Tacking upwind: reducing spending among high-risk commercially insured patients.

OBJECTIVES: The study examined a commercial accountable care organization (ACO) population and then assessed the impact of an integrated care management program on medical spending and clinical event rates. STUDY DESIGN: Retrospective cohort study of high-risk individuals (n = 487) in a population of 365,413 individuals aged 18 to 64 years within the Mass General Brigham health system who were part of commercial ACO contracts with 3 large insurers between 2015 and 2019. METHODS: Using medical spending claims and other enrollment data, the study assessed the demographic and clinical characteristics, medical spending, and clinical event rates of patients in the ACO and its high-risk care management program. The study then examined the impact of the program using a staggered difference-in-difference design with individual-level fixed effects and compared outcomes of those who had entered the program with those of similar patients who had not entered. RESULTS: The commercially insured ACO population was healthy on average but included several hundred high-risk patients (n = 487). After adjustment, patients within the ACO's integrated care management program for high-risk patients had lower monthly medical spending (by $1361 per person per month) as well as lower emergency department visit and hospitalization rates compared with similar patients who had yet to start the program. Accounting for early ACO departure decreased the magnitude of the program effects as expected. CONCLUSIONS: Commercial ACO populations may be healthy on average but still include some high-risk patients. Identifying which patients might benefit from more intensive care management could be critical for reaping the potential savings.

Nursing home infection control strategies during the COVID-19 pandemic.

BACKGROUND: The American Rescue Plan Act of 2021 awarded $500 million toward scaling "strike teams" to mitigate the impact of Coronavirus Disease 2019 (COVID-19) within nursing homes. The Massachusetts Nursing Facility Accountability and Support Package (NFASP) piloted one such model during the first weeks of the pandemic, providing nursing homes financial, administrative, and educational support. For a subset of nursing homes deemed high-risk, the state offered supplemental, in-person technical infection control support. METHODS: Using state death certificate data and federal nursing home occupancy data, we examined longitudinal all-cause mortality per 100,000 residents and changes in occupancy across NFASP participants and subgroups that varied in their receipt of the supplemental intervention. RESULTS: Nursing home mortality peaked in the weeks preceding the NFASP, with a steeper increase among those receiving the supplemental intervention. There were contemporaneous declines in weekly occupancy. The potential for temporal confounding and differential selection across NFASP subgroups precluded estimation of causal effects of the intervention on mortality. CONCLUSIONS: We offer policy and design suggestions for future strike team iterations that could inform the allocation of state and federal funding. We recommend expanded data collection infrastructure and, ideally, randomized assignment to intervention subgroups to support causal inference as strike team models are scaled under the direction of state and federal agencies.

Evaluating The Accuracy Of Medicare Risk Adjustment For Alzheimer's Disease And Related Dementias.

In 2020 Medicare reintroduced Alzheimer's disease and related dementias (ADRD) Hierarchical Condition Categories (HCCs) to risk-adjust Medicare Advantage and accountable care organization (ACO) payments. The potential for Medicare spending increases from this policy change are not well understood because the baseline accuracy of ADRD HCCs is uncertain. Using linked 2016-18 claims and electronic health record data from a large ACO, we evaluated the accuracy of claims-based ADRD HCCs against a reference standard of clinician-adjudicated disease. An estimated 7.5 percent of beneficiaries had clinician-adjudicated ADRD. Among those with ADRD HCCs, 34 percent did not have clinician-adjudicated disease. The false-negative and false-positive rates were 22.7 percent and 3.2 percent, respectively. Medicare spending for those with false-negative ADRD HCCs exceeded that of true positives by $14,619 per beneficiary. If, after the reintroduction of risk adjustment for ADRD, all false negatives were coded as having ADRD, expenditure benchmarks for beneficiaries with ADRD would increase by 9 percent. Monitoring ADRD coding could become challenging in the setting of concurrent incentives to decrease false-negative rates and increase false-positive rates.

Premium tax credits in the American Rescue Plan and off-marketplace enrollees.

