Impact of geriatric co-management on outcomes in hospitalised cardiology patients aged 85 and over.

OBJECTIVE: Cardiovascular disease and frailty are common among the population aged 85+. We hypothesised these patients might benefit from geriatric co-management, as has been shown in other frail patient populations. However, there is limited evidence supporting geriatric co-management in older, hospitalised cardiology patients. METHODS: A retrospective cohort study was performed in a large teaching hospital in the Netherlands. We compared patients aged 85 and over admitted to the cardiology ward before (control group) and after the implementation of standard geriatric co-management (intervention group). Data on readmission, mortality, length of stay, number of consultations, delirium, and falls were analysed. RESULTS: The data of 1163 patients were analysed (n = 542 control, n = 621 intervention). In the intervention group, 251 patients did not receive the intervention because of logistic reasons or the treating physician's decision. Baseline characteristics were comparable in the intervention and control groups. Patients in the intervention group had a shorter length of stay (-1 day, p = 0.01) and were more often discharged to a geriatric rehabilitation facility (odds ratio [OR] 1.97, 95% confidence interval [CI] 1.10-3.54, p = 0.02) compared with the control patients. Other outcomes were not significantly different between the groups. CONCLUSIONS: After implementation of standard geriatric co-management for hospitalised cardiology patients aged 85 and over, the length of hospital stay shortened and the number of patients discharged to a geriatric rehabilitation facility increased. The adherence to geriatric team recommendations was high. Geriatric co-management would appear to optimise care for older hospitalised patients with cardiac disease.

Effect of conventional hemodialysis on the apixaban plasma concentration.

PURPOSE: Apixaban is a factor Xa inhibitor used in patients undergoing hemodialysis treatment. The objective of this study is to investigate the effect of hemodialysis on apixaban plasma concentrations. METHODS: This observational study is on patients treated with apixaban 2.5 mg twice daily on conventional hemodialysis with standard low-molecular-weight heparin (LMWH) anticoagulation (nadroparin 3800-7600 IU). Plasma blood samples were collected before starting dialysis (t1), 2 h after starting dialysis (t2), and directly after dialysis (t3). Apixaban concentration was measured before and after dialysis. Anti-Xa activity was measured for all three samples. RESULTS: A significant difference was observed between the apixaban concentration before and after dialysis (mean before dialysis 141.03 ng/mL; mean after dialysis 102.71 ng/mL; p = 0.003). Nonetheless, both apixaban plasma concentrations and anti-Xa levels remained within the reference range. Anti-Xa levels had a strong correlation with the apixaban concentrations (r = 0.935, p = 0.000). Thus, anti-Xa activity might be used as a surrogate for apixaban plasma concentration. CONCLUSION: There seems to be no need for dose adjustments of apixaban; co-administration of LMWH next to apixaban might also be unnecessary.

Apathy Symptoms, Physical and Cognitive Function, Health-Related Quality of Life, and Mortality in Older Patients With CKD: A Longitudinal Observational Study.

