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Abstract Aims Morphine is shown to relieve chronic breathlessness in chronic obstructive pulmonary disease. There are no definitive data in people with heart failure. We aimed to determine the effectiveness and cost-effectiveness of 12 weeks morphine therapy for the relief of chronic breathlessness in people with chronic heart failure compared with placebo. Methods and results Parallel group, double-blind, randomized, placebo-controlled, phase III trial of 20 mg daily oral modified release morphine was conducted in 13 sites in England and Scotland: hospital/community cardiology or palliative care outpatients. The primary analysis compared between-group numerical rating scale average breathlessness/24 hours at week 4 using a covariance pattern linear mixed model. Secondary outcomes included treatment-emergent harms (worse or new). The trial closed early due to slow recruitment, randomizing 45 participants [average age 72 (range 39–89) years; 84% men; 98% New York Heart Association class III]. For the primary analysis, the adjusted mean difference was 0.26 (95% confidence interval, −0.86 to 1.37) in favour of placebo. All other breathlessness measures improved in both groups (week 4 change-from-baseline) but by more in those assigned to morphine. Neither group was excessively drowsy at baseline or week 4. There were no between-group differences in quality of life (Kansas) or cognition (Montreal) at any time point. There was no exercise-related desaturation and no change between baseline and week 4 in either group. There was no change in vital signs at week 4. The natriuretic peptide measures fell in both groups but by more in the morphine group [morphine 2169 (1092, 3851) pg/mL vs. placebo 2851 (1694, 5437)] pg/mL. There was no excess serious adverse events in the morphine group. Treatment-emergent harms during the first week were more common in the morphine group; all apart from 1 were ≤ grade 2. Conclusions We could not answer our primary objectives due to inadequate power. However, we provide novel placebo-controlled medium-term benefit and safety data useful for clinical practice and future trial design. Morphine should only be prescribed in this population when other measures are unhelpful and with early management of side effects.

Anemia in chronic heart failure (CHF) is common, varying in prevalence between 14.4% and 55%, and is more frequent in patients with more severe heart failure. Patients with CHF who have anemia have a poorer quality of life, higher hospital admission rates, and reduced exercise tolerance. We explored the relation between hematinic levels and hemoglobin (Hb) levels and exercise tolerance in a group of patients with CHF. We analyzed data from 173 patients with left ventricular systolic dysfunction (LVSD), 123 patients with symptoms of heart failure, but preserved left ventricular (LV) systolic function (“diastolic dysfunction”), and 58 control subjects of similar age. Each underwent echocardiography, a 6-minute walk test, and blood tests for renal function and Hb and hematinic levels (vitamin B12, iron, and folate). We classified patients as having no anemia (Hb level >12.5 g/dL), mild anemia (Hb level from 11.5–12.5 g/dL), or moderate anemia (Hb level <11.5 g/dL). Of patients with LVSD, 16% had moderate anemia and 19% had mild anemia. Of patients with preserved LV function, 16% had moderate anemia and 17% had mild anemia. Four control subjects had a Hb level <12.5 g/dL. Of all patients, 6% were vitamin B12 deficient, 13% were iron deficient, and 8% were folate deficient. There was no difference between patients with LVSD and the diastolic dysfunction group. In patients with LVSDS, the average Hb level was lower in New York Heart Association class III than classes II and I. The distance walked in 6 minutes correlated with Hb level in both groups of patients with CHF ( r = 0.29; P <.0001). Patients with anemia achieved a lower pV o 2 (15.0 [2.3] vs 19.5 [4.4], P < .05). Peak oxygen consumption correlated with Hb level ( r = 0.21, P <.05) in the patients, but not in the control subjects. In patients with anemia, the mean creatinine level was higher than in patients with a Hb level >12.5 g/dL, but there was no clear relationship with simple regression. Hematocrit level and mean corpuscular volume were not different in the patients with diastolic dysfunction, patients with LV dysfunction, or the control subjects. Hematocrit levels were not influenced by diuretic dose. Patients with anemia were not more likely to be hematinic deficient than patients without anemia. Patients with symptoms and signs of CHF have a high prevalence of anemia (34%) whether they have LV dysfunction or diastolic dysfunction, but few patients have hematinic deficiency. Hemoglobin levels correlate with subjective and objective measures of severity and renal function.

