Evaluation of continuous ampicillin/sulbactam infusion in critically ill patients.

Continuous infusion (CI) of beta-lactam-antibiotics may improve pharmacodynamics in critically ill patients, but resulting concentrations have not been studied. Therapeutic drug monitoring is increasingly used to ensure antibiotic concentration. The aim of this study is to evaluate therapeutic ampicillin/sulbactam concentrations of a continuous infusion regimen. METHODS: Medical records of all patients admitted to ICU between January 2019 and December 2020 were retrospectively reviewed. Each patient received a 2/1 g ampicillin/sulbactam loading dose, followed by a continuous infusion of 8/4 g per 24 h. Ampicillin serum concentrations were measured. Main outcomes were reaching of plasma concentrations breakpoint defined by minimum inhibitory concentration (MIC at 8 mg/l) and 4-fold MIC (MIC at 32 mg/l) during steady state of CI. RESULTS: In 50 patients a total of 60 concentration measurements were performed. The first concentration was measured after a median of 29 h (IQR 21-61 h). Mean ampicillin concentration was 62.6 ± 39.1 mg/l. Furthermore, serum concentrations exceeded the defined MIC breakpoint in all measurements (100 %) and were above the 4-fold MIC in 43 analyses (71.1 %). However, patients suffering from acute kidney injury exhibited significant higher serum concentrations (81.1 ± 37.7 mg/l vs. 38.2 ± 24.8 mg/l; p < 0.001). Also, there was a negative correlation between ampicillin serum concentrations and GFR (r = -0.659; p < 0.001). CONCLUSION: The described dosing regimen for ampicillin/sulbactam is safe with respect to the defined MIC breakpoints for ampicillin, and continuous subtherapeutic concentration is unlikely. However, with impaired renal function drug accumulation occurs, and with increased renal clearance, drug levels can be below the 4-fold MIC breakpoint.

Cost-effectiveness analysis of resorbable biosynthetic mesh in contaminated ventral hernia repair.

BACKGROUND: The aim of this study was to compare, in terms of cost and serious complications, the use of biosynthetic resorbable parietal mesh with biologic mesh in patients undergoing contaminated ventral hernia repair (modified Ventral Hernia Working Group grade 3). Poly-4-hydroxy-butyrate (P4HB) biosynthetic mesh has rarely been the subject of comparative studies in the context of contamination. Data are required to confirm the effects of a transition from biological mesh to biosynthetic resorbable mesh. PATIENTS AND METHODS: A cost-effectiveness analysis was conducted. It was based on a decision analysis model built with clinical and economic data issued from a before-after study that included 94 patients hospitalized for ventral hernia repair at the University Hospital of Strasbourg (France) from June 2011 to February 2018. The effectiveness endpoint was the number of patients presenting with a serious specific complication or a general complication at 6 months. Data for surgical hospitalization stays, home hospitalizations and ambulatory care costs were included. RESULTS: We found fewer serious complications with biosynthetic mesh: 21% versus 33% with biologic mesh. A cost savings of US $5146 was determined. Deterministic sensitivity analyses and a probabilistic analysis confirmed our findings and the robustness of the model. CONCLUSION: P4HB biosynthetic resorbable mesh appeared to be the most effective and the least costly option. Additional data will be needed to confirm the superiority of biosynthetic mesh in terms of the recurrence risk reduction over a longer period.

Parameters predicting COVID-19-induced myocardial injury and mortality.