RATIONALE & OBJECTIVE: Apathy reflects diminished motivation, goal-directed behavior, and emotions, as well as less engagement in social interactions. Apathy overlaps with depression and is associated with cognitive decline. In the older individuals with chronic kidney disease (CKD), both depression and cognitive impairments are common, but apathy symptoms have been underreported. We investigated the occurrence of apathy symptoms and their associations with physical and cognitive functioning, health-related quality of life (HRQoL), and mortality in older patients with CKD. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 180 outpatients aged≥65 years with estimated glomerular filtration rate≤20mL/min/1.73m2 from 5 Dutch nephrology centers. EXPOSURE: Apathy symptoms at baseline were considered present when a Geriatric Depression Scale's 3-item apathy subscale score was≥2 points. OUTCOME: Physical and cognitive functioning, HRQoL (assessed in annual geriatric assessments), and 4-year mortality. ANALYTICAL APPROACH: Linear regression for cross-sectional associations, linear regression models for longitudinal associations, and Cox regression models for mortality over 4 years of observation. RESULTS: Apathy symptoms were present in 64 patients (36%; 67% men; median age 75.5 years), of whom 32 (50%) had no depressive symptoms. At baseline, the presence of apathy symptoms was associated with significantly more frailty, more functional dependence, less physical capacity, lower visuoconstructive performance, worse delayed recall, and lower HRQoL scores. The presence of apathy symptoms at baseline was also associated with a higher mortality risk (hazard ratio, 2.3 [95% CI, 1.3-4.2], P=0.005 adjusted for age, sex, and high education level), but not with changes in physical and cognitive functioning or HRQoL during the follow-up period. LIMITATIONS: Risk of selection bias and residual confounding. CONCLUSIONS: Apathy symptoms were highly prevalent and associated with concurrent lower physical and cognitive status, lower HRQoL, and increased mortality. These findings highlight apathy as a potentially important clinical phenotype in older CKD patients. PLAIN-LANGUAGE SUMMARY: We observed that older kidney patients often present apathy symptoms, such as less motivation, fewer goal-directed behaviors, fewer emotions, and less social engagement. Prior research has not extensively described apathy in kidney disease. We investigated the link between apathy symptoms and poor outcomes. We measured physical functioning, cognitive functioning, and quality of life. We learned that one-third of our older kidney patients showed symptoms of apathy, only half of whom had symptoms of depression. Patients with apathy symptoms showed lower quality of life and lower physical and cognitive performance. They also had a higher risk of death. These findings highlight the need for awareness of apathy symptoms in older kidney patients.

Concurrent lithium and haemodialysis treatment: Clinical recommendations based on the literature and a multicentre survey.

INTRODUCTION: Lithium has an irreplaceable role in the treatment of severe mood disorders, but declining renal function associated with its use leads to clinical dilemmas. Although not often applied, and requiring close monitoring and multidisciplinary actions, concurrent lithium and haemodialysis treatment (CLHT) is a feasible option. To our knowledge, however, there are no detailed consensus- or evidence-based treatment guidelines or directives on its delivery. METHODS: To fill this gap, we reviewed the literature and surveyed psychiatrists and nephrologists with experience in CLHT using a self-designed questionnaire. Our goal was to form an integrated picture of the current knowledge and clinical practices of CLHT and formulate practical recommendations for colleagues being confronted with patients with renal dysfunction requiring lithium to help manage their mood disorder. RESULTS: We identified 14 case reports and case series describing CLHT and one systematic review concluding CLHT to be effective. Ten nephrologists and six psychiatrists practising in the Netherlands completed our questionnaire, providing details on collaboration, lithium dosing regimens, serum level evaluations and additional amenities and services they deemed necessary during CLHT delivery. DISCUSSION: We found that CLHT appears to be safe and effective and argue that delivery is a shared responsibility and needs continuous multidisciplinary finetuning. To facilitate delivery, we provide a flowchart for the initiation or reinstatement of lithium therapy in haemodialysis patients and a practical guide for CLHT, including an easy-to-use rule of thumb for calculating the lithium target dose.

Registered report protocol: A scoping review to identify potential predictors as features for developing automated estimation of the probability of being frail in secondary care.

INTRODUCTION: The impact of frailty surges, as the prevalence increases with age and the population age is rising. Frailty is associated with adverse health outcomes and increased healthcare costs. Many validated instruments to detect frailty have been developed. Using these in clinical practice takes time. Automated estimation of the probability of being frail using routinely collected data from hospital electronic health records (EHRs) would circumvent that. We aim to identify potential predictors that could be used as features for modeling algorithms on the basis of routine hospital EHR data to incorporate in an automated tool for estimating the probability of being frail. METHODS: PubMed (MEDLINE), CINAHL Plus, Embase, and Web of Science will be searched. The studied population consists of older people (≥65 years). The first step is searching articles published ≥2018. Second, we add two published literature reviews (and the articles included therein) [Bery 2020; Bouillon, 2013] to our search results. In these reviews, articles on potential predictor variables in frailty screening tools were included from inception until March 2018. The goal is to identify and extract all potential predictors of being frail. Domain experts will be consulted to evaluate the results. DISCUSSION: The results of the intended study will increase the quality of the developed algorithms to be used for automated estimation of the probability of being frail in secondary care. This is a promising perspective, being less labor-intensive compared to screening each individual patient by hand. Also, such an automated tool may raise awareness of frailty, especially in those patients who would not be screened for frailty by hand because they seem robust. CONCLUSION: The identified potential predictors of being frail can be used as evidence-based input for machine learning based automated estimation of the probability of being frail using routine EHR data in the near future.

