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1.
Rev. esp. quimioter ; 37(1): 17-28, Feb. 2024.
Artigo em Inglês | IBECS | ID: ibc-230419

RESUMO

Despite having emerged from pandemic status, the incidence of COVID-19 episodes has recently increased in Spain, including pediatric cases and admissions to Intensive Care Units. Several recombinant variants are circulating among us, particularly XBB arising from two Omicron BA.2 sublineages with mutations in the genes encoding the spicule proteins that could increase binding to the ACE2 receptor and be more prone to immune escape. Faced with these, 3 pharmaceutical companies have developed vaccines adapted to the XBB.1.5 sublineage that are already available for administration in our setting with risks that should not be different from those of previous mRNA vaccines and with clearly favorable benefit/risk ratios. They should be applied to patients with potential for poor COVID-19 evolution and to collectives that have a particular relationship of proximity with them. Their application should be understood not only from a perspective of individual convenience but also from that of collective responsibility. The most convenient seems to be a simultaneous immunization of COVID-19 and influenza in our environment. In the therapeutic aspect, there is little to expect right now from antisera, but the already known antiviral drugs are still available and indicated, although their efficacy will have to be reevaluated due to their impact on populations that are mostly immunized and with a better prognosis than in the past. In our opinion, it is necessary to continue to make a reasonable and timely use of masks and other non-pharmacological means of protection. (AU)


Pese a haber salido de la situación de pandemia, la incidencia de episodios de COVID-19 ha aumentado recientemente en España, incluidos los casos pediátricos y los ingresos en Unidades de Cuidados Intensivos. Circulan entre nosotros diversas variantes recombinantes, particularmente la XBB surgidas de dos sublinajes Omicron BA.2 con mutaciones en los genes que codifican las proteínas de la espícula y que pudieran aumentar la unión al receptor ACE2 y ser más propensas al escape inmune. Frente a ellas, 3 empresas farmacéuticas han elaborado vacunas adaptadas al sublinaje XBB.1.5 que ya se encuentran disponibles para su administración en nuestro medio con riesgos que no deben ser diferentes a los de las vacunas mRNA previas y con relaciones beneficio/riesgos claramente favorables. Deben aplicarse a pacientes con potencial de mala evolución de COVID-19 y a los colectivos que tienen una particular relación de proximidad con ellos. Su aplicación debe ser entendida no sólo desde una perspectiva de conveniencia individual sino desde la de la responsabilidad colectiva. Lo más conveniente parece hacer una inmunización simultánea de COVID-19 y gripe en nuestro medio. En el aspecto terapéutico hay poco que esperar ahora mismo de los antisueros pero siguen estando disponibles e indicados los fármacos antivirales ya conocidos aunque su eficacia tendrá que reevaluarse por su impacto en poblaciones mayoritariamente inmunizadas y con pronóstico mejor que las de tiempos pasados. A nuestro juicio, es necesario seguir haciendo un uso razonable y puntual de mascarillas y otros medios no farmacológicos de protección. (AU)


Assuntos
Humanos , /prevenção & controle , /terapia , /instrumentação , /métodos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Máscaras , Vacinas/administração & dosagem , Vacinas/provisão & distribuição , Vacinas/uso terapêutico , Ritonavir
2.
N Engl J Med ; 390(6): 510-521, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38324484

RESUMO

BACKGROUND: The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23-receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production. METHODS: In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16. RESULTS: A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose-response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups. CONCLUSIONS: After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23-receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis. (Funded by Janssen Research and Development; FRONTIER 1 ClinicalTrials.gov number, NCT05223868.).


Assuntos
Anticorpos Monoclonais , Psoríase , Receptores de Interleucina , Humanos , Método Duplo-Cego , Interleucina-23/imunologia , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Peptídeos/uso terapêutico , Psoríase/tratamento farmacológico , Psoríase/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento , Receptores de Interleucina/antagonistas & inibidores , Administração Oral , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Relação Dose-Resposta a Droga
3.
N Engl J Med ; 390(7): 601-610, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38354139

RESUMO

BACKGROUND: Electronic nicotine-delivery systems - also called e-cigarettes - are used by some tobacco smokers to assist with quitting. Evidence regarding the efficacy and safety of these systems is needed. METHODS: In this open-label, controlled trial, we randomly assigned adults who were smoking at least five tobacco cigarettes per day and who wanted to set a quit date to an intervention group, which received free e-cigarettes and e-liquids, standard-of-care smoking-cessation counseling, and optional (not free) nicotine-replacement therapy, or to a control group, which received standard counseling and a voucher, which they could use for any purpose, including nicotine-replacement therapy. The primary outcome was biochemically validated, continuous abstinence from smoking at 6 months. Secondary outcomes included participant-reported abstinence from tobacco and from any nicotine (including smoking, e-cigarettes, and nicotine-replacement therapy) at 6 months, respiratory symptoms, and serious adverse events. RESULTS: A total of 1246 participants underwent randomization; 622 participants were assigned to the intervention group, and 624 to the control group. The percentage of participants with validated continuous abstinence from tobacco smoking was 28.9% in the intervention group and 16.3% in the control group (relative risk, 1.77; 95% confidence interval, 1.43 to 2.20). The percentage of participants who abstained from smoking in the 7 days before the 6-month visit was 59.6% in the intervention group and 38.5% in the control group, but the percentage who abstained from any nicotine use was 20.1% in the intervention group and 33.7% in the control group. Serious adverse events occurred in 25 participants (4.0%) in the intervention group and in 31 (5.0%) in the control group; adverse events occurred in 272 participants (43.7%) and 229 participants (36.7%), respectively. CONCLUSIONS: The addition of e-cigarettes to standard smoking-cessation counseling resulted in greater abstinence from tobacco use among smokers than smoking-cessation counseling alone. (Funded by the Swiss National Science Foundation and others; ESTxENDS ClinicalTrials.gov number, NCT03589989.).