Clinical manifestations of COVID-19 affect many organs, including the heart. Cardiovascular disease is a dominant comorbidity and prognostic factors predicting risk for critical courses are highly needed. Moreover, immunomechanisms underlying COVID-induced myocardial damage are poorly understood. OBJECTIVE: To elucidate prognostic markers to identify patients at risk. RESULTS: Only patients with pericardial effusion (PE) developed a severe disease course, and those who died could be identified by a high CD8/Treg/monocyte ratio. Ten out of 19 COVID-19 patients presented with PE, 7 (78%) of these had elevated APACHE-II mortality risk-score, requiring mechanical ventilation. At admission, PE patients showed signs of systemic and cardiac inflammation in NMR and impaired cardiac function as detected by transthoracic echocardiography (TTE), whereas parameters of myocardial injury e.g. high sensitive troponin-t (hs-TnT) were not yet increased. During the course of disease, hs-TnT rose in 8 of the PE-patients above 16 ng/l, 7 had to undergo ventilatory therapy and 4 of them died. FACS at admission showed in PE patients elevated frequencies of CD3+CD8+ T cells among all CD3+ T-cells, and lower frequencies of Tregs and CD14+HLA-DR+-monocytes. A high CD8/Treg/monocyte ratio predicted a severe disease course in PE patients, and was associated with high serum levels of antiviral cytokines. By contrast, patients without PE and PE patients with a low CD8/Treg/monocyte ratio neither had to be intubated, nor died. CONCLUSIONS: PE predicts cardiac injury in COVID-19 patients. Therefore, TTE should be performed at admission. Immunological parameters for dysfunctional antiviral immunity, such as the CD8/Treg/monocyte ratio used here, supports risk assessment by predicting poor prognosis.

DHA Supplementation Attenuates MI-Induced LV Matrix Remodeling and Dysfunction in Mice.

OBJECTIVE: Myocardial ischemia and reperfusion (I/R) injury is associated with oxidative stress and inflammation, leading to scar development and malfunction. The marine omega-3 fatty acids (ω-3 FA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are mediating cardioprotection and improving clinical outcomes in patients with heart disease. Therefore, we tested the hypothesis that docosahexaenoic acid (DHA) supplementation prior to LAD occlusion-induced myocardial injury (MI) confers cardioprotection in mice. METHODS: C57BL/6N mice were placed on DHA or control diets (CD) beginning 7 d prior to 60 min LAD occlusion-induced MI or sham surgery. The expression of inflammatory mediators was measured via RT-qPCR. Besides FACS analysis for macrophage quantification and subtype evaluation, macrophage accumulation as well as collagen deposition was quantified in histological sections. Cardiac function was assessed using a pressure-volume catheter for up to 14 d. RESULTS: DHA supplementation significantly attenuated the induction of peroxisome proliferator-activated receptor-α (PPAR-α) (2.3 ± 0.4 CD vs. 1.4 ± 0.3 DHA) after LAD occlusion. Furthermore, TNF-α (4.0 ± 0.6 CD vs. 1.5 ± 0.2 DHA), IL-1ß (60.7 ± 7.0 CD vs. 11.6 ± 1.9 DHA), and IL-10 (223.8 ± 62.1 CD vs. 135.5 ± 38.5 DHA) mRNA expression increase was diminished in DHA-supplemented mice after 72 h reperfusion. These changes were accompanied by a less prominent switch in α/ß myosin heavy chain isoforms. Chemokine mRNA expression was stronger initiated (CCL2 6 h: 32.8 ± 11.5 CD vs. 78.8 ± 13.6 DHA) but terminated earlier (CCL2 72 h: 39.5 ± 7.8 CD vs. 8.2 ± 1.9 DHA; CCL3 72 h: 794.3 ± 270.9 CD vs. 258.2 ± 57.8 DHA) in DHA supplementation compared to CD mice after LAD occlusion. Correspondingly, DHA supplementation was associated with a stronger increase of predominantly alternatively activated Ly6C-positive macrophage phenotype, being associated with less collagen deposition and better LV function (EF 14 d: 17.6 ± 2.6 CD vs. 31.4 ± 1.5 DHA). CONCLUSION: Our data indicate that DHA supplementation mediates cardioprotection from MI via modulation of the inflammatory response with timely and attenuated remodeling. DHA seems to attenuate MI-induced cardiomyocyte injury partly by transient PPAR-α downregulation, diminishing the need for antioxidant mechanisms including mitochondrial function, or α- to ß-MHC isoform switch.

