Articular Cartilage Repair After Implantation of Hyaline Cartilage Beads Engineered From Adult Dedifferentiated Chondrocytes: Cartibeads Preclinical Efficacy Study in a Large Animal Model.

BACKGROUND: Chondrocyte-based cell therapy to repair cartilage has been used for >25 years despite current limitations. This work presents a new treatment option for cartilage lesions. HYPOTHESIS: High-quality hyaline cartilage microtissues called Cartibeads are capable of treating focal chondral lesions once implanted in the defect, by complete fusion of Cartibeads among themselves and their integration with the surrounding native cartilage and subchondral bone. STUDY DESIGN: Controlled laboratory study. METHODS: Cartibeads were first produced from human donors and characterized using histology (safranin O staining of glycosaminoglycan [GAG] and immunohistochemistry of collagen I and II) and GAG dosage. Cartibeads from 6 Göttingen minipigs were engineered and implanted in an autologous condition in the knee (4 or 5 lesions per knee). One group was followed up for 3 months and the other for 6 months. Feasibility and efficacy were measured using histological analysis and macroscopic and microscopic scores. RESULTS: Cartibeads revealed hyaline features with strong staining of GAG and collagen II. High GAG content was obtained: 24.6-µg/mg tissue (wet weight), 15.52-µg/mg tissue (dry weight), and 35 ± 3-µg GAG/bead (mean ± SD). Histological analysis of Göttingen minipigs showed good integration of Cartibeads grafts at 3 and 6 months after implantation. The Bern Score of the histological assay comparing grafted versus empty lesions was significant at 3 months (grafted, n = 10; nongrafted, n = 4; score, 3.3 and 5.3, respectively) and 6 months (grafted, n = 11; nongrafted, n = 3; score, 1.6 and 5.1). CONCLUSION: We developed an innovative 3-step method allowing, for the first time, the use of fully dedifferentiated adult chondrocytes with a high number of cell passage (owing to the extensive amplification in culture). Cartibeads engineered from chondrocytes hold potential as an advanced therapy medicinal product for treating cartilage lesions with established efficacy. CLINICAL RELEVANCE: This successful preclinical study, combined with standardized manufacturing of Cartibeads according to good manufacturing practice guidelines, led to the approval of first-in-human clinical trial by the ethics committee and local medical authority. The generated data highlighted a promising therapy to treat cartilage lesions from a small amount of starting biopsy specimen. With our innovative cell amplification technology, very large lesions can be treated, and older active patients can benefit from it.

Hyaline Cartilage Microtissues Engineered from Adult Dedifferentiated Chondrocytes: Safety and Role of WNT Signaling.

The repair of damaged articular cartilage is an unmet medical need. Chondrocyte-based cell therapy has been used to repair cartilage for over 20 years despite current limitations. Chondrocyte dedifferentiation upon expansion in monolayer is well known and is the main obstacle to their use as cell source for cartilage repair. Consequently, current approaches often lead to fibrocartilage, which is biomechanically different from hyaline cartilage and not effective as a long-lasting treatment. Here, we describe an innovative 3-step method to engineer hyaline-like cartilage microtissues, named Cartibeads, from high passage dedifferentiated chondrocytes. We show that WNT5A/5B/7B genes were highly expressed in dedifferentiated chondrocytes and that a decrease of the WNT signaling pathway was instrumental for full re-differentiation of chondrocytes, enabling production of hyaline matrix instead of fibrocartilage matrix. Cartibeads showed hyaline-like characteristics based on GAG quantity and type II collagen expression independently of donor age and cartilage quality. In vivo, Cartibeads were not tumorigenic when transplanted into SCID mice. This simple 3-step method allowed a standardized production of hyaline-like cartilage microtissues from a small cartilage sample, making Cartibeads a promising candidate for the treatment of cartilage lesions.

Generation of human induced pluripotent stem cell line UNIGEi003-A from skin fibroblasts of an apparently healthy male donor.

Dermal fibroblasts isolated from an apparently healthy 50-year-old man were successfully transformed into induced pluripotent stem cells (iPSCs) by using the integration-free CytoTune-iPS Sendai Reprogramming method. The generated iPSC line has been expanded under feeder-free conditions and displayed all hallmarks of a standard pluripotent stem cell line such as a normal karyotype, expression of pluripotent factors and differentiation capacity into the three germ layers.

