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The New England Journal of Medicine Aug 2019Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown.
METHODS
We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508.
RESULTS
A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups.
CONCLUSIONS
Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.).
Topics: Administration, Oral; Aged; Cholecalciferol; Diabetes Mellitus, Type 2; Dietary Supplements; Disease-Free Survival; Double-Blind Method; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prediabetic State; Risk Factors; Treatment Failure; Vitamin D; Vitamins
PubMed: 31173679
DOI: 10.1056/NEJMoa1900906 -
The New England Journal of Medicine Aug 2022New approaches for the prevention and elimination of malaria, a leading cause of illness and death among infants and young children globally, are needed.
BACKGROUND
New approaches for the prevention and elimination of malaria, a leading cause of illness and death among infants and young children globally, are needed.
METHODS
We conducted a phase 1 clinical trial to assess the safety and pharmacokinetics of L9LS, a next-generation antimalarial monoclonal antibody, and its protective efficacy against controlled human malaria infection in healthy adults who had never had malaria or received a vaccine for malaria. The participants received L9LS either intravenously or subcutaneously at a dose of 1 mg, 5 mg, or 20 mg per kilogram of body weight. Within 2 to 6 weeks after the administration of L9LS, both the participants who received L9LS and the control participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying (3D7 strain).
RESULTS
No safety concerns were identified. L9LS had an estimated half-life of 56 days, and it had dose linearity, with the highest mean (±SD) maximum serum concentration (C) of 914.2±146.5 μg per milliliter observed in participants who had received 20 mg per kilogram intravenously and the lowest mean C of 41.5±4.7 μg per milliliter observed in those who had received 1 mg per kilogram intravenously; the mean C was 164.8±31.1 in the participants who had received 5 mg per kilogram intravenously and 68.9±22.3 in those who had received 5 mg per kilogram subcutaneously. A total of 17 L9LS recipients and 6 control participants underwent controlled human malaria infection. Of the 17 participants who received a single dose of L9LS, 15 (88%) were protected after controlled human malaria infection. Parasitemia did not develop in any of the participants who received 5 or 20 mg per kilogram of intravenous L9LS. Parasitemia developed in 1 of 5 participants who received 1 mg per kilogram intravenously, 1 of 5 participants who received 5 mg per kilogram subcutaneously, and all 6 control participants through 21 days after the controlled human malaria infection. Protection conferred by L9LS was seen at serum concentrations as low as 9.2 μg per milliliter.
CONCLUSIONS
In this small trial, L9LS administered intravenously or subcutaneously protected recipients against malaria after controlled infection, without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 614 ClinicalTrials.gov number, NCT05019729.).
Topics: Administration, Cutaneous; Administration, Intravenous; Adult; Animals; Antibodies, Monoclonal; Child; Child, Preschool; Humans; Malaria; Malaria, Falciparum; Parasitemia; Plasmodium falciparum
PubMed: 35921449
DOI: 10.1056/NEJMoa2203067 -
Science (New York, N.Y.) Oct 2020Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2)...
Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer-generated scaffolds were either built around an ACE2 helix that interacts with the spike receptor binding domain (RBD) or docked against the RBD to identify new binding modes, and their amino acid sequences were designed to optimize target binding, folding, and stability. Ten designs bound the RBD, with affinities ranging from 100 picomolar to 10 nanomolar, and blocked SARS-CoV-2 infection of Vero E6 cells with median inhibitory concentration (IC) values between 24 picomolar and 35 nanomolar. The most potent, with new binding modes, are 56- and 64-residue proteins (IC ~ 0.16 nanograms per milliliter). Cryo-electron microscopy structures of these minibinders in complex with the SARS-CoV-2 spike ectodomain trimer with all three RBDs bound are nearly identical to the computational models. These hyperstable minibinders provide starting points for SARS-CoV-2 therapeutics.
Topics: Amino Acid Sequence; Angiotensin-Converting Enzyme 2; Animals; Antiviral Agents; Betacoronavirus; Binding Sites; COVID-19; Chlorocebus aethiops; Coronavirus Infections; Cryoelectron Microscopy; Drug Design; Molecular Docking Simulation; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Vero Cells
PubMed: 32907861
DOI: 10.1126/science.abd9909 -
The New England Journal of Medicine Jun 2021Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein...
BACKGROUND
Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder.
METHODS
We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)-heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4-heparin immunoassay.
RESULTS
Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor-blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4-heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation.
CONCLUSIONS
Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.).