Are comorbidities associated with long-term survival of lung cancer? A population-based cohort study from French cancer registries.

BACKGROUND: Survival rates of lung cancer remains poor and the impact of comorbidities on the prognosis is discussed. The objective of this study was to assess if the Charlson Comorbidity Index (CCI) was associated with 8-year survival rates by histological type. METHODS: A cohort study was conducted using randomly selected cases from 10 French cancer registries. Net survival rates were computed using the Pohar-Perme estimator of the net cumulative rate. Three Cox models were independently built for adenocarcinomas, squamous cell and small cell cancers to estimate prognostic factors including CCI grade. RESULTS: A total of 646 adenocarcinomas, 524 squamous cell and 233 small cell cancers were included in the analysis. The net 8-year survival rate ranged from 12.6% (95% CI: 9.8-15.4%) for adenocarcinomas and 13.4% (95% CI: 10.1-16.7%) for squamous cell carcinomas, to 3.7% (95% CI: 1.1-6.3%) for small cell cancers. Observed and net survival rates decreased for CCI grades ≥3 for all histological group considered. After adjustment for sex, age group, stage and diagnostic mode, CCI grades 1 (HR = 1.6 [95% CI: 1.1-2.3]), 2 (HR = 1.7 [95% CI: 1.1-2.7]) and ≥ 3 (HR = 2.7 [95% CI: 1.7-4.4]) were associated with lower survival rates only for small cell cancers. CONCLUSION: After adjustment for age, sex, stage and diagnostic mode, the presence of comorbidity based on CCI grades 1-2 and ≥ 3 was associated with lower survival rates for small cell cancers whereas no differences were observed for adenocarcinomas and squamous cell cancers.

Merkel cell carcinoma in France: a registries-based, comprehensive epidemiological survey.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine carcinoma. Owing to its low incidence, epidemiological data are scarce and have never been analysed in France to identify the main epidemiological trends. METHODS: Data from MCC patients diagnosed between 1998 and 2010 were obtained from 11 French cancer registries in the FRANCIM network. The main epidemiological characteristics of MCC were investigated between 2006 and 2010 because comprehensive data were only available for this period. The main focus was tumour incidence and mortality over time. RESULTS: Between 1998 and 2010, 562 cases of MCC were reported in the registries. From 2006 to 2010 (290 cases), European- and world-standardized incidence rates were 0.26 and 0.43 per 100,000 person-years in men and 0.24 and 0.38 per 100,000 person-years in women. MCC is more frequent in females in France (56.9%) with male/female ratio 1.1. Relative survival rates were 84%, 56% and 42% at one, three and 5 years, respectively. CONCLUSIONS: The incidence of MCC clearly increased over time in all areas under focus. The standardized incidence in France was comparable to the incidence observed in other countries for the same period, but French data are too recent to conclude on an increase in MCC incidence. Prognosis remains poor in all countries in which data are available.

Are dietary reports in a case-control study on thyroid cancer biased by risk perception of Chernobyl fallout?

BACKGROUND: In retrospective case-control studies performed following nuclear tests or nuclear accidents, individual thyroid radiation dose reconstructions are based on fallout and meteorological data from the residential area, demographic characteristics, and lifestyle as well as dietary information. Collecting the latter is a controversial step, as dietary declarations may be affected by the subjects' beliefs about their risk behavior. This report analyses the potential for such bias in a case-control study performed in eastern France. METHODS: The study included 765 cases of differentiated thyroid carcinoma matched with 831 controls. Risk perceptions and beliefs of cases and controls were compared using Chi2 tests and differences in dietary reports were analyzed using a two-way ANOVA. RESULTS: In general, atmospheric pollution and living near a nuclear power plant were the two major risks that may influence thyroid cancer occurrence cited by cases and controls. When focusing in particular on the consequences of the Chernobyl accident, cases were more likely to think that the consequences were responsible for thyroid cancer occurrence than controls. Vegetable consumption during the two months after the Chernobyl accident was correlated with the status of subjects, but not to their beliefs. Conversely, consumption of fresh dairy products was not correlated with the status or beliefs of subjects. CONCLUSION: We found no evidence of systematic bias in dietary reports according to the status or beliefs held by subjects about the link between thyroid cancer occurrence and Chernobyl fallout. As such, these dietary reports may be used in further studies involving individual dosimetric reconstructions.