Biomarkers for acute kidney injury in decompensated cirrhosis: A prospective study.

AIM: Acute kidney injury (AKI) is a frequent complication in cirrhotic patients. As serum creatinine is a poor marker of renal function in this population, we aimed to study the utility of several biomarkers in this context. METHODS: A prospective study was conducted in hospitalized patients with decompensated cirrhosis. Serum creatinine (SCr), Cystatin C (CystC), NGAL and urinary NGAL, KIM-1, protein, albumin and sodium were measured on three separate occasions. Renal resistive index (RRI) was obtained. We analyzed the value of these biomarkers to determine the presence of AKI, its aetiology [prerenal, acute tubular necrosis (ATN), or hepatorenal (HRS)], its severity and a composite clinical outcome at 30 days (death, dialysis and intensive care admission). RESULTS: We included 105 patients, of which 55 had AKI. SCr, CystC, NGAL (plasma and urinary), urinary sodium and RRI at inclusion were independently associated with the presence of AKI. SCr, CystC and plasma NGAL were able to predict the subsequent development of AKI. Pre-renal state showed lower levels of SCr, NGAL (plasma and urinary) and RRI. ATN patients had high levels of NGAL (plasma and urinary) as well as urinary protein and sodium. HRS patients presented an intermediate pattern. All biomarkers paralleled the severity of AKI. SCr, CystC and plasma NGAL predicted the development of the composite clinical outcome with the same performance as the MELD score. CONCLUSIONS: In patients with decompensated cirrhosis, early measurement of renal biomarkers provides valuable information on AKI aetiology. It could also improve AKI diagnosis and prognosis.

Admission rates in emergency departments in Geneva during tennis broadcasting: a retrospective study.

BACKGROUND: Literature provides mixed results regarding the influence of large-scale sporting events on emergency department attendance. To contribute to the research on the subject, we sought to evaluate whether the broadcasting of major tennis tournaments, one of the most popular sports in Switzerland, has an impact on patient admission rates in emergency units in Geneva including 1) type of match 2) the role of a Swiss player, 3) degree of triage, 4) reason of attendance and 5) age of patients. METHODS: Admission rates between periods with tennis matches regarding the semi-finals and finals of 3 major tennis tournaments were compared to equivalent periods without matches from May 2013 to August 2017. Patient admission data was retrieved retrospectively from administrative databases of two Outpatient Emergency Units in Geneva. Patients' admission rates in periods with and without a tennis match were investigated using a negative binomial regression model with mixed effects. RESULTS: We observed a statistically significant decrease (- 10%, 95% CI -17 to - 2, p = 0.015) in admission rates in periods with a tennis match compared to periods without a tennis match, more pronounced during finals (- 15%, 95% CI -26 to - 3, p = 0.017) than during semi-finals (- 7%, - 16 to 2, p = 0.13). In addition, this effect was more pronounced in patients aged between 26 to 64 years of age, a category representing professionnally active people. No modification in the admission rates was detected in the hours preceding and following the matches, nor in type of consultations (traumatology vs non traumatology related admissions). CONCLUSION: Although modest, the results support the hypothesis that the broadcasting of large-scale sporting events such as tennis matches decreases admission rates in emergency units. Further research is required to explore for a potential causal relationship.

Comparison of Cardiac and Non-Cardiac Biomarkers for Risk Stratification in Elderly Patients with Non-Massive Pulmonary Embolism.