β-Blockers are effective for the treatment of heart failure, but their mechanism of action is unresolved. Heart rate reduction may be a central mechanism or a troublesome side effect. A randomized, double-blind, parallel group study comparing chronic higher-rate (80 pulses per minute) with lower-rate (60 pulses per minute) pacing in pacemaker-dependent patients with symptomatic left ventricular (LV) systolic dysfunction, receiving β-blockers. Gated radionuclide ventriculography (RNVG) was performed at baseline and after at least 9 months. The primary outcome was change in LV volumes, as a marker of beneficial reverse remodeling, from baseline to follow-up. Forty-nine patients were randomized. Mean age was 74 ± 6 years and with LV ejection fraction of 26% ± 9% at baseline. During 14 ± 13 months of follow-up, 21 patients (43%) died and 25 (51%) completed the study protocol: 12 in the higher-rate and 13 in the lower-rate group. Mean LV end-diastolic (higher rate +20 ± 104 mL vs lower rate −65 ± 92 mL, P = .03) and systolic (higher rate +29 ± 83 mL vs lower rate −60 ± 74 mL, P = .006) volumes increased with higher-rate versus lower-rate pacing, whereas LV ejection fraction declined (higher rate −4.2% ± 4.4% vs lower rate +2.2% ± 5.4%, P = .002). Reversal of β-blocker–induced bradycardia has deleterious effects on ventricular function, suggesting heart rate reduction is an important mediator of their effects. The prognosis of patients with pacemakers and heart failure is poor.

ObjectivesIn severe heart disease, parenteral administration of loop diuretic is often needed. We present clinical outcomes from episodes of care using subcutaneous continuous subcutaneous infusion of furosemide (CSCI-furosemide).MethodsRetrospective review of service improvement data. The heart failure nurse specialist, supported by the heart failure-palliative care multidisciplinary team, works with the community or hospice staff who administer the CSCI-furosemide. Data collected for consecutive patients receiving CSCI-furosemide included: age, sex, New York Heart Association (NYHA) class, preferred place of care, goal of treatment, infusion-site reactions, and signs and symptoms of fluid retention (including weight and self-reported breathlessness).Results116 people (men 86 (66%); mean age 79 years, 49–97; NYHA class 3 (36/116, 31%) or 4 heart failure (80/116, 69%)) received 130 episodes of CSCI-furosemide (average duration 10 days, 1–49), over half in the patient’s own home/care home (80/129,; 61%) aiming to prevent hospital admission. 40/129 (31%) were managed in the hospice, and 9 (7.0%) in a community hospital. Average daily furosemide dose was 125 mg (40–300 mg). The goal of treatment was achieved in (119/130, 91.5%) episodes.The median reduction in weight was 4 kg (IQR −7 to −2 kgs, −22 to 9 kgs). Self-reported breathlessness reduced from 8.2 (±1.9) to 5.2 (±1.8). Adverse events occurred in 31/130 (24%) episodes; all but 4/130 (3%, localised skin infection) were mild.ConclusionsThese preliminary data indicate that CSCI-furosemide is safe and effective for people with severe heart failure. An adequately powered randomised controlled trial is indicated.

Background β-Blockers are effective for the treatment of heart failure, but their mechanism of action is unresolved. Heart rate reduction may be a central mechanism or a troublesome side effect. Methods A randomized, double-blind, parallel group study comparing chronic higher-rate (80 pulses per minute) with lower-rate (60 pulses per minute) pacing in pacemaker-dependent patients with symptomatic left ventricular (LV) systolic dysfunction, receiving β-blockers. Gated radionuclide ventriculography (RNVG) was performed at baseline and after at least 9 months. The primary outcome was change in LV volumes, as a marker of beneficial reverse remodeling, from baseline to follow-up. Results Forty-nine patients were randomized. Mean age was 74 ± 6 years and with LV ejection fraction of 26% ± 9% at baseline. During 14 ± 13 months of follow-up, 21 patients (43%) died and 25 (51%) completed the study protocol: 12 in the higher-rate and 13 in the lower-rate group. Mean LV end-diastolic (higher rate +20 ± 104 mL vs lower rate -65 ± 92 mL,P= .03) and systolic (higher rate +29 ± 83 mL vs lower rate -60 ± 74 mL,P= .006) volumes increased with higher-rate versus lower-rate pacing, whereas LV ejection fraction declined (higher rate -4.2% ± 4.4% vs lower rate +2.2% ± 5.4%,P= .002). Conclusion Reversal of β-blocker-induced bradycardia has deleterious effects on ventricular function, suggesting heart rate reduction is an important mediator of their effects. The prognosis of patients with pacemakers and heart failure is poor.

