Guidelines strongly recommend patients with heart failure with reduced ejection fraction (HFrEF) be treated with multiple medications proven to improve clinical outcomes, as tolerated. The degree to ...which gaps in medication use and dosing persist in contemporary outpatient practice is unclear.
This study sought to characterize patterns and factors associated with use and dose of HFrEF medications in current practice.
The CHAMP-HF (Change the Management of Patients with Heart Failure) registry included outpatients in the United States with chronic HFrEF receiving at least 1 oral medication for management of HF. Patients were characterized by baseline use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB), angiotensin receptor neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA). Patient-level factors associated with medication use were examined.
Overall, 3,518 patients from 150 primary care and cardiology practices were included. Mean age was 66 ± 13 years, 29% were female, and mean EF was 29 ± 8%. Among eligible patients, 27%, 33%, and 67% were not prescribed ACEI/ARB/ARNI, beta-blocker, and MRA therapy, respectively. When medications were prescribed, few patients were receiving target doses of ACEI/ARB (17%), ARNI (14%), and beta-blocker (28%), whereas most patients were receiving target doses of MRA therapy (77%). Among patients eligible for all classes of medication, 1% were simultaneously receiving target doses of ACE/ARB/ARNI, beta-blocker, and MRA. In adjusted models, older age, lower blood pressure, more severe functional class, renal insufficiency, and recent HF hospitalization generally favored lower medication utilization or dose. Social and economic characteristics were not independently associated with medication use or dose.
In this contemporary outpatient HFrEF registry, significant gaps in use and dose of guideline-directed medical therapy remain. Multiple clinical factors were associated with medication use and dose prescribed. Strategies to improve guideline-directed use of HFrEF medications remain urgently needed, and these findings may inform targeted approaches to optimize outpatient medical therapy.
Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been ...proposed as part of the consensus panels of the International Workshop on Waldenström's Macroglobulinemia (IWWM). At IWWM-8, a task force for treatment recommendations was impanelled to review recently published and ongoing clinical trial data as well as the impact of new mutations (MYD88 and CXCR4) on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives for WM patients. The panel concluded that therapeutic strategies in WM should be based on individual patient and disease characteristics. Chemoimmunotherapy combinations with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone provide durable responses and are still indicated in most patients. Approval of the BTK inhibitor ibrutinib in the United States and Europe represents a novel and effective treatment option for both treatment-naive and relapsing patients. Other B-cell receptor inhibitors, second-generation proteasome inhibitors (eg, carfilzomib), and mammalian target of rapamycin inhibitors are promising and may increase future treatment options. Active enrollment in clinical trials whenever possible was endorsed by the panel for most patients with WM.
This study compares the occurrence and characteristics of microplastics (MPs) and heavy metal contaminants in the water and sediment of three habitats (corals, seagrass-beds and near-shores) of ...Rameswaram Island, India. The overall mean concentration of MPs varies from 24 ± 9 to 96 ± 57 items/L in water, and from 55 ± 21 to 259 ± 88 items/kg in sediment. The value of abundance is the greatest in the coral reef site CR-1 (96 ± 51 items/L; 259 ± 88 items/kg) followed by the seagrass site SG-2 (94 ± 55 items/L; 203 ± 75 items/kg) and the near-shore site St-15 (95 ± 63 items/L; 193 ± 75 items/kg). PE fiber (<1000 μm) is predominant in water, whereas PP fiber and fragment (between 2000 and 5000 μm) dominate the sediment. The SEM images of MPs reveal features which are characteristic of degradation like surface roughness, cracks, protrusions, and chalking, along with surface precipitates of both chemical and biological origin. EDAX images show the presence of Cr, Fe, Hg, Pb, Cu, As and Cd associated with MP surfaces.