UNLABELLED: Biomarkers unrelated to myocardial necrosis, such as cystatin C, copeptin, and mid-regional pro-adrenomedullin (MR-proADM), showed promise for cardiovascular risk prediction. Knowing whether they are comparable to cardiac biomarkers such as high-sensitive cardiac-troponin T (hs-cTnT) or N-terminal pro-Brain natriuretic peptide (NT-proBNP) in elderly patients with acute non-massive pulmonary embolism (NMPE) remains elusive. This study aims at comparing the prognostic accuracy of cardiac and non-cardiac biomarkers in patients with NMPE aged ≥65 years over time. In the context of the SWITCO65+ cohort, we evaluated 227 elderly patients with an available blood sample taken within one day from diagnosis. The primary study endpoint was defined as PE-related mortality and the secondary endpoint as PE-related complications. The biomarkers' predictive ability at 1, 3, 12 and 24 months was determined using C-statistics and Cox regression. For both study endpoints, C-statistics (95% confidence interval) were stable over time for all biomarkers, with the highest value for hs-cTnT, ranging between 0.84 (0.68-1.00) and 0.80 (0.70-0.90) for the primary endpoint, and between 0.74 (0.63-0.86) and 0.65 (0.57-0.73) for the secondary endpoint. For both study endpoints, cardiac biomarkers were found to be independently associated with risk, NT-proBNP displaying a negative predictive value of 100%. Among non-cardiac biomarkers, only copeptin and MR-proADM were independent predictors of PE-related mortality but they were not independent predictors of PE-related complications, and displayed lower negative predictive values. In elderly NMPE patients, cardiac biomarkers appear to be valuable prognostic to identify very low-risk individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT00973596.

Suspicion of heparin-induced thrombocytopenia in internal medicine: How appropriate is the ordering of anti-PF4/heparin antibody testing?

Thrombocytopenia is frequent in hospitalized patients, and heparin-induced thrombocytopenia (HIT) is often suspected when a decrease in platelet count is concomitant with heparin treatment. ELISA tests used for anti-PF4/heparin antibodies detection usually have high sensitivity but only fair specificity for HIT. Pre-test probability scores (such as 4 Ts or HEP scores) have been validated and a low probability score rules out HIT without anti-PF4/heparin testing. The aims of this study are to evaluate the appropriateness of anti-PF4/heparin testing according to pre-test probabilities of HIT and to compare the abilities of the 4 Ts and HEP scores to avoid inappropriate anti-PF4/heparin testing. This retrospective observational study included 74 consecutive patients hospitalized in a general internal medicine division who had anti-PF4/heparin testing for suspicion of HIT. 4 Ts and HEP scores were computed retrospectively. About 73% of patients who had ordering of an anti-PF4/heparin were at low risk according to the 4 Ts score, and 46% according to the HEP score. Heparin was discontinued in 61% and 62% of low-risk patients according to 4 Ts and HEP scores and switched to alternative anticoagulant in 31% and 32% of them, respectively. No case of HIT was diagnosed in patients with a low-risk score. One major bleeding and no thrombosis were observed. For the 4 Ts score, the sensitivity was 100%, the negative predictive value (NPV) was 100%, the specificity was 77%, and the positive predictive value (PPV) was 20% (95% CI: 7-44). For the HEP score, the sensitivity was 100%, the NPV was 100%, the specificity was 49%, and the PPV was 10%. In conclusion, pre-test probability scores were vastly underused in this internal medicine population despite their ability to rule out HIT without laboratory testing in a large proportion of patients. Appropriate use of those instruments should be actively promoted.

Acute respiratory and cardiovascular admissions after a public smoking ban in Geneva, Switzerland.

BACKGROUND: Many countries have introduced legislations for public smoking bans to reduce the harmful effects of exposure to tobacco smoke. Smoking bans cause significant reductions in admissions for acute coronary syndromes but their impact on respiratory diseases is unclear. In Geneva, Switzerland, two popular votes led to a stepwise implementation of a state smoking ban in public places, with a temporary suspension. This study evaluated the effect of this smoking ban on hospitalisations for acute respiratory and cardiovascular diseases. METHODS: This before and after intervention study was conducted at the University Hospitals of Geneva, Switzerland, across 4 periods with different smoking legislations. It included 5,345 patients with a first hospitalisation for acute coronary syndrome, ischemic stroke, acute exacerbation of chronic obstructive pulmonary disease, pneumonia and acute asthma. The main outcomes were the incidence rate ratios (IRR) of admissions for each diagnosis after the final ban compared to the pre-ban period and adjusted for age, gender, season, influenza epidemic and secular trend. RESULTS: Hospitalisations for acute exacerbation of chronic obstructive pulmonary disease significantly decreased over the 4 periods and were lowest after the final ban (IRR=0.54 [95%CI: 0.42-0.68]). We observed a trend in reduced admissions for acute coronary syndromes (IRR=0.90 [95%CI: 0.80-1.00]). Admissions for ischemic stroke, asthma and pneumonia did not significantly change. CONCLUSIONS: A legislative smoking ban was followed by a strong decrease in hospitalisations for acute exacerbation of chronic obstructive pulmonary disease and a trend for reduced admissions for acute coronary syndrome. Smoking bans are likely to be very beneficial for patients with chronic obstructive pulmonary disease.