Sandwich Technique for Large Osteochondral Lesions of the Knee.

OBJECTIVE: To evaluate whether a sandwich technique procedure for large osteochondral lesions (OCL) of the medial femur condyle reduces clinical symptoms and improves activity level as well as to assess repair tissue integration on MRI over 2 years. DESIGN: Twenty-one patients (median age: 29 years, 18-44 years) who received matrix-associated autologous chondrocyte transplantation (MACT) combined with cancellous bone grafting at the medial femur condyle in a 1-step procedure were prospectively included. Patients were evaluated before surgery (baseline) as well as 3, 6, 12, and 24 months postoperatively, including clinical evaluation, Lysholm score, Tegner Activity Rating Scale, and MRI with Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score and a modified Whole-Organ Magnetic Resonance Imaging Score (WORMS). RESULTS: Seventeen patients were available for the 24-month (final) follow-up (4 dropouts). Lysholm significantly improved from 48 preoperatively stepwise to 95 at final follow-up (P < 0.05). Tegner improvement from 2.5 at baseline to 4.0 at final follow-up was not significant (P = 1.0). MOCART score improved significantly and stepwise from 65 at 3 months to 90 at 24 months (P < 0.05). Total WORMS improved from 14.5 at surgery to 7.0 after 24 months (P < 0.05). Body mass index and defect size at surgery correlated with total WORMS at final follow-up (P < 0.05) but did not correlate with clinical scores or defect filling. CONCLUSION: MACT combined with cancellous bone grafting at the medial femoral condyle reduces symptoms continuously over 2 years. A 1-step procedure may reduce perioperative morbidity. However, despite improvements, patients' activity levels remain low, even 2 years after surgery.

Dialysis or kidney transplantation in older adults? A systematic review summarizing functional, psychological, and quality of life-related outcomes after start of kidney replacement therapy.

BACKGROUND: In older patients, the choice between kidney transplantation (KT) and dialysis may be complicated because of a high prevalence of comorbidities and geriatric syndromes. Ideally, this decision-making process focusses on older patients' outcome priorities, which frequently include functional, psychological, and quality of life (QOL)-related outcomes. PURPOSE: This systematic review aims to summarize functional, psychological (including cognition), and QOL-related outcomes after start of kidney replacement therapy (KRT) in older adults. METHODS: We searched PubMed and Embase for research that investigated change in these variables after start of KRT in patients aged ≥ 60 years. Data were extracted using the summary measures reported in the individual studies. Risk of bias was assessed with the ROBINS-I tool. RESULTS: Sixteen observational studies (prospective n = 9, retrospective n = 7; KT-recipients n = 3, dialysis patients n = 13) were included. The results show that QOL improves in the majority of the older KT recipients. After start of dialysis, QOL improved or remained stable for most patients, but this seems less prevalent than after KT. Functional status decreases in a substantial part of the older dialysis patients. Furthermore, the incidence of serious fall injuries increases after start of dialysis. Nutritional status seems to improve after start of dialysis. CONCLUSION: The interpretability and comparability of the included studies are limited by the heterogeneity in study designs and significant risk of bias in most studies. Despite this, our overview of functional, psychological (including cognition), and QOL-related outcomes is useful for older adults and their clinicians facing the decision between KT and dialysis.

Kidney transplantation or dialysis in older adults-an interview study on the decision-making process.

