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The New England Journal of Medicine Mar 2018Whether hydrocortisone reduces mortality among patients with septic shock is unclear. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Whether hydrocortisone reduces mortality among patients with septic shock is unclear.
METHODS
We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days.
RESULTS
From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia.
CONCLUSIONS
Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .).
Topics: APACHE; Aged; Anti-Inflammatory Agents; Bacteremia; Chemotherapy, Adjuvant; Double-Blind Method; Female; Fungemia; Humans; Hydrocortisone; Infusions, Intravenous; Male; Middle Aged; Recurrence; Renal Replacement Therapy; Respiration, Artificial; Shock, Septic; Survival Rate; Treatment Outcome
PubMed: 29347874
DOI: 10.1056/NEJMoa1705835 -
The New England Journal of Medicine Jun 2008Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors.
METHODS
In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up.
RESULTS
At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001).
CONCLUSIONS
As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)
Topics: Adult; Aged; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypertension; Hypoglycemia; Hypoglycemic Agents; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Treatment Failure
PubMed: 18539917
DOI: 10.1056/NEJMoa0802743 -
Physical Therapy Jan 2022Over the past 3 decades, the volume of human motor learning research has grown enormously. As such, the understanding of motor learning (ie, sustained change in motor...
Over the past 3 decades, the volume of human motor learning research has grown enormously. As such, the understanding of motor learning (ie, sustained change in motor behavior) has evolved. It has been learned that there are multiple mechanisms through which motor learning occurs, each with distinctive features. These mechanisms include use-dependent, instructive, reinforcement, and sensorimotor adaptation-based motor learning. It is now understood that these different motor learning mechanisms contribute in parallel or in isolation to drive desired changes in movement, and each mechanism is thought to be governed by distinct neural substrates. This expanded understanding of motor learning mechanisms has important implications for physical therapy. It has the potential to facilitate the development of new, more precise treatment approaches that physical therapists can leverage to improve human movement. This Perspective describes scientific advancements related to human motor learning mechanisms and discusses the practical implications of this work for physical therapist practice and education.
Topics: Adaptation, Physiological; Humans; Learning; Motor Skills; Physical Therapy Modalities
PubMed: 34718787
DOI: 10.1093/ptj/pzab250 -
Gut Apr 2022Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data...
OBJECTIVE
Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy.
DESIGN
Neutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry.
RESULTS
Neutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1 dendritic cell activation and CD8 T cell numbers which are associated with anti-tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8 T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-associated neutrophils (TANs) which switched from a protumour to anti-tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8 T cells in clusters that were enriched for the cytotoxic anti-tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs.
CONCLUSION
CXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC.
PubMed: 35477863
DOI: 10.1136/gutjnl-2021-326259 -
Scientific Reports Oct 2017Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood... (Clinical Trial)
Clinical Trial
Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other 'psychedelics' yet were related to clinical outcomes. A 'reset' therapeutic mechanism is proposed.
Topics: Adult; Brain; Depression; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Psilocybin
PubMed: 29030624
DOI: 10.1038/s41598-017-13282-7 -
Cell Mar 2021The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population.... (Review)
Review
The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population. The strain on global health care is projected to be colossal. This review explores the latest work and emerging ideas related to genetic and environmental factors influencing metabolism. Translational research and clinical applications, including the impact of the COVID-19 pandemic, are highlighted. Looking forward, strategies to personalize all aspects of prevention, management and care are necessary to improve health outcomes and reduce the impact of these metabolic diseases.
Topics: COVID-19; Circadian Rhythm; Diabetes Mellitus, Type 2; Epigenesis, Genetic; Genetic Predisposition to Disease; Humans; Inflammation; Obesity; Pandemics; Precision Medicine; Prevalence; Risk Factors; SARS-CoV-2; Thermotolerance
PubMed: 33675692
DOI: 10.1016/j.cell.2021.02.012 -
Avicenna Journal of Phytomedicine 2020The principle of the use of leeches is associated with traditional medicine of many countries and its application has different philosophies for use in different areas... (Review)
Review
OBJECTIVE
The principle of the use of leeches is associated with traditional medicine of many countries and its application has different philosophies for use in different areas of the body. Leeches, with all the benefits, can have dangers.
MATERIALS AND METHODS
A review of complications of leech therapy was done based on English articles indexed in the databases up to July 1, 2018. A strategic search has done independently by members of the research team and then all of the articles were +categorized by subject.
RESULTS
Related articles were mostly case-reports. Complications were divided into five categories including infection, allergy, prolonged bleeding, migration, and others. Infection is the most-reported complication related to leech therapy and has the most participation in infections.
CONCLUSION
Leech therapy can be a therapeutic complementary method if the possible complications are managed properly.
PubMed: 32523877
DOI: No ID Found -
JAMA Feb 2022Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19.... (Comparative Study)
Comparative Study Randomized Controlled Trial
Effect of Noninvasive Respiratory Strategies on Intubation or Mortality Among Patients With Acute Hypoxemic Respiratory Failure and COVID-19: The RECOVERY-RS Randomized Clinical Trial.
IMPORTANCE
Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies.
OBJECTIVE
To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure.