OBJECTIVES: The 2021 American Rescue Plan Act (ARPA) increased the availability and magnitude of premium tax credits (PTCs) for consumers purchasing individual marketplace plans in 2021-2022. Millions currently purchase PTC-ineligible plans off of the marketplace. We estimate the proportion of off-marketplace enrollees who would be eligible for the expanded PTCs under ARPA, calculate PTC amounts for eligible enrollees, and examine factors influencing plan choice that could inform outreach efforts. STUDY DESIGN: We analyzed data from a survey of a random sample of off-marketplace enrollees in California in 2017 (n = 829). METHODS: Using survey data including self-reported income, household size, and employment status combined with 2021 benchmark premium data from Covered California, we estimate eligibility for PTCs and potential PTC amounts under ARPA among off-marketplace enrollees. We adjust for both survey design weights and poststratification weights. RESULTS: Among off-marketplace enrollees, we estimate that approximately 12% are potentially ineligible for PTCs because they reported incomes less than 100% of the poverty level or because they had access to employer-sponsored coverage for their family through themselves or their partner. The median annual PTC in 2021 for eligible off-marketplace enrollees was $311 but varied greatly by age, family or individual plan, and household income (5%-95% range, $0-$14,836). In 2017, 69% of off-marketplace enrollees were unaware that they had to enroll in marketplace plans to receive PTCs, and 51% received enrollment assistance from insurance brokers. CONCLUSIONS: These findings suggest the need for targeted outreach to encourage off-marketplace enrollees to switch to marketplace plans.

Identifying Diagnoses of Schizophrenia Spectrum Disorder in Large Data Sets.

Objective: The authors used a large clinical data set to determine which index diagnoses of schizophrenia spectrum disorder were new diagnoses. Methods: Using the Massachusetts All-Payer Claims Database (2012­2016), the authors identified patients with a schizophrenia spectrum disorder diagnosis in 2016 (index diagnosis) and then reviewed patients' care histories for the previous 12, 24, 36, and 48 months to identify previous diagnoses. Logistic regression was used to examine patient characteristics associated with the index diagnosis being a new diagnosis. Results: Overall, 7,217 individuals ages 15­35 years had a 2016 diagnosis of schizophrenia spectrum disorder; 67.7% had at least 48 months of historical data. Among those with at least 48 months of care history, 23% had no previous diagnoses. Diagnoses from inpatient psychiatric admissions or among female or younger patients were more likely to represent new diagnoses, compared with diagnoses from most other diagnosis locations or among males or older age groups, and outpatient diagnoses were less likely to represent new diagnoses than were most other diagnosis settings. Reviewing 48 instead of 12 months of data reduced estimated rates of new diagnoses from 112 to 66 per 100,000 persons; historical diagnoses were detected for 61% and 77% of patients with 12 or 48 months of care history, respectively. Conclusions: Examining multiple years of patient history spanning all payers and providers is critical to identifying new schizophrenia spectrum disorder diagnoses in large data sets. Review of 48 months of care history resulted in lower rates of new schizophrenia spectrum disorder diagnoses than previously reported.

Growth In ACA-Compliant Marketplace Enrollment And Spending Risk Changes During The COVID-19 Pandemic.

In 2020 the COVID-19 pandemic caused millions to lose their jobs and, consequently, their employer-sponsored health insurance. Enacted in 2010, the Affordable Care Act (ACA) created safeguards for such events by expanding Medicaid coverage and establishing Marketplaces through which people could purchase health insurance. Using a novel national data set with information on ACA-compliant individual insurance plans, we found large increases in Marketplace enrollment in 2020 compared with 2019 but with varying percentage increases and spending risk implications across states. States that did not expand Medicaid had enrollment and spending risk increases. States that expanded Medicaid but did not relax 2020 Marketplace enrollment criteria also had spending risk increases. In contrast, states that expanded Medicaid and relaxed 2020 enrollment criteria experienced enrollment increases without spending risk changes. The findings are reassuring with respect to the ability of Marketplaces to buffer employment shocks, but they also provide cautionary signals that risks and premiums could begin to rise either in the absence of Medicaid expansion or when Marketplace enrollment is constrained.

Expanding a single­lead mobile electrocardiographic device to multiple­lead recordings improves diagnostic accuracy and confidence.

