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International Journal of Molecular... Feb 2020Somatostatin analogs are an invaluable therapeutic option in the diagnosis and treatment of somatotropinomas, thyrotropinomas, and functioning and non-functioning... (Review)
Review
Somatostatin analogs are an invaluable therapeutic option in the diagnosis and treatment of somatotropinomas, thyrotropinomas, and functioning and non-functioning gastroenteropancreatic neuroendocrine tumors. They should also be considered an effective and safe therapeutic alternative to corticotropinomas, gonadotropinomas, and prolactinomas resistant to dopamine agonists. Somatostatin analogs have also shown to be useful in the treatment of other endocrine diseases (congenital hyperinsulinism, Graves' orbitopathy, diabetic retinopathy, diabetic macular edema), non-endocrine tumors (breast, colon, prostate, lung, and hepatocellular), and digestive diseases (chronic refractory diarrhea, hepatorenal polycystosis, gastrointestinal hemorrhage, dumping syndrome, and intestinal fistula).
Topics: Antineoplastic Agents, Hormonal; Diabetic Retinopathy; Graves Ophthalmopathy; Growth Hormone-Secreting Pituitary Adenoma; Humans; Intestinal Neoplasms; Macular Edema; Neuroendocrine Tumors; Pancreatic Neoplasms; Pituitary Neoplasms; Somatostatin; Stomach Neoplasms
PubMed: 32121432
DOI: 10.3390/ijms21051682 -
The New England Journal of Medicine Apr 2022Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M) inhibitor with potent pan-human-coronavirus activity in vitro. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M) inhibitor with potent pan-human-coronavirus activity in vitro.
METHODS
We conducted a phase 2-3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19-related hospitalization or death from any cause through day 28, viral load, and safety were evaluated.
RESULTS
A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], -9.04 to -3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of -5.81 percentage points (95% CI, -7.78 to -3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmatrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo.
CONCLUSIONS
Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.).
Topics: Adult; Humans; Administration, Oral; Antiviral Agents; COVID-19 Drug Treatment; Disease Progression; Double-Blind Method; Hospitalization; Lactams; Leucine; Nitriles; Proline; Ritonavir; SARS-CoV-2; Treatment Outcome; Vaccination; Viral Load; Viral Protease Inhibitors; COVID-19
PubMed: 35172054
DOI: 10.1056/NEJMoa2118542 -
The New England Journal of Medicine Feb 2021Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19.
METHODS
This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2.
RESULTS
The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups.
CONCLUSIONS
The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).
Topics: 2019-nCoV Vaccine mRNA-1273; Adolescent; Adult; Aged; COVID-19; COVID-19 Vaccines; Female; Humans; Incidence; Male; Middle Aged; Patient Acuity; SARS-CoV-2; Single-Blind Method; Spike Glycoprotein, Coronavirus; Treatment Outcome; Young Adult
PubMed: 33378609
DOI: 10.1056/NEJMoa2035389 -
The Lancet. Microbe Mar 2023Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the distribution and clinical significance of carbapenemases are unclear. The aim of this... (Observational Study)
Observational Study
BACKGROUND
Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the distribution and clinical significance of carbapenemases are unclear. The aim of this study was to define characteristics and outcomes of CRPA infections and the global frequency and clinical impact of carbapenemases harboured by CRPA.
METHODS
We conducted an observational, prospective cohort study of CRPA isolated from bloodstream, respiratory, urine, or wound cultures of patients at 44 hospitals (10 countries) between Dec 1, 2018, and Nov 30, 2019. Clinical data were abstracted from health records and CRPA isolates were whole-genome sequenced. The primary outcome was 30-day mortality from the day the index culture was collected. We compared outcomes of patients with CRPA infections by infection type and across geographic regions and performed an inverse probability weighted analysis to assess the association between carbapenemase production and 30-day mortality.