BACKGROUND: In older patients with end-stage kidney disease (ESKD), the choice between kidney transplantation (KT) and dialysis may be more complex than in younger patients because of a higher prevalence of comorbidities and frailty. This study aims to provide greater insight into the current decision-making process by exploring the expectations, experiences and health outcome priorities of all stakeholders. METHODS: We performed semi-structured interviews with patients ≥65 years with ESKD (eGFR <15 ml/min/1.73m2, KT recipient or treated with dialysis), patients' relatives and healthcare professionals (nephrologists, nurses and medical social workers). Interviews were conducted until data saturation and thematically analysed. RESULTS: We performed 36 interviews (patients n = 18, relatives n = 5, healthcare professionals n = 13). Thematic analysis revealed five themes. Older patients' health outcome priorities were mostly related to quality of life (QOL). Individual older patients showed marked differences in the preferred level of engagement during the decision-making process (varying from 'wants to be in the lead' to 'follows the nephrologist') and in informational needs (varying from evidence-based to experience-based). On the contrary, healthcare professionals were quite unanimous on all aspects. They focused on determining eligibility for KT as start of the decision-making process, on clear and extensive information provision and on classical, medical outcomes. CONCLUSIONS: The decision-making process could benefit from early identification of older patients' values, needs and health outcome priorities, in parallel with assessment of KT eligibility and before discussing the treatment options, and the explicit use of this information in further steps of the decision-making process.

Bacillus Calmette-Guérin vaccine to reduce healthcare worker absenteeism in COVID-19 pandemic, a randomized controlled trial.

OBJECTIVES: The COVID-19 pandemic increases healthcare worker (HCW) absenteeism. The bacillus Calmette-Guérin (BCG) vaccine may provide non-specific protection against respiratory infections through enhancement of trained immunity. We investigated the impact of BCG vaccination on HCW absenteeism during the COVID-19 pandemic. METHODS: HCWs exposed to COVID-19 patients in nine Dutch hospitals were randomized to BCG vaccine or placebo in a 1:1 ratio, and followed for one year using a mobile phone application. The primary endpoint was the self-reported number of days of unplanned absenteeism for any reason. Secondary endpoints included documented COVID-19, acute respiratory symptoms or fever. This was an investigator-funded study, registered at ClinicalTrials.gov (NCT03987919). RESULTS: In March/April 2020, 1511 HCWs were enrolled. The median duration of follow-up was 357 person-days (interquartile range [IQR], 351 to 361). Unplanned absenteeism for any reason was observed in 2.8% of planned working days in the BCG group and 2.7% in the placebo group (adjusted relative risk 0.94; 95% credible interval, 0.78-1.15). Cumulative incidences of documented COVID-19 were 14.2% in the BCG and 15.2% in the placebo group (adjusted hazard ratio (aHR) 0.94; 95% confidence interval (CI), 0.72-1.24). First episodes of self-reported acute respiratory symptoms or fever occurred in 490 (66.2%) and 443 (60.2%) participants, respectively (aHR: 1.13; 95% CI, 0.99-1.28). Thirty-one serious adverse events were reported (13 after BCG, 18 after placebo), none considered related to study medication. CONCLUSIONS: During the COVID-19 pandemic, BCG-vaccination of HCW exposed to COVID-19 patients did not reduce unplanned absenteeism nor documented COVID-19.

Integrating healthcare for follow-up of adult COVID-19 patients in an outpatient clinic: A matter of cooperation.