Urinary incontinence as a marker of higher mortality in patients receiving home care services.

OBJECTIVE: To evaluate urinary incontinence (UI) as a predictor of nursing home admission, hospitalization or death in patients receiving home care services. SUBJECTS AND METHODS: A total of 699 community-dwelling participants receiving home care services in Geneva were evaluated in Autumn 2004 using the Minimal Data Set-Home Care, a validated instrument that includes grading of UI. Data on death, hospitalization and nursing home admission were collected up until June 2007. The impact of UI on time-dependent outcomes was analysed using survival analysis and multivariate regression Cox models to adjust for age, gender, body mass index, cardiac failure, cognitive impairment, delirium, depression, disability, alcohol and tobacco use, self-rated health, faecal incontinence and number of medications. RESULTS: We found that UI was present in 193 participants (27.8%). After adjustment for confounding factors, UI was associated with a longer length of hospital stay: +36.7 days, (95% confidence interval [CI]: 1.2-72.3) and a higher mortality rate (hazard ratio [HR] 1.6; 95% CI: 1.1-2.6). The HR for death was 1.5 (95% CI: 0.9-2.5) for participants complaining of one episode of urinary leakage per week at most, 2.0 (95% CI: 1.2-3.5) for those presenting with two or more episodes per week and 4.2 (95% CI: 2.3-7.7; P for trend: <0.001) for daily UI compared with participants without UI. Institutionalization (HR 1.1; 95% CI: 0.6-2.2) and hospitalization rates (HR 1.0; 95% CI: 0.7-1.3) were not different between patients with or without UI. CONCLUSION: In a cohort of patients receiving home care services, UI was a strong predictor of length of hospital stay and mortality, increasing with UI severity.

Inclusion into a heart failure critical pathway reduces the risk of death or readmission after hospital discharge.

BACKGROUND: Evidence-based therapies can lower the risk of death or hospital admission in heart failure (HF) patients, but are underprescribed. Critical pathways are one means of supporting systematic use of evidence-based recommendations. METHODS: Patients admitted for HF in one hospital in 2009 and included in a critical pathway were compared with a control group of patients admitted in 2007. The primary endpoint was the risk of death or readmission within 90 days after discharge. The hazard ratio of death or readmission was evaluated in a multivariate Cox proportional hazard model adjusting for age, sex, co-morbidities, and length of stay. RESULTS: Three hundred and sixty-three patients were evaluated (151 in the critical pathway and 212 in the control group). Adjusted hazard ratio for death or readmission at 90 days was 0.72 (95 CI 0.51-1.00, p=0.049). Adhesion to guidelines was significantly better for patients included in the critical pathway (p=0.004), with more frequent prescription of beta-blockers (70.9% (95% CI 62.9-78.0) vs. 56.6% (95% CI 49.6-63.4), p=0.006), and evaluation of left ventricular ejection fraction (LVEF, 73.5% (95% CI 65.7-80.3) vs. 57.5% (95% CI 50.6-64.3), p=0.002). Patients with reduced LVEF seem to have benefited the most from the inclusion in the critical pathway. CONCLUSIONS: Implementation of a critical pathway for patients hospitalized for HF was associated with a 28% reduction of the relative risk of death or readmission and improved adhesion to guidelines.

A survival analysis of the liver-first reversed management of advanced simultaneous colorectal liver metastases: a LiverMetSurvey-based study.