FINDINGS
We enrolled 972 patients (USA n=527, China n=171, south and central America n=127, Middle East n=91, Australia and Singapore n=56), of whom 581 (60%) had CRPA infections. 30-day mortality differed by infection type (bloodstream 21 [30%] of 69, respiratory 69 [19%] of 358, wound nine [14%] of 66, urine six [7%] of 88; p=0·0012) and geographical region (Middle East 15 [29%] of 52, south and central America 20 [27%] of 73, USA 60 [19%] of 308, Australia and Singapore three [11%] of 28, China seven [6%] of 120; p=0·0002). Prevalence of carbapenemase genes among CRPA isolates also varied by region (south and central America 88 [69%] of 127, Australia and Singapore 32 [57%] of 56, China 54 [32%] of 171, Middle East 27 [30%] of 91, USA ten [2%] of 527; p<0·0001). KPC-2 (n=103 [49%]) and VIM-2 (n=75 [36%]) were the most common carbapenemases in 211 carbapenemase-producing isolates. After excluding USA patients, because few US isolates had carbapenemases, patients with carbapenemase-producing CRPA infections had higher 30-day mortality than those with non-carbapenemase-producing CRPA infections in both unadjusted (26 [22%] of 120 vs 19 [12%] of 153; difference 9%, 95% CI 3-16) and adjusted (difference 7%, 95% CI 1-14) analyses.
INTERPRETATION
The emergence of different carbapenemases among CRPA isolates in different geographical regions and the increased mortality associated with carbapenemase-producing CRPA infections highlight the therapeutic challenges posed by these organisms.
FUNDING
National Institutes of Health.
Topics: United States; Humans; Anti-Bacterial Agents; Pseudomonas aeruginosa; Prospective Studies; Pseudomonas Infections; Carbapenems
PubMed: 36774938
DOI: 10.1016/S2666-5247(22)00329-9 -
Journal of Clinical Medicine Oct 2023Nosocomial pneumonia, or hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) are important health problems worldwide, with both being associated... (Review)
Review
Nosocomial pneumonia, or hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) are important health problems worldwide, with both being associated with substantial morbidity and mortality. HAP is currently the main cause of death from nosocomial infection in critically ill patients. Although guidelines for the approach to this infection model are widely implemented in international health systems and clinical teams, information continually emerges that generates debate or requires updating in its management. This scientific manuscript, written by a multidisciplinary team of specialists, reviews the most important issues in the approach to this important infectious respiratory syndrome, and it updates various topics, such as a renewed etiological perspective for updating the use of new molecular platforms or imaging techniques, including the microbiological diagnostic stewardship in different clinical settings and using appropriate rapid techniques on invasive respiratory specimens. It also reviews both Intensive Care Unit admission criteria and those of clinical stability to discharge, as well as those of therapeutic failure and rescue treatment options. An update on antibiotic therapy in the context of bacterial multiresistance, in aerosol inhaled treatment options, oxygen therapy, or ventilatory support, is presented. It also analyzes the out-of-hospital management of nosocomial pneumonia requiring complete antibiotic therapy externally on an outpatient basis, as well as the main factors for readmission and an approach to management in the emergency department. Finally, the main strategies for prevention and prophylactic measures, many of them still controversial, on fragile and vulnerable hosts are reviewed.
PubMed: 37892664
DOI: 10.3390/jcm12206526 -
Neurology Feb 2022The clinical course and outcome of the Guillain-Barré syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS), developed with...
BACKGROUND AND OBJECTIVES
The clinical course and outcome of the Guillain-Barré syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS), developed with data from Dutch patients, is a clinical model that predicts the risk of walking inability in patients with GBS. The study objective was to validate the mEGOS in the International GBS Outcome Study (IGOS) cohort and to improve its performance and region specificity.
METHODS
We used prospective data from the first 1,500 patients included in IGOS, aged ≥6 years and unable to walk independently. We evaluated whether the mEGOS at entry and week 1 could predict the inability to walk unaided at 4 and 26 weeks in the full cohort and in regional subgroups, using 2 measures for model performance: (1) discrimination: area under the receiver operating characteristic curve (AUC) and (2) calibration: observed vs predicted probability of being unable to walk independently. To improve the model predictions, we recalibrated the model containing the overall mEGOS score, without changing the individual predictive factors. Finally, we assessed the predictive ability of the individual factors.
