The role of environmental factors on sporadic Creutzfeldt-Jakob disease mortality: evidence from an age-period-cohort analysis.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of prion diseases. The causes of sCJD are still unknown and exogenous factors may play a role. Worldwide, the number of patients with sCJD has progressively increased over time. This increase can be partly explained by increasing life expectancy and better case ascertainment, but a true increase in the number of sCJD cases cannot be excluded. We estimated mortality rates from sCJD in France (1992-2016) and studied variation in mortality rates by age, period, and time.We included all cases aged 45-89 years old who died with a probable/definite sCJD diagnosis based on the French national surveillance network. We used age-period-cohort (APC) Poisson regression models to study variation in mortality rates by sex, age, period, and time.A total of 2475 sCJD cases aged 45-89 years were included. Mortality rates increased with age, reached a peak between 75 and 79 years, and decreased thereafter. Mortality rates were higher in women than men at younger ages and lower at older ages. The full APC model with a sex×age interaction provided the best fit to the data, thus in favour of sex, age, period, and cohort effects on mortality rates. In particular, mortality rates increased progressively with successive birth cohorts.Based on 25 years of active surveillance in France, we show evidence for sex, age, period, and cohort effects on sCJD mortality. The identification of cohort effects suggests that environmental exposures may play a role in sCJD etiology.

Prospective 25-year surveillance of prion diseases in France, 1992 to 2016: a slow waning of epidemics and an increase in observed sporadic forms.

BackgroundPrion diseases are rare, fatal disorders that have repeatedly raised public health concerns since the early 1990s. An active prion disease surveillance network providing national level data was implemented in France in 1992.AimWe aimed to describe the epidemiology of sporadic, genetic and infectious forms of prion diseases in France since surveillance implementation.MethodsWe included all suspected cases notified from January 1992 to December 2016, and cases who died during the period with a definite or probable prion disease diagnosis according to EuroCJD criteria. Demographic, clinical, genetic, neuropathological and biochemical data were collected.ResultsIn total, 25,676 suspected cases were notified and 2,907 were diagnosed as prion diseases, including 2,510 (86%) with sporadic Creutzfeldt-Jakob disease (sCJD), 240 (8%) genetic and 157 (6%) with infectious prion disease. Suspected cases and sCJD cases increased over time. Younger sCJD patients (≤ 50 years) showed phenotypes related to a distinct molecular subtype distribution vs those above 50 years. Compared to other European countries, France has had a higher number of cases with iatrogenic CJD after growth hormone treatment and variant CJD (vCJD) linked to bovine spongiform encephalopathy (second after the United Kingdom), but numbers slowly decreased over time.ConclusionWe observed a decrease of CJD infectious forms, demonstrating the effectiveness of measures to limit human exposure to exogenous prions. However, active surveillance is needed regarding uncertainties about future occurrences of vCJD, possible zoonotic potential of chronic wasting diseases in cervids and increasing trends of sCJD observed in France and other countries.

Global and Regional Burden of Hospital Admissions for Pneumonia in Older Adults: A Systematic Review and Meta-Analysis.

Pneumonia constitutes a substantial disease burden among adults overall and those who are elderly. We aimed to identify all studies investigating the disease burden among older adults (age, ≥65 years) admitted to the hospital with pneumonia. We estimated the hospital admission rate and in-hospital case-fatality ratio (CFR) of pneumonia in older adults, stratified by age and economic status (industrialized vs developing), with data from a systematic review of studies published from 1996 through 2017 and from 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burden in older adults who would have been admitted to the hospital with pneumonia that year. We estimated the number of in-hospital pneumonia deaths by combining in-hospital CFRs with hospital admission estimates from hospital-based studies. We identified 109 eligible studies; 73 used clinical pneumonia as the case definition, and 36 used radiologically confirmed pneumonia as the case definition. We estimated that, in 2015, 6.8 million episodes (uncertainty range [UR], 5.8-8.0 episodes) of clinical pneumonia resulted in hospital admissions of older adults worldwide. The hospital admission rate increased with advancing age and was higher in men. The total disease burden was likely underestimated when using the definition of radiologically confirmed pneumonia. Based on data from 52 hospital studies reporting data on pneumonia mortality, we estimated that about 1.1 million in-hospital deaths (UR, 0.9-1.4 in-hospital deaths) occurred among older adults. The burden of pneumonia requiring hospitalization among older adults is substantial. Appropriate prevention and management strategies should be developed to reduce its impact.

Global Disease Burden Estimates of Respiratory Syncytial Virus-Associated Acute Respiratory Infection in Older Adults in 2015: A Systematic Review and Meta-Analysis.