Oral cancer characteristics in France: Descriptive epidemiology for early detection.

Despite the frequency and lethality of oral cancers in France, there are no detailed general population data regarding the characteristics of these patients to fuel the public health authorities' reflections about early detection policies. Thus, the objective of this study was to determine, in the general population, the characteristics of both patients and tumours at the time of the diagnosis. A high-resolution, population-based study using 13 French registries was conducted on 1089 tumours diagnosed in 2010. Men accounted for 75% of cases. The most frequent sites were tonsil (28.4%) and oral tongue (21.1%). The median age varied from 56.7 years for floor of mouth to 66.4 years for gum. The lesions were mainly diagnosed on pain and those diagnosed after routine clinical examination were scarce (2.6%). There were 65.5% stage III and IV at diagnosis. Oral tongue, floor of mouth and palate presented tumours less than 2cm only in 34 to 40% of cases. Advanced stage was associated with the presence of comorbidities, and tonsil or base of tongue topography. Stage was not associated with Département, deprivation index or gender. This study provided a picture of the characteristics of oral cancer patients and their tumours and showed that diagnoses are often made late, even for those tumours most easily accessible to direct visual and tactile examination. Nevertheless, it remains to define the target population of an early detection and to evaluate the benefit of such detection on the mortality rate.

Biosimilar infliximab for the management of rheumatoid arthritis in France: what are the expected savings?

OBJECTIVES: Biosimilar infliximab, the first similar biological medicinal product containing monoclonal antibodies to be commercialised, is likely to contribute to a significant reduction in healthcare costs. We aimed to assess the cost savings potential over 1 year of the use of biosimilar infliximab for the treatment of rheumatoid arthritis (RA) patients in Alsace and in France, in a real-life setting. METHODS: The analysis was based on a previously conducted observational study which evaluated the annual cost of the care of patients with RA treated with biological therapies in 2012 in Alsace. Average annual costs to manage RA patients were calculated, taking into account the decrease in the retail price between 2012 and 2015 (as given in the official national price list) and the local negotiated price for biosimilar infliximab. Annual cost savings for different biosimilar prescription scenarios were calculated using 2015 prices. RESULTS: Management of RA patients with biosimilar infliximab was significantly cheaper than with adalimumab or etanercept (€11 907 vs €12 981 and €13 551, respectively). The projected annual cost savings reached €13.6 million nationally, if all adult RA patients treated with the originator infliximab switched to the biosimilar drug. These savings, if fully reallocated for the treatment of RA, would enable the treatment of 1141 additional patients. CONCLUSIONS: The study showed a positive financial impact of introducing biosimilar infliximab for the treatment of RA patients in France. Such savings could contribute to improved patient care by allowing more patients to be treated without more money being spent.

[Prostate cancer incidence and mortality trends in France from 1980 to 2011]. / Le cancer de la prostate, évolution de l'incidence et de la mortalité en France entre 1980 et 2011.

UNLABELLED: The prostate cancer became for two decades the most frequent cancer in men. We describe the evolution of its incidence and mortality from 1980 to 2011 for France. METHODS: Incidence data were collected from registries and national incidence estimates were based on the use of mortality as a correlate of incidence. RESULTS: After a very strong increase of incidence between 1980 (24.8/100,000) and 2005 (124.5/100,000), we observe a net decline since (97.7/100,000, in 2011). The reduction began earlier for the old patients. The evolution of mortality is very different. We observe a regular reduction since the end of 1990s (from 18.0/100,000 in 1990 to 10.5/100,000 in 2011). The reduction began earlier for the young patients. CONCLUSION: This pattern of evolution is observed in all the countries where the use of the PSA had caused an important increase of the diagnosis of prostate cancer. LEVEL OF EVIDENCE: 3.