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•Mean MPs ranges from 24±9 to 96±57 items/L in water, and 55±21 to 259±88 items/kg in sediment.•Fibers of size<1000μm, fibers and fragments with 2000 - 5000μm predominant in water and sediment.•The predominant polymer type in surface water is PE and that in sediment is PP.•SEM image shows complex surface morphology of MPs, and EDAX indicates that most MPs contain metals.•ICP-MS results reveal MPs act as carriers of trace elements, which is threat to marine species.
Microbial metabolites, such as short-chain fatty acids (SCFAs), are highly produced in the intestine and potentially regulate the immune system. We studied the function of SCFAs in the regulation of ...T-cell differentiation into effector and regulatory T cells. We report that SCFAs can directly promote T-cell differentiation into T cells producing interleukin-17 (IL-17), interferon-γ, and/or IL-10 depending on cytokine milieu. This effect of SCFAs on T cells is independent of GPR41 or GPR43, but dependent on direct histone deacetylase (HDAC) inhibitor activity. Inhibition of HDACs in T cells by SCFAs increased the acetylation of p70 S6 kinase and phosphorylation rS6, regulating the mTOR pathway required for generation of Th17 (T helper type 17), Th1, and IL-10(+) T cells. Acetate (C2) administration enhanced the induction of Th1 and Th17 cells during Citrobacter rodentium infection, but decreased anti-CD3-induced inflammation in an IL-10-dependent manner. Our results indicate that SCFAs promote T-cell differentiation into both effector and regulatory T cells to promote either immunity or immune tolerance depending on immunological milieu.
The prevalence of head and neck cancer (HNC) survivors is on the rise. Treatments for HNC can have a major deleterious impact on functions such as swallowing and voice. Poor functional outcomes are ...strongly correlated with distress, low quality of life, difficulties returning to work and socializing. Furthermore, dysphagia can have serious medical consequences such as malnutrition, dehydration, and pneumonia. A conservative estimate of the percentage of survivors living with dysphagia in the long-term is between 50 and 60%. Evidence is emerging that functions can worsen over time, sometimes several years following treatment due to radiation-associated fibrosis, neuropathy, intractable edema, and atrophy. Muscles lose their strength, pliability, stamina, and range, speed, precision, and initiation of movements necessary for swallowing and voice functions. Late treatment effects can go unrecognized, and may only be identified when there is a medical complication such as hospitalization for aspiration pneumonia. In the routine healthcare setting methods of evaluation include a detailed case history, a thorough clinical examination and instrumental assessments. Interventions for late treatment effects are limited and it is imperative that patients at risk are identified as early as possible. This paper considers the role of screening tests in monitoring swallowing and detecting aspiration in the long-term. Further work is indicated for addressing this pressing and increasingly common clinical problem.
Guidelines recommend that patients with heart failure with reduced ejection fraction (HFrEF) have medical therapy titrated to target doses derived from clinical trials, as tolerated. The degree to ...which titration occurs in contemporary U.S. practice is unknown.
This study sought to characterize longitudinal titration of HFrEF medical therapy in clinical practice and to identify associated factors and reasons for medication changes.
Among 2,588 U.S. outpatients with chronic HFrEF in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry with complete medication data and no contraindications to medical therapy, use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB), angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA) were examined at baseline and at 12-month follow-up.
At baseline, 658 (25%), 525 (20%), 287 (11%), and 45 (2%) patients were receiving target doses of MRA, beta-blocker, ACEI/ARB, and ARNI therapy, respectively. At 12 months, proportions of patients with medication initiation or dose increase were 6% for MRA, 10% for beta-blocker, 7% for ACEI/ARB, and 10% for ARNI; corresponding proportions with discontinuation or dose decrease were 4%, 7%, 11%, and 3%, respectively. Over 12 months, <1% of patients were simultaneously treated with target doses of ACEI/ARB/ARNI, beta-blocker, and MRA. In multivariate analysis, across the classes of medications, multiple patient characteristics were associated with a higher likelihood of initiation or dose increase (e.g., previous HF hospitalization, higher blood pressure, lower ejection fraction) and discontinuation or dose decrease (e.g., previous HF hospitalization, impaired quality of life, more severe functional class). Medical reasons were the most common reasons for discontinuations and dose decreases of each therapy, but the relative contributions from patient preference, health team, and systems-based reasons varied by medication.