BACKGROUND: Mobile electrocardiographic (mECG) devices that record ECG lead I have been used to detect atrial fibrillation. Other arrhythmias may not be readily diagnosed with one lead. Obtaining multi­lead tracings from an mECG (MLmECG) to simulate a 12­lead ECG may lead to more accurate diagnoses. METHODS: We developed a method to generate multi­lead ECGs using a mECG device by attaching it with alligator clips connected to an insulated copper wire to adhesive electrodes on the patient's limbs and torso according to standard lead configurations. Different rhythm and conduction abnormalities from a sample of inpatients were collected. Arrhythmias were recorded in three ways (single lead, MLmECG, and standard 12­lead) and grouped by category. Recordings were sent to cardiology fellows in the form of a multiple choice survey. Participants were asked for their diagnosis and confidence in their decision. RESULTS: Survey response rate was 100%. Single­lead, MLmECG, and 12­lead yielded 48.2%, 81.6%, and 88.6% of agreement with the correct diagnosis, respectively (single­lead vs. MLmECG or 12­lead; p < 0.01). Overall mean confidence scores were 3.34, 4.35, and 4.53 out of 5, for single­lead, MLmECG, and 12­lead ECG, respectively (single­lead vs. MLmECG or 12­lead; p < 0.01, MLmECG vs. 12­lead; p = 0.09). CONCLUSION: The diagnostic accuracy of MLmECGs were similar to that of a standard 12­lead ECG. Fellows' confidence in their diagnosis were similar between MLmECG or 12­lead ECG, and higher with both modalities compared to a single­lead tracing. The ability to recreate, as fully as possible, a standard 12­lead ECG is a reasonable goal for mobile technology.

Political frames of public health crises: Discussing the opioid epidemic in the US Congress.

When and how do politicians talk about public health crises? Using evidence from the opioid crisis in the United States, this paper assembles and analyzes novel data on Congressional statements to explore the conditions under which politicians (1) issue public statements about opioids and (2) frame the opioid crisis as a predominantly public health or law enforcement problem. We examined 3.8 million Congressional floor speeches and 111,000 public statements to identify (1) floor speeches about drug crises in the 97th to 114th Congresses (1981-2017) and (2) public statements about the opioid crisis in the 116th Congress (2019-2020). Moderate ideology, women, greater overdose deaths, and larger white populations are associated with significantly higher frequencies of opioid statements. Using a dictionary-based text analysis approach, we find that ideologically liberal and African American legislators are more likely to use public health framing, while ideologically conservative members are more likely to use law enforcement framing and refer to national borders or foreign countries in opioid statements. Democrats/liberals more often referenced medication treatment for opioids. These findings imply two broader conclusions about the nature of political discourse in public health crises. First, that political extremists are least likely to talk about opioids suggests that increasing partisan polarization may result in less discussion, emphasis, and expertise in public health issues. Second, the tenor of discourse about opioids and other public health crises is likely to change with partisan electoral waves, potentially hindering long term planning of public health capacity.

Identifying Medicare beneficiaries with dementia.

BACKGROUND/OBJECTIVES: No data exist regarding the validity of International Classification of Disease (ICD)-10 dementia diagnoses against a clinician-adjudicated reference standard within Medicare claims data. We examined the accuracy of claims-based diagnoses with respect to expert clinician adjudication using a novel database with individual-level linkages between electronic health record (EHR) and claims. DESIGN: In this retrospective observational study, two neurologists and two psychiatrists performed a standardized review of patients' medical records from January 2016 to December 2018 and adjudicated dementia status. We measured the accuracy of three claims-based definitions of dementia against the reference standard. SETTING: Mass-General-Brigham Healthcare (MGB), Massachusetts, USA. PARTICIPANTS: From an eligible population of 40,690 fee-for-service (FFS) Medicare beneficiaries, aged 65 years and older, within the MGB Accountable Care Organization (ACO), we generated a random sample of 1002 patients, stratified by the pretest likelihood of dementia using administrative surrogates. INTERVENTION: None. MEASUREMENTS: We evaluated the accuracy (area under receiver operating curve [AUROC]) and calibration (calibration-in-the-large [CITL] and calibration slope) of three ICD-10 claims-based definitions of dementia against clinician-adjudicated standards. We applied inverse probability weighting to reconstruct the eligible population and reported the mean and 95% confidence interval (95% CI) for all performance characteristics, using 10-fold cross-validation (CV). RESULTS: Beneficiaries had an average age of 75.3 years and were predominately female (59%) and non-Hispanic whites (93%). The adjudicated prevalence of dementia in the eligible population was 7%. The best-performing definition demonstrated excellent accuracy (CV-AUC 0.94; 95% CI 0.92-0.96) and was well-calibrated to the reference standard of clinician-adjudicated dementia (CV-CITL <0.001, CV-slope 0.97). CONCLUSION: This study is the first to validate ICD-10 diagnostic codes against a robust and replicable approach to dementia ascertainment, using a real-world clinical reference standard. The best performing definition includes diagnostic codes with strong face validity and outperforms an updated version of a previously validated ICD-9 definition of dementia.