Trends in breast cancer incidence and mortality in France 1990-2008.

The objective of this work was to detail the incidence and mortality trends of invasive and in situ breast cancer (BC) in France, especially regarding the development of screening, over the 1990-2008 period. Data issued from nine population-based cancer registries were studied. The incidence of invasive BC increased annually by 0.8 % from 1990 to 1996 and more markedly by 3.2 % from 1996 to 2003, and then sharply decreased until 2006 (-2.3 % per year), especially among women aged 50-69 years (-4.9 % per year). This trend was similar whatever the introduction date of the organized screening (OS) program in the different areas. The incidence of ductal carcinoma in situ steadily increased between 1990 and 2005, particularly among women aged 50-69 years and 70 and older. At the same time, the mortality from BC decreased annually by 1.1 % over the entire study period. This decrease was more pronounced in women aged 40-49 and 50-69 and, during the 1990-1999 period, in the areas where OS began in 1989-1991. The similarity in the incidence trends for all periods of implementation of OS in the different areas was striking. This suggests that OS alone does not explain the changes observed in incidence rate. Our study highlights the importance of closely monitoring the changes in incidence and mortality indicators, and of better understanding the factors causing variation.

Role of thyroid surgery in the obstructive sleep apnea syndrome.

OBJECTIVES: To study the impact of thyroid surgery on obstructive sleep apnea syndrome (OSAS) evaluated by the apnea/hypopnea index (AHI) was studied. Secondary objectives were to evaluate the impact on the positional component of OSAS and to highlight possible predictors of improvement of OSAS after thyroidectomy. METHODS: Twenty-eight patients with OSAS are included in this monocentric study: they underwent total thyroidectomy (n = 26) or left loboisthmectomy. Postoperative assessment involves a nocturnal control polysomnography as of 60 days after surgery. RESULTS: The mean age at the time of surgery is 61.3 years (standard deviation ±7.3) and average body mass index is 29.6 kg/m2 (±7.3). Continuous positive airway pressure (CPAP) treatment is introduced preoperatively in 82% of patients. The statistical analysis shows a significant decrease of 33% in postoperative AHI for the total population (p = 0.001), 77% in patients under CPAP (p = 0.05), and 27% in patients without CPAP (p = 0.02). CPAP therapy could be released in four patients. Given the limited number of subjects studied, the surgery did not impact on the positional component of the OSAS. Statistical analysis failed to link a predictive factor to AHI reduction. CONCLUSIONS: We propose thyroid surgery as an alternative or as a complement to CPAP treatment for the patients with goitre: it allows a significant decrease in postoperative AHI, allowing adaptation of the CPAP treatment downward, or even a release in some cases. These results need to be confirmed on a larger series of patients in a prospective study with standardized criteria for polysomnography and multivariate analysis.

Asthma among workers in healthcare settings: role of disinfection with quaternary ammonium compounds.

INTRODUCTION: An increased incidence of asthma has been reported among healthcare workers. The role of quaternary ammonium compounds (QACs), commonly used in cleaning/disinfection products, has not been clearly defined. The aim of this study was to analyse associations between asthma and occupational exposure to disinfectants, especially QACs. METHODS: The study was performed on a stratified random sample of the various healthcare departments of 7 healthcare settings. The study included: questionnaire, physical examination and specific IgE assays. Occupational exposure assessment was performed by means of a work questionnaire, workplace studies and a review of products ingredients. Data were analysed by logistic regression. RESULTS: Response rate was 77%; 543 workers (89% female) participated; 37.1% were registered nurses (RNs), 16.4% auxiliary nurses (ANs), 17.3% cleaners; 32.8% were atopic. 335 participants were exposed to QACs. Nursing professionals reported a significantly higher risk of reported physician-diagnosed asthma and, for RNs, of nasal symptoms at work than administrative staff working in healthcare sector. This risk was particularly marked during disinfection tasks and when exposure to QACs. Exposure to QACs increased significantly the risk of reported physician-diagnosed asthma and nasal symptoms at work (adjusted OR = 7.5 and 3.2, respectively). No significant association was found with other exposures such as latex glove use, chlorinated products/bleach or glutaraldehyde. CONCLUSION: RNs and ANs presented a higher risk of reported asthma than administrative staff. The highest risk was associated with tasks involving dilution of disinfection products by manual mixing, suggesting possible exposure to repeated peaks of concentrated products known to be strong respiratory irritants. Workplace interventions should be conducted to more clearly determine QAC exposure and improve disinfection procedures.