Topics: Adult; Autoantibodies; Autoimmune Diseases; Blood Chemical Analysis; COVID-19 Vaccines; ChAdOx1 nCoV-19; Disseminated Intravascular Coagulation; Enzyme-Linked Immunosorbent Assay; Fatal Outcome; Female; Humans; Intracranial Hemorrhages; Male; Middle Aged; Platelet Activation; Platelet Factor 4; Thrombocytopenia; Thrombosis; Young Adult
PubMed: 33835769
DOI: 10.1056/NEJMoa2104840 -
The New England Journal of Medicine Jul 2020Vitamin D metabolites support innate immune responses to . Data from phase 3, randomized, controlled trials of vitamin D supplementation to prevent tuberculosis... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vitamin D metabolites support innate immune responses to . Data from phase 3, randomized, controlled trials of vitamin D supplementation to prevent tuberculosis infection are lacking.
METHODS
We randomly assigned children who had negative results for infection according to the QuantiFERON-TB Gold In-Tube assay (QFT) to receive a weekly oral dose of either 14,000 IU of vitamin D or placebo for 3 years. The primary outcome was a positive QFT result at the 3-year follow-up, expressed as a proportion of children. Secondary outcomes included the serum 25-hydroxyvitamin D (25[OH]D) level at the end of the trial and the incidence of tuberculosis disease, acute respiratory infection, and adverse events.
RESULTS
A total of 8851 children underwent randomization: 4418 were assigned to the vitamin D group, and 4433 to the placebo group; 95.6% of children had a baseline serum 25(OH)D level of less than 20 ng per milliliter. Among children with a valid QFT result at the end of the trial, the percentage with a positive result was 3.6% (147 of 4074 children) in the vitamin D group and 3.3% (134 of 4043) in the placebo group (adjusted risk ratio, 1.10; 95% confidence interval [CI], 0.87 to 1.38; P = 0.42). The mean 25(OH)D level at the end of the trial was 31.0 ng per milliliter in the vitamin D group and 10.7 ng per milliliter in the placebo group (mean between-group difference, 20.3 ng per milliliter; 95% CI, 19.9 to 20.6). Tuberculosis disease was diagnosed in 21 children in the vitamin D group and in 25 children in the placebo group (adjusted risk ratio, 0.87; 95% CI, 0.49 to 1.55). A total of 29 children in the vitamin D group and 34 in the placebo group were hospitalized for treatment of acute respiratory infection (adjusted risk ratio, 0.86; 95% CI, 0.52 to 1.40). The incidence of adverse events did not differ significantly between the two groups.
CONCLUSIONS
Vitamin D supplementation did not result in a lower risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection than placebo among vitamin D-deficient schoolchildren in Mongolia. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02276755.).
Topics: Child; Cholecalciferol; Dietary Supplements; Double-Blind Method; Female; Follow-Up Studies; Humans; Incidence; Latent Tuberculosis; Male; Mycobacterium tuberculosis; Respiratory Tract Infections; Treatment Failure; Tuberculin Test; Vitamin D; Vitamins
PubMed: 32706534
DOI: 10.1056/NEJMoa1915176 -
Cureus Aug 2022This case study aims to demonstrate the use of cannabidiol (CBD) with low-dose tetrahydrocannabinol (THC) in managing symptoms associated with autism spectrum disorder...
This case study aims to demonstrate the use of cannabidiol (CBD) with low-dose tetrahydrocannabinol (THC) in managing symptoms associated with autism spectrum disorder (ASD) to increase the overall quality of life for these individuals and their families. ASD is a neurodevelopmental disorder affecting cognitive development, behavior, social communication, and motor skills. Despite the increasing awareness of ASD, there is still a lack of safe and effective treatment options. The study includes a nine-year-old male patient who was diagnosed with nonverbal ASD. He exhibited emotional outbursts, inappropriate behaviors, and social deficits including challenges in communicating his needs with others. Since the patient was unable to attain independence at school and at home, his condition was a significant burden to his caregivers. The patient was treated with full-spectrum high CBD and low THC oil formulation, with each milliliter containing 20 mg of CBD and <1 mg of THC. CBD oil starting dose was 0.1ml twice daily, increased every three to four days to 0.5ml twice daily. Overall, the patient experienced a reduction in negative behaviors, including violent outbursts, self-injurious behaviors, and sleep disruptions. There was an improvement in social interactions, concentration, and emotional stability. A combination of high CBD and low-dose THC oil was demonstrated to be an effective treatment option for managing symptoms associated with autism, leading to a better quality of life for both the patient and the caregivers.
