Does sertraline provide symptomatic relief for chronic breathlessness in people with advanced disease whose underlying cause(s) are optimally treated?223 participants with chronic breathlessness ...(modified Medical Research Council breathlessness scale ≥2) who had optimal treatment of underlying cause(s) were randomised 1:1 to sertraline 25-100 mg (titrated upwards over 9 days) or placebo for 4 weeks. The primary outcome was the proportion who had an improvement in intensity of current breathlessness >15% from baseline on a 100-mm visual analogue scale.The proportion of people responding to sertraline was similar to placebo for current breathlessness on days 26-28 (OR 1.00, 95% CI 0.71-1.40) and for other measures of breathlessness. Quality of life in the sertraline arm had a higher likelihood of improving than in the placebo arm over the 4 weeks (OR 0.21, 95% CI 0.01-0.41; p=0.044). No differences in performance status, anxiety and depression, or survival were observed. Adverse event rates were similar between arms.Sertraline does not appear to provide any benefit over placebo in the symptomatic relief of chronic breathlessness in this patient population.
Genome sequencing is enabling precision medicine—tailoring treatment to the unique constellation of variants in an individual’s genome. The impact of recurrent pathogenic variants is often ...understood, however there is a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.
Genome sequencing is enabling precision medicine—tailoring treatment to the unique constellation of variants in an individual’s genome. The impact of recurrent pathogenic variants is often understood, leaving a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.
Accepting Brain Death Magnus, David C; Wilfond, Benjamin S; Caplan, Arthur L
The New England journal of medicine,
03/2014, Letnik:
370, Številka:
10
Journal Article
Recenzirano
The cases of Jahi McMath and Marlise Muñoz have reopened public debate about brain death. But the law and ethics have long recognized that deferring to medical expertise regarding the diagnosis of ...brain death is the most reasonable way to manage the process of dying.
Two cases in which patients have been determined to be dead according to neurologic criteria (“brain death”) have recently garnered national headlines. In Oakland, California, Jahi McMath's death was determined by means of multiple independent neurologic examinations, including one ordered by a court. Her family refused to accept that she had died and went to court to prevent physicians at Children's Hospital and Research Center in Oakland from discontinuing ventilator support. Per a court-supervised agreement, the body was given to the family 3 weeks after the initial determination. The family's attorney stated that ventilatory support was continued and nutritional support . . .
The intermediate- and long-term effects of regular low-dose sustained-release (SR) morphine on the testosterone levels of people with persistent breathlessness are unknown.
Exploratory analysis of a ...randomized controlled trial of the effects of regular SR morphine (0/8/16/24 mg every 24 hours) for persistent breathlessness associated with chronic obstructive pulmonary disease. Total testosterone was measured at baseline and at cessation (greater than or equal to three months on stable medication).
Among 20 participants (9 males; median treatment duration between measurements 169 days IQR 162-175), only 3 had substantial declines in testosterone levels during the study (morphine 8, 16, 24 mg groups). All three had worsening illness at the time of the second assessment. There was no apparent relationship between change in testosterone, morphine dose, and change in breathlessness.
Substantial declines in testosterone were uncommon and were not apparently related to changes in morphine dose or breathlessness, but they were possibly related with worsening illness.
Background:
Sleep, a multi-dimensional experience, is essential for optimal physical and mental wellbeing. Poor sleep is associated with worse wellbeing but data are scarce from multi-site studies on ...sleeping-related distress in palliative care populations.
Aim:
To evaluate patient-reported distress related to sleep and explore key demographic and symptom distress related to pain, breathing or fatigue.
Design:
Australian national, consecutive cohort study with prospectively collected point-of-care data using symptoms from the Symptom Assessment Scale (SAS).
Setting/Participants:
People (n = 118,117; 475,298 phases of care) who died while being seen by specialist palliative care services (n = 152) 2013–2019. Settings: inpatient (direct care, consultative); community (outpatient clinics, home, residential aged care).
Results:
Moderate/severe levels of sleeping-related distress were reported in 11.9% of assessments, more frequently by males (12.7% vs 10.9% females); people aged <50 years (16.2% vs 11.5%); and people with cancer (12.3% vs 10.0% for other diagnoses). Sleeping-related distress peaked with mid-range Australia-modified Karnofsky Performance Status scores (40–60).
Strong associations existed between pain-, breathing- and fatigue-related distress in people who identified moderate/severe sleeping-related distress, adjusted for age, sex and functional status. Those reporting moderate/severe sleeping-related distress were also more likely to experience severe pain-related distress (adjusted odds ratios OR 6.6; 95% confidence interval (CI) 6.3, 6.9); breathing-related distress (OR 6.2; 95% CI 5.8, 6.6); and fatigue-related distress (OR 10.4; 95% CI 9.99–10.8).
Conclusions:
This large, representative study of palliative care patients shows high prevalence of sleeping-related distress, with strong associations shown to distress from other symptoms including pain, breathlessness and fatigue.
With regard to the letter from Morélot-Panzini and colleagues in response to our Perspective 1, it is good to see support for the concept of a clinical syndrome and its potential in raising ...awareness of the needs of such patients in the minds of all clinicians; we welcome the ongoing discussion. It serves to highlight the importance of this neglected patient group and clinical topic, as well as the process for how an internationally agreed name and definition in English can be translated both linguistically and culturally in non-English-speaking countries. This letter highlights the thought processes that will need to occur in each translation of the concept. In seeing this work already occurring, our Perspective 1 has already achieved one of its aims.
Chronic breathlessness is a cardinal symptom in cardiopulmonary disease where both overall intensity or severity (S) and unpleasantness (U) are commonly quantified.
We aimed to evaluate agreement ...between breathlessness severity and unpleasantness over eight days in patients with chronic breathlessness.
Longitudinal analysis of 265 patients with chronic breathlessness who rated current overall breathlessness severity and unpleasantness on a 0–100 mm visual analogue scale (VAS) in the morning and evening over eight days. A total of 3630 paired overall severity-unpleasantness (S−U) differences were analyzed; median 15 (IQR 13–16) per patient. Agreement was evaluated using Bland-Altman plots. Associations of the difference between severity and unpleasantness (S−U difference) with clinical factors and perceived quality of life were analyzed using multilevel linear regression adjusted for confounders.
Over eight days, severity and unpleasantness scores were highly correlated, had similar variability, and varied more between patients than within patients. The mean S−U difference was small at 2.1 mm. Agreement between overall severity and unpleasantness was similar or higher than expected from the variability in individual scores. The S−U difference was similar across evaluated factors including age, sex, diagnosis, morning/evening assessment, modified Medical Research Council breathlessness score, morphine treatment, and presence of different sensory qualities of breathlessness. Higher overall severity and unpleasantness associated with worse perceived quality of life in a similar way.
In patients with chronic breathlessness over eight days, overall severity and unpleasantness of breathlessness were comparable and associated to other clinical factors in a similar manner.
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