RATIONALE AIMS AND OBJECTIVES: A large number of patients infected with SARS-CoV-2 (COVID-19) need outpatient follow-up after hospitalization. As these patients may experience a broad range of symptoms, as do patients infected with the related SARS-CoV-1 virus, we set up a multidisciplinary outpatient clinic involving pulmonologists, internists, and geriatricians. Patients were allocated to a specialist based on symptoms reported on a self-developed questionnaire of expected symptoms of COVID-19. This study aimed to evaluate the effectiveness of this outpatient clinic. METHODS: In this retrospective study, the medical records of patients who presented to the outpatient clinic for follow-up after hospitalization for COVID-19 up to 31 August 2020, were reviewed. RESULTS: In total, 266 patients were seen at the outpatient clinic at least once. Overall, 100 patients were seen by a pulmonologist, 97 by an internist, and 65 by a geriatrician. A referral between these 3 medical specialists was needed for only 14 patients (5.3%). Fifty patients were seen by a psychologist, mostly those with a HADS score >10. Only 5 (2.2%) of the 221 patients who were not directly referred to a psychologist based on triage needed psychological support. Forty-eight patients (18%) were also seen by a physiatrist. CONCLUSION: Identifying which medical specialist (pulmonologist, internist, and/or geriatrician) should see patients attending a post-COVID outpatient clinic based on patient-reported symptoms proved an effective approach to managing the flow of post-COVID patients.

Few bacterial co-infections but frequent empiric antibiotic use in the early phase of hospitalized patients with COVID-19: results from a multicentre retrospective cohort study in The Netherlands.

BACKGROUND: Knowledge on bacterial co-infections in COVID-19 is crucial to use antibiotics appropriately. Therefore, we aimed to determine the incidence of bacterial co-infections, antibiotic use and application of antimicrobial stewardship principles in hospitalized patients with COVID-19. METHODS: We performed a retrospective observational study in four hospitals (1 university, 2 non-university teaching, 1 non-teaching hospital) in the Netherlands from March to May 2020 including consecutive patients with PCR-confirmed COVID-19. Data on first microbiological investigations obtained at the discretion of the physician and antibiotic use in the first week of hospital admission were collected. RESULTS: Twelve (1.2%) of the 925 patients included had a documented bacterial co-infection (75.0% pneumonia) within the first week. Microbiological testing was performed in 749 (81%) patients: sputum cultures in 105 (11.4%), blood cultures in 711 (76.9%), pneumococcal urinary antigen testing in 202 (21.8%), and Legionella urinary antigen testing in 199 (21.5%) patients, with clear variation between hospitals. On presentation 556 (60.1%; range 33.3-73.4%) patients received antibiotics for a median duration of 2 days (IQR 1-4). Intravenous to oral switch was performed in 41 of 413 (9.9%) patients who received intravenous treatment >48 h. Mean adherence to the local guideline on empiric antibiotic therapy on day 1 was on average 60.3% (range 45.3%-74.7%). CONCLUSIONS: On presentation to the hospital bacterial co-infections are rare, while empiric antibiotic use is abundant. This implies that in patients with COVID-19 empiric antibiotic should be withheld. This has the potential to dramatically reduce the current overuse of antibiotics in the COVID-19 pandemic.

Immunosuppressive Drugs and COVID-19: A Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is currently unknown whether immunosuppressive drugs are advantageous or detrimental in patients with COVID-19. Immunosuppressive drugs could be harmful in the initial phase of COVID-19. In this phase, the host immune response is necessary to inhibit viral replication. However, immunosuppressive drugs might have a beneficial effect in the later, more severe phase of COVID-19. In this phase, an overshoot of the host immune response (the "cytokine storm") can cause ARDS, multiorgan failure and mortality. AIM: To summarize the available evidence on the effect of immunosuppressive drugs on infection with SARS-CoV-2. The effects of immunosuppressive drugs on similar pandemic coronaviruses may resemble the effects on SARS-CoV-2. Thus, we also included studies on the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). METHODS: The study protocol was registered in PROSPERO (registration number CRD42020181137). We included randomized controlled trials (RCTs), cohort studies with a control group and case-control studies concerning humans ≥ 18 years old. We also included in-vitro studies and animal studies with a control group. RESULTS AND CONCLUSION: Sixty-nine studies were included. Interestingly, MPA inhibits SARS-CoV-2 replication in-vitro. Clinical studies are needed to confirm the inhibitory effect of MPA on SARS-CoV-2 replication in-vivo. There are indications that corticosteroids and IL-6 inhibitors, like tocilizumab, can reduce mortality and prevent mechanical ventilation in patients with COVID-19. However, observational studies have contradictory results and the risk of bias is high. Thus, these results have to be confirmed in high-quality clinical trials before these drugs can be implemented as standard care. Based on the positive results of CNIs, mTOR inhibitors and thiopurine analogues in in-vitro studies with SARS-CoV and MERS-CoV, it would be interesting to investigate their effects on SARS-CoV-2 replication.