Respiratory syncytial virus-associated acute respiratory infection (RSV-ARI) constitutes a substantial disease burden in older adults aged ≥65 years. We aimed to identify all studies worldwide investigating the disease burden of RSV-ARI in this population. We estimated the community incidence, hospitalization rate, and in-hospital case-fatality ratio (hCFR) of RSV-ARI in older adults, stratified by industrialized and developing regions, using data from a systematic review of studies published between January 1996 and April 2018 and 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burdens in older adults with RSV-ARI in the community and in hospitals for that year. We estimated the number of in-hospital deaths due to RSV-ARI by combining hCFR data with hospital admission estimates from hospital-based studies. In 2015, there were about 1.5 million episodes (95% confidence interval [CI], .3 million-6.9 million) of RSV-ARI in older adults in industrialized countries (data for developing countries were missing), and of these, approximately 14.5% (214 000 episodes; 95% CI, 100 000-459 000) were admitted to hospitals. The global number of hospital admissions for RSV-ARI in older adults was estimated at 336 000 hospitalizations (uncertainty range [UR], 186 000-614 000). We further estimated about 14 000 in-hospital deaths (UR, 5000-50 000) related to RSV-ARI globally. The hospital admission rate and hCFR were higher for those aged ≥65 years than for those aged 50-64 years. The disease burden of RSV-ARI among older adults is substantial, with limited data from developing countries. Appropriate prevention and management strategies are needed to reduce this burden.

Validation of the Medical Research Council prion disease rating scale in France.

The development of assessment tools other than survival time is necessary to conduct therapeutic trials in prion diseases (also known as subacute transmissible encephalopathies). The Medical Research Council Prion Disease Rating Scale published by Thompson et al. (The Medical Research Council prion disease rating scale: A new outcome measure for prion disease therapeutic trials developed and validated using systematic observational studies. Brain. 2013; 136: 1116-27.) is the first attempt at a specific evaluation of prion diseases to avoid the floor effect seen in other scales. Validation of this scale in other countries is essential because, given the rarity of these diseases, therapeutic trials are likely to be multi-centre and international. After translation into French, we assessed by phone 173 cases classified as sporadic Creutzfeldt-Jakob disease out of 852 patients notified to the French national surveillance network between November 2014 and May 2021. Data showed that the natural history of the disease is similar in the UK and France. Patients who have a heterozygous genotype at codon 129 of the prion protein gene have a slower decline than homozygous patients. In rapidly progressing patients, death occurs shortly after reaching a low score or after a 'pre-terminal plateau' at a very low score. The similarities of disease progression profile observed in France and the UK with somewhat different surveillance systems and by distinct procedures highlight the robustness of the Medical Research Council Prion Disease Rating Scale that can be thus used to define primary endpoints of future trials at the international level.

Validation of Revised International Creutzfeldt-Jakob Disease Surveillance Network Diagnostic Criteria for Sporadic Creutzfeldt-Jakob Disease.

Importance: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly lethal disease. Rapid, accurate diagnosis is imperative for epidemiological surveillance and public health activities to exclude treatable differentials and facilitate supportive care. In 2017, the International CJD Surveillance Network diagnostic criteria were revised to incorporate cortical ribboning on magnetic resonance imaging and the real-time quaking-induced conversion (RT-QuIC) assay, developments that require multicenter evaluation. Objective: To evaluate the accuracy of revised diagnostic criteria through the retrospective diagnosis of autopsy-confirmed cases (referred to as in-life diagnosis). Design, Setting, and Participants: This diagnostic study used a 3-year clinicopathological series using all cases of autopsy-confirmed sCJD and a noncase group with alternative neuropathological diagnoses from national surveillance centers in the United Kingdom, France, Germany, and Italy. Data were collected from January 2017 to December 2019 and analyzed from January 2020 to November 2021. Main Outcomes and Measures: Sensitivity and specificity of revised diagnostic criteria and diagnostic investigations. Secondary analyses assessing sCJD subgroups by genotype, pathological classification, disease duration, and age. Results: A total of 501 sCJD cases and 146 noncases were included. Noncase diagnoses included neurodegenerative diseases, autoimmune encephalitis, and cerebral insults such as anoxia. Participants in the sCJD cases cohort were younger (mean [SD] age, 68.8 [9.8] years vs 72.8 [10.9] years; P < .001) and had longer median (IQR) disease duration (118 [74.8-222.3] days vs 85 [51.5-205.5] days; P = .002); sex ratios were equivalent (253 [50.5%] male cases vs 74 [50.7%] male noncases). Sensitivity of revised criteria in in-life diagnosis (450 of 488 [92.2%] diagnoses; 95% CI, 89.5%-94.4%) was increased compared with prior criteria (378 of 488 [77.5%] diagnoses; 95% CI, 73.5%-81.1%; P < .001), while specificity (101 of 125 [80.8%] diagnoses; 95% CI, 72.8%-87.3%) was unchanged (102 of 125 [81.6%] diagnoses; 95% CI, 73.7%-88.0%; P > .99). Among 223 cases and 52 noncases with the full panel of investigations performed, sensitivity of revised criteria (97.8%; 95% CI, 94.9%-99.3%) was increased compared with prior criteria (76.2%; 95% CI, 70.1%-81.7%; P < .001) while specificity was unchanged (67.3%; 95% CI, 52.9%-79.7% vs 69.2%; 95% CI, 54.9%-81.3%; P > .99). In 455 cases and 111 noncases, cortical ribboning was 67.9% sensitive (95% CI, 63.4%-72.2%) and 86.5% specific (95% CI, 78.7%-92.2%). In 274 cases and 77 noncases, RT-QuIC was 91.6% sensitive (95% CI, 87.7%-94.6%) and 100% specific (95% CI, 96.2%-100%). Investigation sensitivity varied with genetic and pathological features, disease duration, and age. Conclusions and Relevance: This diagnostic study demonstrated significantly improved sensitivity of revised sCJD diagnostic criteria with unaltered specificity. The revision has enhanced diagnostic accuracy for clinical care and surveillance.