Atrioventricular Nodal Reentrant Tachycardia Ablation with a Power-controlled, Contact-force Catheter.

Radiofrequency catheter ablation is a safe and effective treatment option for atrioventricular nodal reentrant tachycardia (AVNRT). A nonirrigated ablation catheter used in a temperature-controlled mode is traditionally used for AVNRT ablation due to the shallow lesion depth required for successful slow-pathway ablation. In this case, a nonirrigated ablation catheter established inadequate lesions to ablate the slow pathway successfully. The adoption of an irrigated contact-force ablation catheter used in a power-controlled mode was necessary to provide higher power and possibly create a deeper lesion to ablate the slow pathway successfully, thus eliminating AVNRT inducibility in this patient.

Pathophysiology, Diagnosis, and Ablation of Atrioventricular Node-dependent Long-R-P Tachycardias.

Atrioventricular (AV) node-dependent long-R-P tachycardias are a unique group of supraventricular tachycardias that include atypical AV nodal reentrant tachycardia (AVNRT), atypical AVNRT with a concealed bystander nodofascicular (NF)/nodoventricular (NV) accessory pathway inserting into the slow pathway of the AV node, the permanent form of junctional reciprocating tachycardia, and orthodromic NF/NV reciprocating tachycardia. Here, we discuss the complex pathophysiology, diagnosis, and ablation of these intriguing arrhythmias.

Physician adherence to 'Seattle' and 'International' ECG criteria in adolescent athletes: An analysis of compliance by specialty, experience, and practice environment.

BACKGROUND: Screening electrocardiography (ECG) for athletes is both controversial and rapidly evolving. While identifying an abnormal ECG could detect a serious cardiovascular disease, falsely interpreting a benign ECG pattern as abnormal can lead to unnecessary testing, cost, and anxiety. Though recent refinements of athlete screening ECG criteria have significantly improved its accuracy, in clinical practice physician adherence to these criteria may vary. METHODS: We analyzed physician adherence to contemporary athlete ECG criteria in a large, national athlete screening registry. 1577 consecutive screening ECGs were independently re- interpreted to assess for physician adherence to Seattle Criteria or International Criteria, respective to the criteria in place when the screening was performed. We further determined the most common ECG interpretations that deviated from these criteria, and analyzed physician characteristics for independent predictors of adherence to published ECG criteria. RESULTS: Though overall adherence to contemporary criteria was high, 60.4% of ECGs interpreted as abnormal did not meet athlete ECG criteria for pathology when independently re- read. The most common ECG patterns misinterpreted as abnormal were isolated left ventricular hypertrophy (LVH) and non-pathologic T-wave inversions (TWI). Multivariate regression identified three independent predictors of adherence to athlete ECG criteria: participating in a screening overseen by the organization's medical leadership, electrophysiology specialists and adult cardiologists. CONCLUSION: This study highlights the need for quality control measures and continued clinician education in a controversial and rapidly evolving field. Clinician education for athlete screening ECG criteria should emphasize the recent changes in how TWI and LVH voltage criteria should be interpreted in this patient population.

Improved accuracy and confidence with multiple-lead recordings from a single-lead mobile electrocardiographic device.