Platelet-rich plasma (PRP) as therapy for cartilage, tendon and muscle damage - German working group position statement.

PURPOSE: Platelet rich plasma (PRP) is widely used in orthopaedics, but is still heavily debated. Therefore, a survey among the German "Working Group for Clinical Tissue Regeneration" of the German Society of Orthopaedics and Traumatology was conducted to achieve a consensus about the current therapeutical potential of PRP. METHODS: A first survey (n = 65 experts, all orthopaedic/trauma surgeons) was conducted (n = 13 questions). Following, a second round (n = 40 experts) was conducted with 31 questions to achieve consensus in 5 categories: three most common indications, PRP application, future research areas. RESULTS: Therapeutic PRP application was regarded as useful (89%), possibly even more important in the future (90%). Most common indications were tendon pathologies (77%), osteoarthritis (OA) (68%), muscle injuries (57%) and cartilage damage (51%). Consensus was reached in 16/31 statements. The application of PRP for early knee OA (Kellgren-Lawrence grade II) was regarded as potentially useful, as well as for acute and chronic tendinopathies. For chronic lesions (cartilage, tendons), multiple injections (2-4) were seen preferable to singular injections. However, no sufficient data exists on the time interval between the injections. Standardization of PRP preparation, application, frequency, as well as determining the range of indication is strongly recommended. CONCLUSIONS: There is a need of further standardization of the PRP preparation methods, indication and application protocols for knee OA and other indications, which must be further evaluated in basic science studies and randomized controlled clinical trials. LEVEL OF EVIDENCE: Consensus of expert opinion, Level V.

A systems approach to inflammation identifies therapeutic targets in SARS-CoV-2 infection

BackgroundInfection with SARS-CoV-2 manifests itself as a mild respiratory tract infection in the majority of individuals, which progresses to a severe pneumonia and acute respiratory distress syndrome (ARDS) in 10-15% of patients. Inflammation plays a crucial role in the pathogenesis of ARDS, with immune dysregulation in severe COVID-19 leading to a hyperinflammatory response. A comprehensive understanding of the inflammatory process in COVID-19 is lacking. MethodsIn this prospective, multicenter observational study, patients with PCR-proven or clinically presumed COVID-19 admitted to the intensive care unit (ICU) or clinical wards were included. Demographic and clinical data were obtained and plasma was serially collected. Concentrations of IL-6, TNF-, complement components C3a, C3c and the terminal complement complex (TCC) were determined in plasma by ELISA. Additionally, 269 circulating biomarkers were assessed using targeted proteomics. Results were compared between ICU and non ICU patients. FindingsA total of 119 (38 ICU and 91 non ICU) patients were included. IL-6 plasma concentrations were elevated in COVID-19 (ICU vs. non ICU, median 174.5 pg/ml [IQR 94.5-376.3] vs. 40.0 pg/ml [16.5-81.0]), whereas TNF- concentrations were relatively low and not different between ICU and non ICU patients (median 24.0 pg/ml [IQR 16.5-33.5] and 21.5 pg/ml [IQR 16.0-33.5], respectively). C3a and terminal complement complex (TCC) concentrations were significantly higher in ICU vs. non ICU patients (median 556.0 ng/ml [IQR 333.3-712.5]) vs. 266.5 ng/ml [IQR 191.5-384.0] for C3a and 4506 mAU/ml [IQR 3661-6595] vs. 3582 mAU/ml [IQR 2947-4300] for TCC) on the first day of blood sampling. Targeted proteomics demonstrated that IL-6 (logFC 2.2), several chemokines and hepatocyte growth factor (logFC 1.4) were significantly upregulated in ICU vs. non ICU patients. In contrast, stem cell factor was significantly downregulated (logFC -1.3) in ICU vs. non ICU patients, as were DPP4 (logFC -0.4) and protein C inhibitor (log FC -1.0), the latter two factors also being involved in the regulation of the kinin-kallikrein pathway. Unsupervised clustering pointed towards a homogeneous pathogenetic mechanism in the majority of patients infected with SARS-CoV-2, with patient clustering mainly based on disease severity. InterpretationWe identified important pathways involved in dysregulation of inflammation in patients with severe COVID-19, including the IL-6, complement system and kinin-kallikrein pathways. Our findings may aid the development of new approaches to host-directed therapy. FundingVidi grant (F.L.v.d.V.) and Spinoza grant (M.G.N.) from the Netherlands Organization for Scientific Research, and ERC Advanced Grant (#833247 to M.G.N.).