PubMed: 36176817
DOI: 10.7759/cureus.28442 -
MedRxiv : the Preprint Server For... Jun 2023To compare the frequency of replication-competent virologic rebound with and without nirmatrelvir-ritonavir treatment for acute COVID-19. Secondary aims were to estimate...
OBJECTIVE
To compare the frequency of replication-competent virologic rebound with and without nirmatrelvir-ritonavir treatment for acute COVID-19. Secondary aims were to estimate the validity of symptoms to detect rebound and the incidence of emergent nirmatrelvir-resistance mutations after rebound.
DESIGN
Observational cohort study.
SETTING
Multicenter healthcare system in Boston, Massachusetts.
PARTICIPANTS
We enrolled ambulatory adults with a positive COVID-19 test and/or a prescription for nirmatrelvir-ritonavir.
EXPOSURES
Receipt of 5 days of nirmatrelvir-ritonavir treatment versus no COVID-19 therapy.
MAIN OUTCOME AND MEASURES
The primary outcome was COVID-19 virologic rebound, defined as either (1) a positive SARS-CoV-2 viral culture following a prior negative culture or (2) two consecutive viral loads ≥4.0 log copies/milliliter after a prior reduction in viral load to <4.0 log copies/milliliter.
RESULTS
Compared with untreated individuals (n=55), those taking nirmatrelvir-ritonavir (n=72) were older, received more COVID-19 vaccinations, and were more commonly immunosuppressed. Fifteen individuals (20.8%) taking nirmatrelvir-ritonavir experienced virologic rebound versus one (1.8%) of the untreated (absolute difference 19.0% [95%CI 9.0-29.0%], P=0.001). In multivariable models, only N-R was associated with VR (AOR 10.02, 95%CI 1.13-88.74). VR occurred more commonly among those with earlier nirmatrelvir-ritonavir initiation (29.0%, 16.7% and 0% when initiated days 0, 1, and ≥2 after diagnosis, respectively, P=0.089). Among participants on N-R, those experiencing rebound had prolonged shedding of replication-competent virus compared to those that did not rebound (median: 14 vs 3 days). Only 8/16 with virologic rebound reported worsening symptoms (50%, 95%CI 25%-75%); 2 were completely asymptomatic. We detected no post-rebound nirmatrelvir-resistance mutations in the NSP5 protease gene.
CONCLUSIONS AND RELEVANCE
Virologic rebound occurred in approximately one in five people taking nirmatrelvir-ritonavir and often occurred without worsening symptoms. Because it is associated with replication-competent viral shedding, close monitoring and potential isolation of those who rebound should be considered.
PubMed: 37425934
DOI: 10.1101/2023.06.23.23288598 -
Cureus Nov 2022Sperm cryopreservation has been used as a sperm preservation solution for infertility issues faced by men undergoing cancer treatment for over 40 years. Recent... (Review)
Review
Sperm cryopreservation has been used as a sperm preservation solution for infertility issues faced by men undergoing cancer treatment for over 40 years. Recent developments in sperm cryopreservation and its wide variety of therapeutic uses are discussed in this article, which offers a succinct and up-to-date overview of the relevant literature. Recently, sperm cryopreservation has been employed for a wider variety of therapeutic purposes. As a result, sperm freezing is becoming available to a wider variety of patients, which requires more specialized personnel and increases overhead expenses. While sperm cryopreservation before cancer treatment is accessible in many countries, oncology doctors' referral rates and patient participation with cryopreservation services have been observed to be poor. In addition, there are still moral concerns with sperm banking, including whether or not donors' identities should be protected and whether or not a deceased person's sperm should be used after his or her death. This article discusses the recent developments in sperm cryopreservation technology and the moral questions that have arisen around this practice, with an eye toward how a deeper knowledge of these concerns can help more people get access to treatments that might help preserve their fertility. A sperm bank will notify clients about the screenings it does and the background information it gathers on individual donors to guarantee the safety and quality of the sperm they get. The viability and quantity of viable sperm in a thawed sample are often guaranteed by a sperm bank. They will look for very fertile males who can donate sperm that can withstand the freezing and thawing procedure. In many cases, sperm banks advertise their samples as having a certain number of viable sperm per milliliter, and they may provide many sample types for various applications (intracytoplasmic sperm injection and intrauterine insemination).
PubMed: 36523734
DOI: 10.7759/cureus.31402