That cardiac dyssynchrony can contribute to a decline in cardiac efficiency has been recognized in one form or another for at least 50 years. Although revascularization and β-blockers can improve cardiac synchrony, there was little interest in or awareness of this clinical entity until the advent of specific, highly effective therapy using atriobiventricular pacing, often described as cardiac resynchronization therapy. Over the last few years, significant advances in cardiac resynchronization therapy technology and the publication of large-scale clinical trials using cardiac resynchronization therapy devices in patients with heart failure have led to the widespread use of these devices. This review will briefly describe the complex nature of cardiac dyssynchrony, what is known about its epidemiology, the effects of cardiac resynchronization therapy, appropriate patient selection, practical aspects, such as implantation and monitoring, and some still unanswered questions.

Inflammatory bowel disease is a global disease in the 21st century. We aimed to assess the changing incidence and prevalence of inflammatory bowel disease around the world. We searched MEDLINE and Embase up to and including Dec 31, 2016, to identify observational, population-based studies reporting the incidence or prevalence of Crohn's disease or ulcerative colitis from 1990 or later. A study was regarded as population-based if it involved all residents within a specific area and the patients were representative of that area. To be included in the systematic review, ulcerative colitis and Crohn's disease needed to be reported separately. Studies that did not report original data and studies that reported only the incidence or prevalence of paediatric-onset inflammatory bowel disease (diagnosis at age <16 years) were excluded. We created choropleth maps for the incidence (119 studies) and prevalence (69 studies) of Crohn's disease and ulcerative colitis. We used temporal trend analyses to report changes as an annual percentage change (APC) with 95% CI. We identified 147 studies that were eligible for final inclusion in the systematic review, including 119 studies of incidence and 69 studies of prevalence. The highest reported prevalence values were in Europe (ulcerative colitis 505 per 100 000 in Norway; Crohn's disease 322 per 100 000 in Germany) and North America (ulcerative colitis 286 per 100 000 in the USA; Crohn's disease 319 per 100 000 in Canada). The prevalence of inflammatory bowel disease exceeded 0·3% in North America, Oceania, and many countries in Europe. Overall, 16 (72·7%) of 22 studies on Crohn's disease and 15 (83·3%) of 18 studies on ulcerative colitis reported stable or decreasing incidence of inflammatory bowel disease in North America and Europe. Since 1990, incidence has been rising in newly industrialised countries in Africa, Asia, and South America, including Brazil (APC for Crohn's disease +11·1% [95% CI 4·8–17·8] and APC for ulcerative colitis +14·9% [10·4–19·6]) and Taiwan (APC for Crohn's disease +4·0% [1·0–7·1] and APC for ulcerative colitis +4·8% [1·8–8·0]). At the turn of the 21st century, inflammatory bowel disease has become a global disease with accelerating incidence in newly industrialised countries whose societies have become more westernised. Although incidence is stabilising in western countries, burden remains high as prevalence surpasses 0·3%. These data highlight the need for research into prevention of inflammatory bowel disease and innovations in health-care systems to manage this complex and costly disease. None.

An antibody to CD47 used in combination with rituximab induced responses in half of a small group of patients with refractory B-cell lymphoma. Inhibiting the macrophage checkpoint overcame rituximab resistance by activating macrophage-mediated tumor phagocytosis.

Older individuals with chronic health conditions are at highest risk of adverse clinical outcomes from COVID-19, but there is widespread belief that risk to younger, relatively lower-risk individuals is negligible. We assessed the rate and predictors of life-threatening complications among relatively lower-risk adults hospitalized with COVID-19. Of 3766 adults hospitalized with COVID-19 to three hospitals in New York City from March to May 2020, 963 were relatively lower-risk based on absence of preexisting health conditions. Multivariable logistic regression models examined in-hospital development of life-threatening complications (major medical events, intubation, or death). Covariates included age, sex, race/ethnicity, hypertension, weight, insurance type, and area-level sociodemographic factors (poverty, crowdedness, and limited English proficiency). In individuals ≥55 years old (n = 522), 33.3% experienced a life-threatening complication, 17.4% were intubated, and 22.6% died. Among those <55 years (n = 441), 15.0% experienced a life-threatening complication, 11.1% were intubated, and 5.9% died. In multivariable analyses among those ≥55 years, age (OR 1.03 [95%CI 1.01–1.06]), male sex (OR 1.72 [95%CI 1.14–2.64]), being publicly insured (versus commercial insurance: Medicare, OR 2.02 [95%CI 1.22–3.38], Medicaid, OR 1.87 [95%CI 1.10–3.20]) and living in areas with relatively high limited English proficiency (highest versus lowest quartile: OR 3.50 [95%CI 1.74–7.13]) predicted life-threatening complications. In those <55 years, no sociodemographic factors significantly predicted life-threatening complications. A substantial proportion of relatively lower-risk patients hospitalized with COVID-19 experienced life-threatening complications and more than 1 in 20 died. Public messaging needs to effectively convey that relatively lower-risk individuals are still at risk of serious complications.