In this contemporary U.S. registry, most eligible HFrEF patients did not receive target doses of medical therapy at any point during follow-up, and few patients had doses increased over time. Although most patients had no alterations in medical therapy, multiple clinical factors were independently associated with medication changes. Further quality improvement efforts are urgently needed to improve guideline-directed medication titration for HFrEF.
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Waldenström's macroglobulinemia is an incurable, IgM-secreting lymphoplasmacytic lymphoma (LPL). The underlying mutation in this disorder has not been delineated.
We performed whole-genome sequencing ...of bone marrow LPL cells in 30 patients with Waldenström's macroglobulinemia, with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings in samples from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors.
Among the patients with Waldenström's macroglobulinemia, a somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-κB signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenström's macroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenström's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced IκBα and NF-κB p65 phosphorylation, as well as NF-κB nuclear staining, in Waldenström's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenström's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2.
MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating Waldenström's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.).
To determine the efficacy of tenofovir disoproxil fumarate (TDF) in adults with chronic hepatitis B virus (HBV) infection who had previously failed lamivudine (LAM) and had significant viral ...replication (HBV DNA >10⁵ copies/ml if HBeAg positive, > 10⁴ copies/ml if HBeAg negative) despite at least 24 weeks of treatment with adefovir dipivoxil (ADV).
A prospective open-label study of TDF 300 mg daily. Patients receiving combination ADV/LAM prior to baseline were switched to TDF/LAM.
Multiple tertiary referral centres.
Sixty patients were enrolled. The median age was 48.5 years (range 21e80), 46 (77%) were male and 40 (67%) were HBeAg positive. Thirty-eight patients (63%) were switched from ADV to TDF, the remainder from ADV/LAM to TDF/LAM. At baseline, substitutions conferring resistance to LAM or ADV were present in 20 patients (33%) and 17 patients (28%), respectively. The median baseline viral load was 5.33 log₁₀ IU/ml (range 2.81-8.04). Patients initially treated with TDF monotherapy with persistent viral replication at or after 24 weeks were switched to TDF/LAM. The main outcome measures were change in HBV viral load from baseline and percentage of patients achieving an undetectable viral load (<15 IU/ml).
Results are reported at 96 weeks of treatment. One patient discontinued TDF at 10 days due to rash. The time-weighted change in viral load from baseline to week 12 was -2.19 log10 IU/ml overall. The median change in HBV DNA from baseline to weeks 12, 24, 48 and 96 was -2.86, -3.23, -3.75 and -4.03 log₁₀ IU/ml, respectively. At 48 and 96 weeks, 27/59 (46%) and 38/59 (64%) patients achieved a HBV DNA <15 IU/ml. The response was independent of baseline LAM therapy or mutations conferring ADV resistance.
In heavily pretreated patients with a high rate of genotypic resistance, TDF retains significant activity against HBV although this appears diminished in comparison with studies of naïve patients.
A new 16-phase interleaved bidirectional dc/dc converter is developed featuring smaller input/output filters, faster dynamic response and lower device stress than conventional designs, for hybrid ...vehicle applications. The converter is connected between the ultracapacitor (UC) pack and the battery pack in a multisource energy storage system of a hybrid vehicle. Typically, multiphase interleaved converters require a current control loop in each phase to avoid imbalanced current between phases. This increases system cost and control complexity. In this paper, in order to minimize imbalance currents and remove the current control loop in each phase, the converter is designed to operate in discontinuous conduction mode (DCM). The high current ripple associated with DCM operation is then alleviated by interleaving. The design, construction, and testing of an experimental hardware prototype is presented, with the test results included. Finally, a novel soft switch topology for DCM operation is proposed for future research, to achieve zero-voltage switching (ZVS), or zero-current switching (ZCS) in all transitions.
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