BACKGROUND: Mobile electrocardiograms (mECGs) utilizing smartphone applications are an emerging technology. Typically, a Lead I rhythm strip is recorded. However, interpretation can be difficult in patients with sinus rhythm and low amplitude P-waves (SR-LAP) or atrial flutter (AFL). We hypothesized that patients could independently obtain multi-lead tracings using a commercial mECG device, and that cardiologists who interpreted the multi-lead tracings would make more accurate diagnoses and have more confidence in their interpretation compared to a single lead only. METHODS: Thirty sets of recordings were obtained from 10 patients with either SR-LAP or AFL that was not apparent on Lead I on a standard ECG. Patients recorded Lead I, Lead II, and Lead V1 tracings using AliveCor's KardiaMobile mECG device. Twenty-nine cardiologists reviewed each patient's Lead I tracing, multi-lead tracings (Leads I, II, V1), and 12-lead ECG. Accuracy was noted and each cardiologist rated their level of confidence in their interpretation. RESULTS: All patients were able to record their own single and multi-lead tracings. Single lead, multi-lead, and the 12-lead ECG yielded 36.4%, 84.3%, and 97.7% agreement with the established diagnosis, respectively (P < .01 for each comparison). Overall mean confidence scores (out of a score of 5) were 2.95, 3.50, and 4.47 for single lead, multi-lead, and the 12-lead ECG, respectively (P < .01 for each comparison). CONCLUSIONS: Patients were able to record their own multi-lead mECG tracings. Compared to a single lead recording, multi-lead mECGs significantly improved cardiologists' diagnostic accuracy and confidence in their interpretation approaching that of a standard 12-lead ECG.

Dynamic polyhedral actomyosin lattices remodel micron-scale curved membranes during exocytosis in live mice.

Actomyosin networks, the cell's major force production machineries, remodel cellular membranes during myriad dynamic processes1,2 by assembling into various architectures with distinct force generation properties3,4. While linear and branched actomyosin architectures are well characterized in cell-culture and cell-free systems3, it is not known how actin and myosin networks form and function to remodel membranes in complex three-dimensional mammalian tissues. Here, we use four-dimensional spinning-disc confocal microscopy with image deconvolution to acquire macromolecular-scale detail of dynamic actomyosin networks in exocrine glands of live mice. We address how actin and myosin organize around large membrane-bound secretory vesicles and generate the forces required to complete exocytosis5-7. We find that actin and non-muscle myosin II (NMII) assemble into previously undescribed polyhedral-like lattices around the vesicle membrane. The NMII lattice comprises bipolar minifilaments8-10 as well as non-canonical three-legged configurations. Using photobleaching and pharmacological perturbations in vivo, we show that actomyosin contractility and actin polymerization together push on the underlying vesicle membrane to overcome the energy barrier and complete exocytosis7. Our imaging approach thus unveils a force-generating actomyosin lattice that regulates secretion in the exocrine organs of live animals.

Case report: de novo ANCA-associated vasculitis after kidney transplantation treated with rituximab and plasma exchange.

BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis causes end-stage renal failure in up to a third of cases even with treatment. The disease recurs occasionally after kidney transplantation, but new onset of ANCA-associated vasculitis after transplantation is highly unusual. The use of rituximab or plasmapheresis for de novo disease after transplantation has not previously been reported. CASE PRESENTATION: Routine post-transplant follow-up for a 66-year old asymptomatic woman revealed a rise in creatinine from 1.8 to 2.6 mg/dl and increased proteinuria. She had received a cadaveric kidney transplant 20 months previously for end-stage autosomal dominant polycystic kidney disease. Renal allograft biopsy unexpectedly demonstrated pauci-immune glomerulonephritis with extracapillary proliferation and interstitial inflammation. Concurrent serum tested strongly positive for ANCA specific to proteinase 3 (PR3), but stored pre- and post-transplantation serum samples tested negative. These findings established a diagnosis of de novo ANCA-associated vasculitis in the renal allograft. We started treatment with high-dose corticosteroid and rituximab. Despite this, serum creatinine continued to rise and glomerulonephritis remained active in a repeat biopsy. Escalation of the treatment with seven sessions of plasmapheresis led to a temporary improvement in creatinine. No further features of vasculitis emerged and PR3-ANCA titres declined. However, multiple infections complicated the recovery period and were associated with progressive loss of renal transplant function. Four months after the index presentation, transplant function became insufficient and dialysis was restarted. CONCLUSIONS: De novo ANCA-associated vasculitis after renal transplantation is exceptionally rare. It poses a significant risk to graft survival even in the context of intensified immunosuppression. Management relies on clinical evidence from populations with native renal function, yet post-transplant patients may be at increased risk of treatment-related adverse events. Precautions against these risks are crucial in the delivery of care.

