Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches.
...To compare the effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for weight management as an adjunct to intensive behavioral therapy with initial low-calorie diet in adults with overweight or obesity.
Randomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites in the US from August 2018 to April 2020 in adults without diabetes (N = 611) and with either overweight (body mass index ≥27) plus at least 1 comorbidity or obesity (body mass index ≥30).
Participants were randomized (2:1) to semaglutide, 2.4 mg (n = 407) or placebo (n = 204), both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (ie, 30 counseling visits) during 68 weeks.
The co-primary end points were percentage change in body weight and the loss of 5% or more of baseline weight by week 68. Confirmatory secondary end points included losses of at least 10% or 15% of baseline weight.
Of 611 randomized participants (495 women 81.0%, mean age 46 years SD, 13, body weight 105.8 kg SD, 22.9, and body mass index 38.0 SD, 6.7), 567 (92.8%) completed the trial, and 505 (82.7%) were receiving treatment at trial end. At week 68, the estimated mean body weight change from baseline was -16.0% for semaglutide vs -5.7% for placebo (difference, -10.3 percentage points 95% CI, -12.0 to -8.6; P < .001). More participants treated with semaglutide vs placebo lost at least 5% of baseline body weight (86.6% vs 47.6%, respectively; P < .001). A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P < .001). Gastrointestinal adverse events were more frequent with semaglutide (82.8%) vs placebo (63.2%). Treatment was discontinued owing to these events in 3.4% of semaglutide participants vs 0% of placebo participants.
Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings.
ClinicalTrials.gov Identifier: NCT03611582.
Alternative treatment modes for antibiotic-resistant bacterial pathogens have become a public health priority. Bacteriophages are bacterial viruses that infect and lyse bacterial cells. Since ...bacteriophages are frequently bacterial host species-specific and can often also infect antibiotic-resistant bacterial cells, they could represent ideal antimicrobials for fighting the antibiotic resistance crisis. The medical use of bacteriophages has become known as phage therapy. It is widely used in Russia, where phage cocktails are sold in pharmacies as an over-the-counter drug. However, no phage product has been registered for medical purposes outside of the former Soviet Union. The current Special Issue of Viruses contains a collection of papers from opinion leaders in the field who explore hurdles to the introduction of phage therapy in western countries. The articles cover diverse topics ranging from patent to regulatory issues, the targeting of suitable bacterial infections, and the selection and characterization of safe and efficient phage cocktails. Phage resistance is discussed, and gaps in our knowledge of phage–bacterium interactions in the mammalian body are revealed, while other articles explore the use of phages in food production and processing.
The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on noninvasive treatment of low back pain.
Using the ACP grading system, ...the committee based these recommendations on a systematic review of randomized, controlled trials and systematic reviews published through April 2015 on noninvasive pharmacologic and nonpharmacologic treatments for low back pain. Updated searches were performed through November 2016. Clinical outcomes evaluated included reduction or elimination of low back pain, improvement in back-specific and overall function, improvement in health-related quality of life, reduction in work disability and return to work, global improvement, number of back pain episodes or time between episodes, patient satisfaction, and adverse effects.
The target audience for this guideline includes all clinicians, and the target patient population includes adults with acute, subacute, or chronic low back pain.
Given that most patients with acute or subacute low back pain improve over time regardless of treatment, clinicians and patients should select nonpharmacologic treatment with superficial heat (moderate-quality evidence), massage, acupuncture, or spinal manipulation (low-quality evidence). If pharmacologic treatment is desired, clinicians and patients should select nonsteroidal anti-inflammatory drugs or skeletal muscle relaxants (moderate-quality evidence). (Grade: strong recommendation).
For patients with chronic low back pain, clinicians and patients should initially select nonpharmacologic treatment with exercise, multidisciplinary rehabilitation, acupuncture, mindfulness-based stress reduction (moderate-quality evidence), tai chi, yoga, motor control exercise, progressive relaxation, electromyography biofeedback, low-level laser therapy, operant therapy, cognitive behavioral therapy, or spinal manipulation (low-quality evidence). (Grade: strong recommendation).
In patients with chronic low back pain who have had an inadequate response to nonpharmacologic therapy, clinicians and patients should consider pharmacologic treatment with nonsteroidal anti-inflammatory drugs as first-line therapy, or tramadol or duloxetine as second-line therapy. Clinicians should only consider opioids as an option in patients who have failed the aforementioned treatments and only if the potential benefits outweigh the risks for individual patients and after a discussion of known risks and realistic benefits with patients. (Grade: weak recommendation, moderate-quality evidence).
Supplemental oxygen is often administered liberally to acutely ill adults, but the credibility of the evidence for this practice is unclear. We systematically reviewed the efficacy and safety of ...liberal versus conservative oxygen therapy in acutely ill adults.