BACKGROUND: Liver-first reversed management (RM) for the treatment of patients with simultaneous colorectal liver metastases (CRLM) includes liver-directed chemotherapy, the resection of the CRLM, and the subsequent resection of the primary cancer. Retrospective data have shown that up to 80% of patients can successfully undergo a complete RM, whereas less than 30% of those undergoing classical management (CM) do so. This registry-based study compared the 2 approaches. METHODS: The study was based on the LiverMetSurvey (January 1, 2000 to December 31, 2010) and included patients with 2 or more metastases. All patients had irinotecan and/or oxaliplatin-based chemotherapy before liver surgery. Patients undergoing simultaneous liver and colorectal surgery were excluded. RESULTS: A total of 787 patients were included: 729 in the CM group and 58 in the RM group. Patients in the 2 groups had similar numbers of metastases (4.20 vs 4.80 for RM and CM, P = 0.231) and Fong scores of 3 or more (79% vs 87%, P = 0.164). Rectal cancer, neoadjuvant rectal radiotherapy, and the use of combined irinotecan/oxaliplatin chemotherapy were more frequent in the RM group (P < 0.001), whereas colorectal lymph node involvement was more frequent in the CM group (P < 0.001). Overall survival and disease-free survival were similar in the RM and CM groups (48% vs 46% at 5 years, P = 0.965 and 30% vs 26%, P = 0.992). CONCLUSIONS: Classical and reversed managements of metastatic liver disease in colorectal cancer are associated with similar survival when successfully completed.

A score predicting survival after liver retransplantation for hepatitis C virus cirrhosis.

BACKGROUND: Approximately one fourth of patients transplanted for hepatitis C virus (HCV)-induced liver failure progress to cirrhosis within 5 years, potentially requiring retransplantation. Although the relisting decision can be difficult in these patients, a score could help in selection of candidates with the best potential outcomes. METHODS: A total of 1422 HCV-positive patients having undergone a retransplantation were included in this registry-based study. A multivariate Cox regression was performed, and an Akaike procedure was applied to design a score predicting survival after retransplantation and to allow an internal validation. Retained variables were donor age (DnAge), serum creatinine (Creat), International Normalized Ratio (INR), and serum albumin (Alb) at the second transplantation, recipient age (RecAge) at the first transplantation, and the interval between both transplantations (Int). RESULTS: The score was designed as 0.23×DnAge+4.86×log Creat-2.45×log Int+2.69×INR+0.10×RecAge-3.27× Alb+40. The receiver operating characteristic area under curve was 0.643 at 3 years, and survivals were 71%, 56%, and 37% for scores <30, 30 to 40, and >40, respectively (log rank <0.0001). CONCLUSIONS: Overall, the proposed score is specifically designed for HCV-positive patients, accurately predicts survival after a liver retransplantation, and is helpful in the selection of candidates with the best potential outcomes.

[Is there a role for prophylactic antibiotic treatment with macrolides in bronchiectasis?]. / Ouelle est la place de l'antibio- thérapie prophylactique par macro- lides dans les bronchiectasies?

Prophylactic antibiotherapy with macrolides is commonly used to prevent bronchiectasis exacerbations. Indeed, there is evidence that macrolides possess immunomodulatory and anti-inflammatory properties, which explains their possible efficacy in this condition despite the presence of resistant germs. This treatment seems to improve the clinical evolution of bronchectasis and to reduce the frequency and intensity of the exacerbations. However, available data concerning this issue is limited and remains insufficient to recommend its systematic use. Until larger studies with long-term follow up are available, the use of macrolides in bronchiectasis should be restricted to selected cases and should take into account their potential side effects.

[Should we believe in the interaction between proton pump inhibitors (PPI) and clopidogrel]. / Faut-il croire à l'interaction entre les inhibiteurs de la pompe à protons et le clopidogrel?

Recently, some authors have examined the possibility of an interaction between proton pump inhibitors (especially omeprazole) and clopidogrel. Pharmacodynamically, this interaction is proven and leads to a reduction in anti-aggregation activity. Nevertheless, the clinical implications are not fully clarified. We are all waiting for a randomised prospective study assessing specifically this issue. Meanwhile, caution is recommended when prescribing PPI in patients taking clopidogrel.

[Hospital based internal medicine: the year 2009 in review (2)]. / Médecine interne hospitalière: l'année 2009 en revue (2).