H2S mediates the vasodilator effect of endothelin-1 in the cerebral circulation.

H2S is an endogenous gasotransmitter that increases cerebral blood flow. In the cerebral vascular endothelium, H2S is produced by cystathionine δ-lyase (CSE). Endothelin-1 (ET-1) has constrictor and dilator influences on the cerebral circulation. The mechanism of the vasodilation caused by ET-1 may involve endothelium-derived factors. We hypothesize that ET-1-elicited dilation of pial arterioles requires an elevation of H2S production in the cerebral vascular endothelium. We investigated the effects of ET-1 on CSE-catalyzed brain H2S production and pial arteriolar diameter using cranial windows in newborn pigs in vivo. H2S was measured in periarachnoid cerebrospinal fluid. ET-1 (10-12-10-8 M) caused an elevation of H2S that was reduced by the CSE inhibitors propargylglycine (PPG) and ß-cyano-l-alanine (BCA). Low doses of ET-1 (10-12-10-11 M) produced vasodilation of pial arterioles that was blocked PPG and BCA, suggesting the importance of H2S influences. The vasodilator effects of H2S may require activation of smooth muscle cell membrane ATP-sensitive K+ (KATP) channels and large-conductance Ca2+-activated K+ (BK) channels. The KATP inhibitor glibenclamide and the BK inhibitor paxilline blocked CSE/H2S-dependent dilation of pial arterioles to ET-1. In contrast, the vasoconstrictor response of pial arterioles to 10-8 M ET-1 was not modulated by PPG, BCA, glibenclamide, or paxilline and, therefore, was independent of CSE/H2S influences. Pial arteriolar constriction response to higher levels of ET-1 was independent of CSE/H2S and KATP/BKCa channel activation. These data suggest that H2S is an endothelium-derived factor that mediates the vasodilator effects of ET-1 in the cerebral circulation via a mechanism that involves activation of KATP and BK channels in vascular smooth muscle. NEW & NOTEWORTHY Disorders of the cerebral circulation in newborn infants may lead to lifelong neurological disabilities. We report that vasoactive peptide endothelin-1 exhibits vasodilator properties in the neonatal cerebral circulation by stimulating production of H2S, an endothelium-derived messenger with vasodilator properties. The ability of endothelin-1 to stimulate brain production of H2S may counteract the reduction in cerebral blood flow and prevent the cerebral vascular dysfunction caused by stroke, asphyxia, cerebral hypoxia, ischemia, and vasospasm.

Lower frequency routine surveillance endomyocardial biopsies after heart transplantation.

In heart transplantation (HTx) patients, routine surveillance endomyocardial biopsies (rsEMB) are recommended for the detection of early cardiac allograft rejection. However, there is no consensus on the optimal frequency of rsEMB. Frequent rsEMB have shown a low diagnostic yield in the new era of potent immunosuppressive regimen. Efficacy and safety of lower frequency rsEMB have not been investigated so far. In this retrospective, single centre, observational study we evaluated 282 patients transplanted between 2004 and 2014. 218 of these patients were investigated by rsEMB and symptom-triggered EMB (stEMB). We evaluated EMB results, complications, risk factors for rejection, survival 1 and 5 years as well as incidence of cardiac allograft vasculopathy (CAV) 3 years after HTx. A mean of 7.1 ± 2.5 rsEMB were conducted per patient within the first year after HTx identifying 7 patients with asymptomatic and 9 patients with symptomatic acute rejection requiring glucocorticoide pulse therapy. Despite this relatively low frequency of rsEMB, only 6 unscheduled stEMB were required in the first year after HTx leading to 2 additional treatments. In 6 deaths among all 282 patients (2.1%), acute rejection could not be ruled out as a potential underlying cause. Overall survival at 1 year was 78.7% and 5-year survival was 74%. Incidence of CAV was 17% at 3-year follow-up. Morbidity and mortality of lower frequency rsEMB are comparable with data from the International Society for Heart and Lung Transplantation (ISHLT) registry. Consensus is needed on the optimal frequency of EMB.