Systematic review and practical guideline for the prevention and management of the renal side effects of lithium therapy.

Lithium is the first line therapy of bipolar mood disorder. Lithium-induced nephrogenic diabetes insipidus (Li-NDI) and lithium nephropathy (Li-NP, i.e., renal insufficiency) are prevalent side effects of lithium therapy, with significant morbidity. The objective of this systematic review is to provide an overview of preventive and management strategies for Li-NDI and Li-NP. For this, the PRISMA guideline for systematic reviews was used. Papers on the prevention and/or treatment of Li-NDI or Li-NP, and (influenceable) risk factors for development of Li-NDI or Li-NP were included. We found that the amount of evidence on prevention and treatment of Li-NDI and Li-NP is scarce. To prevent Li-NDI and Li-NP we advise to use a once-daily dosing schedule, target the lowest serum lithium level that is effective and prevent lithium intoxication. We emphasize the importance of monitoring for Li-NDI and Li-NP, as early diagnosis and treatment can prevent further progression and permanent damage. Collaboration between psychiatrist, nephrologist and patients themselves is essential. In patients with Li-NDI and/or Li-NP cessation of lithium therapy and/or switch to another mood stabilizer should be considered. In patients with Li-NDI, off label therapy with amiloride can be useful.

Cells under pressure - the relationship between hydrostatic pressure and mesenchymal stem cell chondrogenesis.

Early osteoarthritis (OA), characterised by cartilage defects, is a degenerative disease that greatly affects the adult population. Cell-based tissue engineering methods are being explored as a solution for the treatment of these chondral defects. Chondrocytes are already in clinical use but other cell types with chondrogenic properties, such as mesenchymal stem cells (MSCs), are being researched. However, present methods for differentiating these cells into stable articular-cartilage chondrocytes that contribute to joint regeneration are not effective, despite extensive investigation. Environmental stimuli, such as mechanical forces, influence chondrogenic response and are beneficial with respect to matrix formation. In vivo, the cartilage is subjected to multiaxial loading involving compressive, tensile, shear and fluid flow and cellular response. Tissue formation mechanobiology is being intensively studied in the cartilage tissue-engineering research field. The study of the effects of hydrostatic pressure on cartilage formation belongs to the large area of mechanobiology. During cartilage loading, interstitial fluid is pressurised and the surrounding matrix delays pressure loss by reducing fluid flow rate from pressurised regions. This fluid pressurisation is known as hydrostatic pressure, where a uniform stress around the cell occurs without cellular deformation. In vitro studies, examining chondrocytes under hydrostatic pressure, have described its anabolic effect and similar studies have evaluated the effect of hydrostatic pressure on MSC chondrogenesis. The present review summarises the results of these studies and discusses the mechanisms through which hydrostatic pressure exerts its effects.

Mechanosensitive MiRs regulated by anabolic and catabolic loading of human cartilage.

