG158 will be reviewed, including an analysis of second‐look surgical outcomes, followed by an update on the current status of GOG0182‐ICON5.

.  Bookman MA. Standard treatment in advanced ovarian cancer in 2005: the state of the art. Int J Gynecol Cancer 2005;15(Suppl. 3):212–220. What are standards? The oncology community expends considerable effort to review the results from definitive treatment studies and define recommendations for future studies, as well as standards of care for the community and patients who are not participating in clinical trials. This is a thoughtful and well‐intentioned process but subject to considerable bias due to limitations in the data and/or their interpretation. While ovarian cancer is highly responsive to platinum‐based therapy after initial cytoreductive surgery, there is a substantial risk of recurrence, which is accompanied by the emergence of drug‐resistant disease. Better treatments with improved long‐term outcomes are needed. From this perspective, standards can help to provide a baseline for assessing gaps in our current knowledge and defining priorities for future clinical trials. While not an exhaustive review, this study will focus on key clinical concepts that are guiding ovarian cancer research and treatment.

.  Bookman MA. Gemcitabine monotherapy in recurrent ovarian cancer: from the bench to the clinic. Int J Gynecol Cancer 2005;15(Suppl. 1):12–17. Gemcitabine (2′2′‐difluorodeoxycytidine [dFdC]) is a synthetic analog of deoxycytidine with two fluorine atoms at the 2′ position of the carbohydrate. As a hydrophobic molecule, dFdC competes for intracellular access via membrane‐associated nucleoside transporter proteins. Following intracellular transport, dFdC is phosphorylated sequentially by deoxycytidine kinase to gemcitabine triphosphate, which inhibits ribonucleotide metabolism, hinders DNA processing, and increases accumulation of intrastrand adducts and interstrand cross‐links, thereby leading to a G1 block in the cell cycle. dFdC monotherapy has been extensively evaluated at doses of 800–1250 mg/m2. dFdC is generally well tolerated, with the most frequently occurring dose‐limiting toxicities being hematologic, noncumulative, and easily managed by dose alteration. Several studies involving treatment of recurrent ovarian cancer patients with dFdC monotherapy, most of whom had platinum‐resistant disease and/or prior exposure to paclitaxel, led to overall response rates of 14–22% and a median duration of response of 4.0–10.6 months. An additional one third of the participants experienced stable disease for an overall clinical benefit in approximately one half of the treated patients. Tumor cells with a multidrug resistance phenotype have increased sensitivity to dFdC (collateral sensitivity). As dFdC is unaffected by platinum resistance, and not susceptible to classic multidrug resistance, it could be particularly beneficial to administer following treatment with agents that induce multidrug resistance. Integration of dFdC with platinum and/or radiation should also be investigated.