Waiting time disparities in breast cancer diagnosis and treatment: a population-based study in France.

Waiting times are key indicators of a health's system performance, but are not routinely available in France. We studied waiting times for diagnosis and treatment according to patients' characteristics, tumours' characteristics and medical management options in a sample of 1494 breast cancers recorded in population-based registries. The median waiting time from the first imaging detection to the treatment initiation was 34 days. Older age, co-morbidity, smaller size of tumour, detection by organised screening, biopsy, increasing number of specimens removed, multidisciplinary consulting meetings and surgery as initial treatment were related to increased waiting times in multivariate models. Many of these factors were related to good practices guidelines. However, the strong influence of organised screening programme and the disparity of waiting times according to geographical areas were of concern. Better scheduling of diagnostic tests and treatment propositions should improve waiting times in the management of breast cancer in France.

Response shift effects on measuring post-operative quality of life among breast cancer patients: a multicenter cohort study.

PURPOSE: To characterize response shift effects in patients with breast cancer (BC). METHODS: The QLQ-C30, BR23, and EurQOL-EQ-5D were assessed at baseline and at the end of the first hospitalization. We used the then-test approach to characterize changes in internal standards by calculating the mean difference between the then-test (retrospective measure) and pre-test baseline QoL assessments. The Ideal Scale Approach was also used to assess changes in standards by comparing health and QoL expectancies between baseline and the end of the first hospitalization. Successive Comparison Approach was used to assess changes in values through the longitudinal assessment of the relative importance of EuroQOL dimensions. RESULTS: The results of this study showed that recalibration RS effects occurred early after the first hospitalization for 6/15 dimensions of QLQ-C30 (emotional, cognitive, fatigue, insomnia, appetite loss, diarrhea) and 2/8 of BR-23 (future perspective, systemic therapy side effects). Moreover, health and QoL expectancies changed between the baseline and the end of the first hospitalization, and changes in values were seen for the self-care and usual activities dimensions of the EuroQOL-EQ-5D. CONCLUSIONS: The occurrence of RS early after the first hospitalization suggests that it needs to be taken into account to interpret QoL changes in BC.

[Incidence and mortality of urological cancers in 2012 in France]. / Projection de l'incidence et de la mortalité par cancer urologique en France en 2012.

OBJECTIVES: Present national estimations of the incidence and mortality trends in urological cancers in France between 1980 and 2012. MATERIAL AND METHODS: Francim database and French Register of Cancers. RESULTS: Analysis of the current data shows a regular increase of the incidence of renal cancer in men and women (7,781 cases in men and 3,792 in women in 2012). For bladder cancer, trends are divergent. There is a small reduction in incidence for men and an increase for women (9,549 cases in men and 2,416 in women in 2012). Testicular cancer is still increasing slightly (2,317 incidental cases in 2012). The incidence of prostate cancer experienced a huge increase up until 2005, and thereafter it decreased sharply, though it is difficult to discern whether this drop (which was observed up until 2008) continued at the same rate after that point (56,841 incidences in 2012 based on the rates calculated for 2009). CONCLUSION: The analyses by organ database show that there are significant variations in the incidence of urological cancers, particularly for prostate cancer, which shows that both the natural history of urological tumours and the methods of detection have an impact on incidence.