OBJECTIVE: Elucidation of whether miRs are involved in mechanotransduction pathways by which cartilage is maintained or disturbed has a particular importance in our understanding of osteoarthritis (OA) pathophysiology. The aim was to investigate whether mechanical loading influences global miR-expression in human chondrocytes and to identify mechanosensitive miRs responding to beneficial and non-beneficial loading regimes as potential to obtain valuable diagnostic or therapeutic targets to advance OA-treatment. METHOD: Mature tissue-engineered human cartilage was subjected to two distinct loading regimes either stimulating or suppressing proteoglycan-synthesis, before global miR microarray analysis. Promising candidate miRs were selected, re-evaluated by qRT-PCR and tested for expression in human healthy vs OA cartilage samples. RESULTS: After anabolic loading, miR microarray profiling revealed minor changes in miR-expression while catabolic stimulation produced a significant regulation of 80 miRs with a clear separation of control and compressed samples by hierarchical clustering. Cross-testing of selected miRs revealed that miR-221, miR-6872-3p, miR-6723-5p were upregulated by both loading conditions while others (miR-199b-5p, miR-1229-5p, miR-1275, miR-4459, miR-6891-5p, miR-7150) responded specifically after catabolic loading. Mechanosensitivity of miR-221 correlated with pERK1/2-activation induced by both loading conditions. The miR-response to loading was transient and a constitutive deregulation of mechano-miRs in OA vs healthy articular cartilage was not observed. CONCLUSIONS: MiRs with broader vs narrower mechanosensitivity were discovered and the first group of mechanosensitive miRs characteristic for non-beneficial loading was defined that may shape the proteome differentially when cartilage tissue is disturbed. The findings prompt future investigations into miR-relevance for mechano-responsive pathways and the corresponding miR-target molecules.

Degenerative isolated cartilage defects of the patellofemoral joint are associated with more severe symptoms compared to trauma-related defects: results of the German Cartilage Registry (KnorpelRegister DGOU).

PURPOSE: The purpose of this study was to utilize data from the German Cartilage Registry (KnorpelRegister DGOU) to examine the hypothesis that degenerative cartilage defects of the patellofemoral joint are associated with more severe clinical symptoms compared to trauma-related defects. METHODS: All patients with isolated focal cartilage defects of the patellofemoral joint registered in the German Cartilage Registry until May 2017 were included in the study. Patients with previous surgery of the ipsilateral knee were excluded. Baseline data including etiology (traumatic, degenerative), size, location and ICRS grade of the cartilage defects as well as the duration of symptoms were analyzed. Clinical symptoms were evaluated by means of the numeric analog scale (NAS) for pain and the Knee injury and Osteoarthritis Outcome Score (KOOS). Group comparisons were performed using the Mann-Whitney-U test along with the Chi-squared test and Fisher's exact test. A bivariate correlation analysis and a multivariable linear regression analysis were performed to investigate the association between the defect characteristics and the clinical scores. RESULTS: A total of 423 patients (203 traumatic and 220 degenerative defects) were included. Isolated degenerative cartilage defects were found to have significantly more trochlear locations (28% vs. 18%; p = 0.006), significantly less ICRS grade 4 lesions (50% vs. 73%; p = 0.002) and a significantly smaller defect size [median 300 (IQR 105-400) vs. 300 (200-400) mm2] when compared to those from traumatic etiology. Traumatic defects showed significantly better KOOS-ADL [77 (60-90) vs. 69 (56-82); p = 0.005], KOOS-pain [69 (56-81) vs. 61 (47-75); p = 0.001] and NAS [2 (1-5) vs. 4 (1-6); p = 0.005] scores compared to degenerative defects. The correlation analysis revealed only weak correlations between the quantitative defect characteristics and clinical scores. CONCLUSIONS: Degenerative isolated cartilage defects in the patellofemoral joint are associated with more severe clinical symptoms in comparison to trauma-related defects. Additionally, they show a larger variance regarding their location with more trochlear defects. LEVEL OF EVIDENCE: III.