DESIGN, SETTING, AND PARTICIPANTS
A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021.
INTERVENTIONS
Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475).
MAIN OUTCOMES AND MEASURES
The primary outcome was a composite of tracheal intubation or mortality within 30 days.
RESULTS
The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, -8% [95% CI, -15% to -1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, -1% [95% CI, -8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group.
CONCLUSIONS AND RELEVANCE
Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings.
TRIAL REGISTRATION
isrctn.org Identifier: ISRCTN16912075.
Topics: Adult; COVID-19; Cannula; Continuous Positive Airway Pressure; Female; Hospital Mortality; Humans; Intubation, Intratracheal; Length of Stay; Male; Middle Aged; Noninvasive Ventilation; Oxygen Inhalation Therapy; Respiratory Insufficiency
PubMed: 35072713
DOI: 10.1001/jama.2022.0028 -
The Archives of Bone and Joint Surgery Mar 2022The use of free cutaneous or myocutaneous flaps in some surgeries, especially in reconstructive surgeries, is routine and imperative; nevertheless, it is controversial... (Review)
Review
The use of free cutaneous or myocutaneous flaps in some surgeries, especially in reconstructive surgeries, is routine and imperative; nevertheless, it is controversial because of fear of flap loss due to tissue congestion and partial or complete necrosis. Different mechanisms are discussed in this process, and based on the involved mechanisms, various agents and approaches are suggested for flap salvage. Among these agents and strategies, leech therapy (hirudotherapy) can be a valuable complementary treatment; however, in this way, full attention should be given to all beneficial and harmful aspects to reach the best results. This study included a literature review of the essential complications following free tissue transfer and explained the effects of leech therapy for the respective complications. Based on the review of the literature, the essential complications following free tissue transfer were (I) venous obstruction and congestion, (II) delay in blood flow reestablishment, (III) ischemia/reperfusion injuries, and (IV) thrombus formation. Leech therapy can protect free flaps against the mentioned complications as a complementary treatment. Leech therapy is an appropriate complement, however, not a definite approach for flap salvage. Therefore, in some patients, other alternative methods or even flap removal may be a better option.
PubMed: 35514759
DOI: 10.22038/ABJS.2022.55013.2736 -
JAMA Nov 2023Critical bleeding is associated with a high mortality rate in patients with trauma. Hemorrhage is exacerbated by a complex derangement of coagulation, including an acute...
IMPORTANCE
Critical bleeding is associated with a high mortality rate in patients with trauma. Hemorrhage is exacerbated by a complex derangement of coagulation, including an acute fibrinogen deficiency. Management is fibrinogen replacement with cryoprecipitate transfusions or fibrinogen concentrate, usually administered relatively late during hemorrhage.
OBJECTIVE
To assess whether survival could be improved by administering an early and empirical high dose of cryoprecipitate to all patients with trauma and bleeding that required activation of a major hemorrhage protocol.
DESIGN, SETTING, AND PARTICIPANTS
CRYOSTAT-2 was an interventional, randomized, open-label, parallel-group controlled, international, multicenter study. Patients were enrolled at 26 UK and US major trauma centers from August 2017 to November 2021. Eligible patients were injured adults requiring activation of the hospital's major hemorrhage protocol with evidence of active hemorrhage, systolic blood pressure less than 90 mm Hg at any time, and receiving at least 1 U of a blood component transfusion.
INTERVENTION
Patients were randomly assigned (in a 1:1 ratio) to receive standard care, which was the local major hemorrhage protocol (reviewed for guideline adherence), or cryoprecipitate, in which 3 pools of cryoprecipitate (6-g fibrinogen equivalent) were to be administered in addition to standard care within 90 minutes of randomization and 3 hours of injury.
MAIN OUTCOMES AND MEASURES
The primary outcome was all-cause mortality at 28 days in the intention-to-treat population.
RESULTS
Among 1604 eligible patients, 799 were randomized to the cryoprecipitate group and 805 to the standard care group. Missing primary outcome data occurred in 73 patients (principally due to withdrawal of consent) and 1531 (95%) were included in the primary analysis population. The median (IQR) age of participants was 39 (26-55) years, 1251 (79%) were men, median (IQR) Injury Severity Score was 29 (18-43), 36% had penetrating injury, and 33% had systolic blood pressure less than 90 mm Hg at hospital arrival. All-cause 28-day mortality in the intention-to-treat population was 26.1% in the standard care group vs 25.3% in the cryoprecipitate group (odds ratio, 0.96 [95% CI, 0.75-1.23]; P = .74). There was no difference in safety outcomes or incidence of thrombotic events in the standard care vs cryoprecipitate group (12.9% vs 12.7%).
CONCLUSIONS AND RELEVANCE
Among patients with trauma and bleeding who required activation of a major hemorrhage protocol, the addition of early and empirical high-dose cryoprecipitate to standard care did not improve all cause 28-day mortality.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04704869; ISRCTN Identifier: ISRCTN14998314.
Topics: Adult; Male; Humans; Middle Aged; Female; Hemorrhage; Fibrinogen; Blood Transfusion; Blood Component Transfusion; Wounds, Penetrating
PubMed: 37824155
DOI: 10.1001/jama.2023.21019