Preclinical progress and first translational steps for a liposomal chemotherapy protocol against adrenocortical carcinoma.

Systemic therapy of adrenocortical carcinoma (ACC) is limited by heterogeneous tumor response and adverse effects. Recently, we demonstrated anti-tumor activity of LEDP-M (etoposide, liposomal doxorubicin, liposomal cisplatin, mitotane), a liposomal variant of EDP-M (etoposide, doxorubicin, cisplatin, mitotane). To improve the therapeutic efficacy and off-target profiles of the clinical gold standard EDP-M, we investigated liposomal EDP-M regimens in different preclinical settings and in a small number of ACC patients with very advanced disease. Short- and long-term experiments were performed on two ACC models (SW-13 and SJ-ACC3) in vivo We evaluated the anti-tumoral effects and off-target profiles of EDP-M, LEDP-M and a novel regimen L(l)EDP-M including liposomal etoposide. Furthermore, the role of plasma microRNA-210 as a therapeutic biomarker and first clinical data were assessed. Classical and liposomal protocols revealed anti-proliferative efficacy against SW-13 (EDP-M P < 0.01; LEDP-M: P < 0.001; L(l)EDP-M: P < 0.001 vs controls), whereas in SJ-ACC3, only EDP-M (P < 0.05 vs controls) was slightly effective. Long-term experiments in SW-13 demonstrated anti-tumor efficacy for all treatment schemes (EDP-M: P < 0.01, LEDP-M: P < 0.05, L(l)EDP-M P < 0.001 vs controls). The analysis of pre-defined criteria leading to study termination revealed significant differences for control (P < 0.0001) and EDP-M (P = 0.003) compared to L(l)EDP-M treatment. Raising its potential for therapy monitoring, we detected elevated levels of circulating microRNA-210 in SW-13 after LEDP-M treatment (P < 0.05). In contrast, no comparable effects were detectable for SJ-ACC3. However, overall histological evaluation demonstrated improved off-target profiles following liposomal regimens. The first clinical data indicate improved tolerability of liposomal EDP-M, thus confirming our results. In summary, liposomal EDP-M regimens represent promising treatment options to improve clinical treatment of ACC.

Osteochondrosis dissecans of the temporomandibular joint: a case report and a review of literature.

A case of a 71-year-old female patient with osteochondrosis dissecans of the right temporomandibular joint is presented. Osteochondrosis dissecans usually occurs at the weight-bearing convex cartilage in all larger joints. It is rarely found in the temporomandibular joint and usually shows one or two loose bodies dislodged from defects which are present on the condylar head. Because of multiple loose bodies and a defect on the temporomandibular fossa, the case presented here is very uncommon.

Acute kidney injury after ingestion of rhubarb: secondary oxalate nephropathy in a patient with type 1 diabetes.

BACKGROUND: Oxalosis is a metabolic disorder characterized by deposition of oxalate crystals in various organs including the kidney. Whereas primary forms result from genetic defects in oxalate metabolism, secondary forms of oxalosis can result from excessive intestinal oxalate absorption or increased endogenous production, e.g. after intoxication with ethylene glycol. CASE PRESENTATION: Here, we describe a case of acute crystal-induced renal failure associated with excessive ingestion of rhubarb in a type 1 diabetic with previously normal excretory renal function. Renal biopsy revealed mild mesangial sclerosis, but prominent tubular deposition of oxalate crystals in the kidney. Oxalate serum levels were increased. CONCLUSION: Acute secondary oxalate nephropathy due to excessive dietary intake of oxalate may lead to acute renal failure in patients with preexisting renal disease like mild diabetic nephropathy. Attention should be payed to special food behaviors when reasons for acute renal failure are explored.