Establishing chronic condition concordance and discordance with diabetes: a Delphi study

Background The vast majority of patients with diabetes have multiple chronic conditions, increasing complexity of care; however, clinical practice guidelines, interventions, and public reporting metrics do not adequately address the interaction of these multiple conditions. To advance the understanding of diabetes clinical care in the context of multiple chronic conditions, we must understand how care overlaps, or doesn’t, between diabetes and its co-occurring conditions. This study aimed to determine which chronic conditions are concordant (share care goals with diabetes) and discordant (do not share care goals) with diabetes care, according to primary care provider expert opinion. Methods Using the Delphi technique, we administered an iterative, two-round survey to 16 practicing primary care providers in an academic practice in the Midwestern USA. The expert panel determined which specific diabetes care goals were also care goals for other chronic conditions (concordant) and which were not (discordant). Our diabetes care goals were those commonly used in quality reporting, and the conditions were 62 ambulatory-relevant condition categories. Results Sixteen experts participated and all completed both rounds. Consensus was reached on the first round for 94% of the items. After the second round, 12 conditions were concordant with diabetes care and 50 were discordant. Of the concordant conditions, 6 overlapped in care for 4 of 5 diabetes care goals and 6 overlapped for 3 of 5 diabetes care goals. Thirty-one discordant conditions did not overlap with any of the diabetes care goals, and 19 overlapped with only 1 or 2 goals. Conclusions This study significantly adds to the number of conditions for which we have information on concordance and discordance for diabetes care. The results can be used for future studies to assess the impact of concordant and discordant conditions on diabetes care, and may prove useful in developing multimorbidity guidelines and interventions

Treatment of gastrointestinal stromal tumours in paediatric and young adult patients with sunitinib: a multicentre case series

Background: Gastrointestinal stromal tumours (GIST) are rarely encountered mesenchymal tumours of the gastrointestinal tract (1.5 people per 100,000/year) that are even more rarely seen in paediatric patients (1-2% of all cases). The standard treatment for advanced adult GIST is imatinib with sunitinib as a second-line option. Although the efficacy and tolerability of sunitinib in adults with GIST has been established, little is known of the profile of sunitinib in paediatric/young adult patients with GIST given the rarity of this disease. Methods: Paediatric/young adult patients aged up to 21 years with diagnosis of GIST who were treated with sunitinib were identified from retrospective records from three centres in Europe and the US. Most patients commenced sunitinib in a 6-week cycle, however, dosing could be reduced, delayed, changed to (or initiated with) a continuous schedule. Objective response (Response Evaluation Criteria In Solid Tumours [RECIST]) and adverse events were recorded. Results: We identified 9 paediatric/young adult patients (aged 11-21 years) with GIST who were treated with sunitinib de novo (n = 1) or following failure of imatinib (n = 8). Progressive disease was previously documented for all patients including 7 patients during imatinib therapy. Baseline patient and tumour profile characteristics showed a distinct profile (notably all were wild-type KIT/PDGFR) compared to that established for adults. Sunitinib treatment was associated with a best response of stable disease for 7 patients, with disease stabilisation lasting from 1 month to > 73 months and a median progression free survival time of 15 months. There was some evidence of better disease control for sunitinib when compared to prior imatinib. Most adverse events with sunitinib were manageable and all were consistent with the known profile of the agent. Conclusion: The ability to draw firm conclusions from this case series is limited by the small number of patients and the use of retrospective data which is largely reflective of the rarity of this condition. However, our findings provide initial evidence of clinical benefit and a generally manageable toxicity profile for sunitinib when administered to paediatric/young adult patients with GIST, most of whom had documented progressive disease during prior imatinib treatment

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Diagnosis and Treatment of Incident Hypertension Among Patients with Diabetes: a U.S. Multi-Disciplinary Group Practice Observational Study

BackgroundEarly hypertension control reduces the risk of cardiovascular complications among patients with diabetes mellitus. There is a need to improve hypertension management among patients with diabetes mellitus.ObjectiveWe aimed to evaluate rates and associations of hypertension diagnosis and treatment among patients with diabetes mellitus and incident hypertension.DesignThis was a 4-year retrospective analysis of electronic health records.ParticipantsAdults ≥ 18 years old (n = 771) with diabetes mellitus, who met criteria for incident hypertension and received primary care at a large, Midwestern academic group practice from 2008 to 2011 were includedMain measuresCut-points of 130/80 and 140/90 mmHg were used to identify incident cases of hypertension. Kaplan-Meier analysis estimated the probability of receiving: 1) an initial hypertension diagnosis and 2) antihypertensive medication at specific time points. Cox proportional-hazard frailty models (HR; 95 % CI) were fit to identify associations of time to hypertension diagnosis and treatment.Key resultsAmong patients with diabetes mellitus who met clinical criteria for hypertension, 41 % received a diagnosis and 37 % received medication using the 130/80 mmHg cut-point. At the 140/90 mmHg cut-point, 52 % received a diagnosis and 49 % received medication. Atrial fibrillation (HR 2.18; 1.21-4.67) was associated with faster diagnosis rates; peripheral vascular disease (HR 0.18; 0.04-0.74) and fewer primary care visits (HR 0.93; 0.88-0.98) were associated with slower diagnosis rates. Atrial fibrillation (HR 3.07; 1.39-6.74) and ischemic heart disease/congestive heart failure (HR 2.16; 1.24-3.76) were associated with faster treatment rates; peripheral vascular disease (HR 0.16; 0.04-0.64) and fewer visits (HR 0.93; 0.88-0.98) predicted slower medication initiation. Diagnosis and treatment of incident hypertension were similar using cut-points of 130/80 and 140/90 mmHg.ConclusionsAmong patients with diabetes mellitus, even using a cut-point of 140/90 mmHg, approximately 50 % remained undiagnosed and untreated for hypertension. Future interventions should target patients with multiple comorbidities to improve hypertension and diabetes clinical care

Myeloablative Chemotherapy with Autologous Stem Cell Transplant for Desmoplastic Small Round Cell Tumor

Desmoplastic small round cell tumor (DSRCT), a rare, aggressive neoplasm, has a poor prognosis. In this prospective study, we evaluated the role of myeloablative chemotherapy, followed by autologous stem cell transplant in improving survival in DSRCT. After high-dose induction chemotherapy and surgery, 19 patients with chemoresponsive DSRCT underwent autologous stem cell transplant. Myeloablative chemotherapy consisted of carboplatin (400–700 mg/m2/day for 3 days) + thiotepa (300 mg/m2/day for 3 days) ± topotecan (2 mg/m2/day for 5 days). All patients were engrafted and there was no treatment-related mortality. Seventeen patients received radiotherapy to sites of prior or residual disease at a median of 12 weeks after transplant. Five-year event-free and overall survival were 11 ± 7% and 16 ± 8%, respectively. Two patients survive disease-free 16 and 19 years after transplant (both in complete remission before transplant). 14 patients had progression and died of disease at a median of 18 months following autologous transplant. These data do not justify the use of myeloablative chemotherapy with carboplatin plus thiotepa in patients with DSRCT. Alternative therapies should be considered for this aggressive neoplasm