In the Improving Oxygen Therapy in Acute-illness (IOTA) systematic review and meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, HealthSTAR, LILACS, PapersFirst, and the WHO International Clinical Trials Registry from inception to Oct 25, 2017, for randomised controlled trials comparing liberal and conservative oxygen therapy in acutely ill adults (aged ≥18 years). Studies limited to patients with chronic respiratory diseases or psychiatric disease, patients on extracorporeal life support, or patients treated with hyperbaric oxygen therapy or elective surgery were excluded. We screened studies and extracted summary estimates independently and in duplicate. We also extracted individual patient-level data from survival curves. The main outcomes were mortality (in-hospital, at 30 days, and at longest follow-up) and morbidity (disability at longest follow-up, risk of hospital-acquired pneumonia, any hospital-acquired infection, and length of hospital stay) assessed by random-effects meta-analyses. We assessed quality of evidence using the grading of recommendations assessment, development, and evaluation approach. This study is registered with PROSPERO, number CRD42017065697.
25 randomised controlled trials enrolled 16 037 patients with sepsis, critical illness, stroke, trauma, myocardial infarction, or cardiac arrest, and patients who had emergency surgery. Compared with a conservative oxygen strategy, a liberal oxygen strategy (median baseline saturation of peripheral oxygen SpO2 across trials, 96% range 94–99%, IQR 96–98) increased mortality in-hospital (relative risk RR 1·21, 95% CI 1·03–1·43, I2=0%, high quality), at 30 days (RR 1·14, 95% CI 1·01–1·29, I2=0%, high quality), and at longest follow-up (RR 1·10, 95% CI 1·00–1·20, I2=0%, high quality). Morbidity outcomes were similar between groups. Findings were robust to trial sequential, subgroup, and sensitivity analyses.
In acutely ill adults, high-quality evidence shows that liberal oxygen therapy increases mortality without improving other patient-important outcomes. Supplemental oxygen might become unfavourable above an SpO2 range of 94–96%. These results support the conservative administration of oxygen therapy.
None.
Dominant negative genetic disorders, in which a mutant allele of a gene causes disease in the presence of a second, normal copy, have been challenging since there is no cure and treatments are only ...to alleviate the symptoms. Current therapies involving pharmacological and biological drugs are not suitable to target mutant genes selectively due to structural indifference of the normal variant of their targets from the disease-causing mutant ones. In instances when the target contains single nucleotide polymorphism (SNP), whether it is an enzyme or structural or receptor protein are not ideal for treatment using conventional drugs due to their lack of selectivity. Therefore, there is a need to develop new approaches to accelerate targeting these previously inaccessible targets by classical therapeutics. Although there is a cooling trend by the pharmaceutical industry for the potential of RNA interference (RNAi), RNAi and other RNA targeting drugs (antisense, ribozyme, etc.) still hold their promise as the only drugs that provide an opportunity to target genes with SNP mutations found in dominant negative disorders, genes specific to pathogenic tumor cells, and genes that are critical for mediating the pathology of various other diseases. Because of its exquisite specificity and potency, RNAi has attracted a considerable interest as a new class of therapeutic for genetic diseases including amyotrophic lateral sclerosis, Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD), spinocerebellar ataxia, dominant muscular dystrophies, and cancer. In this review, progress and challenges in developing RNAi therapeutics for genetic diseases will be discussed.
Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient ...responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.
Highlights • Role of immune checkpoint inhibition in the management of key malignancies. • Description of rates of immune-related adverse events and timing of their onset. • Management strategies for ...immune-related toxicities.
Neuroinflammation is a physiological response aimed at maintaining the homodynamic balance and providing the body with the fundamental resource of adaptation to endogenous and exogenous stimuli. ...Although the response is initiated with protective purposes, the effect may be detrimental when not regulated. The physiological control of neuroinflammation is mainly achieved via regulatory mechanisms performed by particular cells of the immune system intimately associated with or within the nervous system and named "non-neuronal cells." In particular, mast cells (within the central nervous system and in the periphery) and microglia (at spinal and supraspinal level) are involved in this control, through a close functional relationship between them and neurons (either centrally, spinal, or peripherally located). Accordingly, neuroinflammation becomes a worsening factor in many disorders whenever the non-neuronal cell supervision is inadequate. It has been shown that the regulation of non-neuronal cells-and therefore the control of neuroinflammation-depends on the local "
" synthesis of the endogenous lipid amide Palmitoylethanolamide and related endocannabinoids. When the balance between synthesis and degradation of this bioactive lipid mediator is disrupted in favor of reduced synthesis and/or increased degradation, the behavior of non-neuronal cells may not be appropriately regulated and neuroinflammation exceeds the physiological boundaries. In these conditions, it has been demonstrated that the increase of endogenous Palmitoylethanolamide-either by decreasing its degradation or exogenous administration-is able to keep neuroinflammation within its physiological limits. In this review the large number of studies on the benefits derived from oral administration of micronized and highly bioavailable forms of Palmitoylethanolamide is discussed, with special reference to neuroinflammatory disorders.
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