RESULTS
For validation of mEGOS at entry, 809 patients were eligible (Europe/North America [n = 677], Asia [n = 76], other [n = 56]), and 671 for validation of mEGOS at week 1 (Europe/North America [n = 563], Asia [n = 65], other [n = 43]). AUC values were >0.7 in all regional subgroups. In the Europe/North America subgroup, observed outcomes were worse than predicted; in Asia, observed outcomes were better than predicted. Recalibration improved model accuracy and enabled the development of a region-specific version for Europe/North America (mEGOS-Eu/NA). Similar to the original mEGOS, severe limb weakness and higher age were the predominant predictors of poor outcome in the IGOS cohort.
DISCUSSION
mEGOS is a validated tool to predict the inability to walk unaided at 4 and 26 weeks in patients with GBS, also in countries outside the Netherlands. We developed a region-specific version of mEGOS for patients from Europe/North America.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that the mEGOS accurately predicts the inability to walk unaided at 4 and 26 weeks in patients with GBS.
TRIAL REGISTRATION INFORMATION
NCT01582763.
Topics: Child; Cohort Studies; Guillain-Barre Syndrome; Humans; Outcome Assessment, Health Care; Prognosis; Prospective Studies
PubMed: 34937789
DOI: 10.1212/WNL.0000000000013139 -
JAMA Surgery Mar 2022Ischemic cold storage (ICS) of livers for transplant is associated with serious posttransplant complications and underuse of liver allografts. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Ischemic cold storage (ICS) of livers for transplant is associated with serious posttransplant complications and underuse of liver allografts.
OBJECTIVE
To determine whether portable normothermic machine perfusion preservation of livers obtained from deceased donors using the Organ Care System (OCS) Liver ameliorates early allograft dysfunction (EAD) and ischemic biliary complications (IBCs).
DESIGN, SETTING, AND PARTICIPANTS
This multicenter randomized clinical trial (International Randomized Trial to Evaluate the Effectiveness of the Portable Organ Care System Liver for Preserving and Assessing Donor Livers for Transplantation) was conducted between November 2016 and October 2019 at 20 US liver transplant programs. The trial compared outcomes for 300 recipients of livers preserved using either OCS (n = 153) or ICS (n = 147). Participants were actively listed for liver transplant on the United Network of Organ Sharing national waiting list.
INTERVENTIONS
Transplants were performed for recipients randomly assigned to receive donor livers preserved by either conventional ICS or the OCS Liver initiated at the donor hospital.
MAIN OUTCOMES AND MEASURES
The primary effectiveness end point was incidence of EAD. Secondary end points included OCS Liver ex vivo assessment capability of donor allografts, extent of reperfusion syndrome, incidence of IBC at 6 and 12 months, and overall recipient survival after transplant. The primary safety end point was the number of liver graft-related severe adverse events within 30 days after transplant.
RESULTS
Of 293 patients in the per-protocol population, the primary analysis population for effectiveness, 151 were in the OCS Liver group (mean [SD] age, 57.1 [10.3] years; 102 [67%] men), and 142 were in the ICS group (mean SD age, 58.6 [10.0] years; 100 [68%] men). The primary effectiveness end point was met by a significant decrease in EAD (27 of 150 [18%] vs 44 of 141 [31%]; P = .01). The OCS Liver preserved livers had significant reduction in histopathologic evidence of ischemia-reperfusion injury after reperfusion (eg, less moderate to severe lobular inflammation: 9 of 150 [6%] for OCS Liver vs 18 of 141 [13%] for ICS; P = .004). The OCS Liver resulted in significantly higher use of livers from donors after cardiac death (28 of 55 [51%] for the OCS Liver vs 13 of 51 [26%] for ICS; P = .007). The OCS Liver was also associated with significant reduction in incidence of IBC 6 months (1.3% vs 8.5%; P = .02) and 12 months (2.6% vs 9.9%; P = .02) after transplant.
CONCLUSIONS AND RELEVANCE
This multicenter randomized clinical trial provides the first indication, to our knowledge, that normothermic machine perfusion preservation of deceased donor livers reduces both posttransplant EAD and IBC. Use of the OCS Liver also resulted in increased use of livers from donors after cardiac death. Together these findings indicate that OCS Liver preservation is associated with superior posttransplant outcomes and increased donor liver use.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02522871.
Topics: Death; Female; Humans; Liver; Liver Transplantation; Living Donors; Male; Middle Aged; Organ Preservation; Perfusion
PubMed: 34985503
DOI: 10.1001/jamasurg.2021.6781