Sexual Disorders of Patients With Metastatic Renal Cell Carcinoma (mRCC) Treated With Antiangiogenic Therapies.

BACKGROUND: Targeted therapies, in particular antiangiogenic therapies (AATs), have become the standard of treatment for metastatic renal cell carcinoma (mRCC). Although common adverse effects like fatigue have been well-established, sexual disorders induced by these treatments, although often reported, have been poorly evaluated. The aim of this study was to evaluate the impact of AATs on the sexual life of patients with mRCC and the relationships with quality of life (QoL), fatigue, and biologic parameters. PATIENTS AND METHODS: This longitudinal study included patients with mRCC on first- or second-line AATs. Sexuality was evaluated by the French version of Changes in Sexual Functioning Questionnaire short-Form (CSFQ); QoL and fatigue were measured by the Functional Assessment of Cancer Therapy General (FACT-G) and the Multidimensional Fatigue Inventory (MFI-20), respectively. Biologic parameters were also assessed. RESULTS: Among 75 patients included in the study, 39 agreed to respond to the sexual functioning questionnaire (CSFQ). At baseline, all patients had at least 1 sexual dysfunction. No relationship with QoL, fatigue, and biologic parameters was shown. After 3 months of treatment, a decrease in at least 1 sexual dimension was observed in 69% of patients. The most affected sexual dimensions were pleasure (34%) and desire/interest (38%). No significant relationship between sexual dysfunctions and biologic parameters was found. The percentage of non-participants (50%) and the absence of a control arm are the main limitations. DISCUSSION: Patients with mRCC exhibit sexual dysfunction that could be increased by AATs independently of the impact on fatigue and QoL. Further studies aiming to define the role of biologic parameters like inflammatory markers and thyroid parameters are warranted. CONCLUSION: Sexual disorders induced or degraded by AAT are an independent side effect that should be taken into account in oncology supportive care departments.

Biomarkers Associated with Cognitive Impairment in Treated Cancer Patients: Potential Predisposition and Risk Factors.

Purpose: Cognitive impairment in cancer patients induced, at least in part, by treatment are frequently observed and likely have negative impacts on patient quality of life. Such cognitive dysfunctions can affect attention, executive functions, and memory and processing speed, can persist after treatment, and their exact causes remain unclear. The aim of this review was to create an inventory and analysis of clinical studies evaluating biological markers and risk factors for cognitive decline in cancer patients before, during, or after therapy. The ultimate objectives were to identify robust markers and to determine what further research is required to develop original biological markers to enable prevention or adapted treatment management of patients at risk. Method: This review was guided by the PRISMA statement and included a search strategy focused on three components: "cognition disorders," "predictive factors"/"biological markers," and "neoplasms," searched in PubMed since 2005, with exclusion criteria concerning brain tumors, brain therapy, and imaging or animal studies. Results: Twenty-three studies meeting the criteria were analyzed. Potential associations/correlations were identified between cognitive impairments and specific circulating factors, cerebral spinal fluid constituents, and genetic polymorphisms at baseline, during, and at the end of treatment in cancer populations. The most significant results were associations between cognitive dysfunctions and genetic polymorphisms, including APOE-4 and COMT-Val; increased plasma levels of the pro-inflammatory cytokine, IL-6; anemia; and hemoglobin levels during chemotherapy. Plasma levels of specific hormones of the hypothalamo-pituitary-adrenal axis are also modified by treatment. Discussion: It is recognized in the field of cancer cognition that cancer and comorbidities, as well as chemotherapy and hormone therapy, can cause persistent cognitive dysfunction. A number of biological circulating factors and genetic polymorphisms, can predispose to the development of cognitive disorders. However, many predictive factors remain unproven and discordant findings are frequently reported, warranting additional clinical and preclinical longitudinal cohort studies, with goals of better characterization of potential biomarkers and identification of patient populations at risk and/or particularly deleterious treatments. Research should focus on prevention and personalized cancer management, to improve the daily lives, autonomy, and return to work of patients.