The recommended best clinical management of common pathologies encountered in the practice of internal medicine in a hospital setting evolves with time. This selective review covers recent studies that may significantly contribute to the decision process at several stages of such management. The areas that are addressed are those of screening, namely for coronary heart disease in diabetic patients, and those of therapeutic choices, such as for severe pneumonia, hypertension as well as coronary heart disease and anemia in patients with renal failure. The presurgical evaluation of lung cancer, the level of glucose control to be achieved in the intensive care unit, and novel methods of teaching medicine are also discussed.

[Severe community-acquired pneumonia: which score for determining the in-hospital level of care?]. / Pneumonie sévère: scores a utiliser pour orienter la prise en charge intrahospitalière.

Patients presenting with severe community-acquired pneumonia (CAP) should be accurately identified, since they need admission to acute care units. Prognostic scores routinely used for CAP (PSI and CURB-65) predict 30-day mortality, and are helpful for hospitalization decisions. However, 30-day death risk is largely determined by age and comorbidities, and does not correlate well with the severity of CAP. PSI and CURB-65 are therefore not efficient for identifying patients who require intensive monitoring. Specifically developed scores are either not accurate enough or insufficiently validated to help determine the best site of care for hospitalized patients with CAP.

Duration of withdrawal of life support in the intensive care unit and association with family satisfaction.

RATIONALE: Most deaths in the intensive care unit (ICU) involve withholding or withdrawing multiple life-sustaining therapies, but little is known about how to proceed practically and how this process affects family satisfaction. OBJECTIVES: To examine the duration of life-support withdrawal and its association with overall family satisfaction with care in the ICU. METHODS: We studied family members of 584 patients who died in an ICU at 1 of 14 hospitals after withdrawal of life support and for whom complete medical chart and family questionnaires were available. MEASUREMENTS AND MAIN RESULTS: Data concerning six life-sustaining interventions administered during the last 5 days of life were collected. Families were asked to rate their satisfaction with care using the Family Satisfaction in the ICU questionnaire. For nearly half of the patients (271/584), withdrawal of all life-sustaining interventions took more than 1 day. Patients with a prolonged (>1 d) life-support withdrawal were younger, stayed longer in the ICU, had more life-sustaining interventions, had less often a diagnosis of cancer, and had more decision makers involved. Among patients with longer ICU stays, a longer duration in life-support withdrawal was associated with an increase in family satisfaction with care (P = 0.037). Extubation before death was associated with higher family satisfaction with care (P = 0.009). CONCLUSIONS: Withdrawal of life support is a complex process that depends on patient and family characteristics. Stuttering withdrawal is a frequent phenomenon that seems to be associated with family satisfaction. Extubation before death should be encouraged if possible.

Patients' knowledge of drug treatments after hospitalisation: the key role of information.

QUESTION UNDER STUDY: Patients often do not know the reasons for taking their medications after hospital discharge. We investigated whether lack of such knowledge was associated with patients' report of not having received information about their medications while hospitalised. METHODS: Patients with at least one long-term drug (ie, prescribed for more than 30 days) discharged from the wards of general internal medicine of a teaching hospital were included in the study. Patients' knowledge of the reasons for taking these drugs and their report of having received information while hospitalised were assessed by phone one week after discharge. RESULTS: 362 (98.6%) of 367 enrolled patients could be interviewed and provided data on 1693/1871 (90.5%) long-term drugs prescribed at discharge. Patients knew the reasons for taking 1382 (81.6%) drugs and reported having received information about 259 (15.3%) of them. In the adjusted analysis, the reason for taking a drug was less likely to be known when introduced during hospitalisation (OR: 0.7; 95%CI: 0.5 to 0.9), among older patients (OR for > or =80 years of age v/s 20-59: 0.41; 95%CI: 0.22 to 0.76) and among those staying longer (OR per additional hospital day: 0.96; 95%CI: 0.94 to 0.99); such knowledge was strongly and positively associated with the report of having received information during hospitalisation (OR: 7.3; 95%CI: 3.2 to 16.1). CONCLUSION: Patients' report of having received information about their long-term drugs during hospitalisation was associated with a significantly higher knowledge of the reasons for taking them. However, receipt of such information was only infrequently reported.