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Abandono do Hábito de Fumar , Adulto , Humanos , Nicotina/administração & dosagem , Nicotina/efeitos adversos , Abandono do Hábito de Fumar/métodos , Dispositivos para o Abandono do Uso de Tabaco/efeitos adversos
4.
N Engl J Med ; 390(7): 611-622, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38354140

RESUMO

BACKGROUND: Carbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime-taniborbactam is an investigational ß-lactam and ß-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-ß-lactamases. METHODS: In this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime-taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority. RESULTS: Of the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime-taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime-taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P = 0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime-taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime-taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups. CONCLUSIONS: Cefepime-taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.).


Assuntos
Antibacterianos , Ácidos Borínicos , Ácidos Carboxílicos , Cefepima , Meropeném , Infecções Urinárias , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Administração Intravenosa , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , beta-Lactamases/administração & dosagem , beta-Lactamases/efeitos adversos , beta-Lactamases/uso terapêutico , Ácidos Borínicos/administração & dosagem , Ácidos Borínicos/efeitos adversos , Ácidos Borínicos/uso terapêutico , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/efeitos adversos , Ácidos Carboxílicos/uso terapêutico , Cefepima/administração & dosagem , Cefepima/efeitos adversos , Cefepima/uso terapêutico , Quimioterapia Combinada , Hospitalização , Meropeném/administração & dosagem , Meropeném/efeitos adversos , Meropeném/uso terapêutico , Testes de Sensibilidade Microbiana , Pielonefrite/tratamento farmacológico , Pielonefrite/microbiologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Farmacorresistência Bacteriana
5.
MMWR Morb Mortal Wkly Rep ; 73(5): 99-103, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38329923

RESUMO

Meningococcal disease, caused by the bacterium Neisseria meningitidis, is a rare but life-threatening illness that requires prompt antibiotic treatment for patients and antibiotic prophylaxis for their close contacts. Historically, N. meningitidis isolates in the United States have been largely susceptible to the antibiotics recommended for prophylaxis, including ciprofloxacin. Since 2019, however, the number of meningococcal disease cases caused by ciprofloxacin-resistant strains has increased. Antibiotic prophylaxis with ciprofloxacin in areas with ciprofloxacin resistance might result in prophylaxis failure. Health departments should preferentially consider using antibiotics other than ciprofloxacin as prophylaxis for close contacts when both of the following criteria have been met in a local catchment area during a rolling 12-month period: 1) the reporting of two or more invasive meningococcal disease cases caused by ciprofloxacin-resistant strains, and 2) ≥20% of all reported invasive meningococcal disease cases are caused by ciprofloxacin-resistant strains. Other than ciprofloxacin, alternative recommended antibiotic options include rifampin, ceftriaxone, or azithromycin. Ongoing monitoring for antibiotic resistance of meningococcal isolates through surveillance and health care providers' reporting of prophylaxis failures will guide future updates to prophylaxis considerations and recommendations.


Assuntos
Infecções Meningocócicas , Neisseria meningitidis , Humanos , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Ceftriaxona/uso terapêutico , Ciprofloxacina/farmacologia , Ciprofloxacina/uso terapêutico , Infecções Meningocócicas/tratamento farmacológico , Infecções Meningocócicas/epidemiologia , Infecções Meningocócicas/prevenção & controle , Estados Unidos/epidemiologia
6.
Niger Postgrad Med J ; 31(1): 8-13, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38321792

RESUMO

BACKGROUND: This was a cross-sectional community-based survey to study the prevalence of serum antibodies against the severe acute respiratory syndrome coronavirus 1 (SARS-COV-1) and determine possible source of antibodies as to whether from vaccination or from natural infection as well as attempt to compare antibody levels in response to the different four types of vaccines administered in Nigeria. METHODS: A cross-sectional community-based study of the prevalence of serum antibodies against all four vaccine types used in Nigeria amongst a representative sample of people aged 18 years and above in the six geopolitical zones of the country using a multistage sampling technique covering 12 states of the country with two states being randomly selected from each geopolitical zone. High-throughput Roche electrochemiluminescence immunoassay system (Elecsys Anti-SARS-COV-1 Cobas) was used for qualitative and quantitative detection of antibodies to SARS-COV-1 in human plasma. RESULTS: There was no statistically significant difference between the proportions with seropositivity for both the vaccinated and the unvaccinated (P = 0.95). The nucleocapsid antibody (anti-Nc) titres were similar in both the vaccinated and the unvaccinated, whereas the Spike protein antibody (anti-S) titres were significantly higher amongst the vaccinated than amongst the unvaccinated. Antibody levels in subjects who received different vaccines were compared to provide information for policy. CONCLUSION: While only 45.9% of the subjects were reported to have been vaccinated, 98.7% of the subjects had had contact with the SARS-COV-1 as evidenced by the presence of nucleocapsid (NC) antibodies in their plasma. The 1.3% who had not been exposed to the virus, had spike protein antibodies which most likely resulted from vaccination in the absence of NC antibodies. Successive vaccination and booster doses either through heterogeneous or homologous vaccines increased antibody titres, and this stimulation of immune memory may offer greater protection against coronavirus disease 2019.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Cobertura Vacinal , População da África Ocidental , Humanos , COVID-19/prevenção & controle , Estudos Transversais , Nigéria , Glicoproteína da Espícula de Coronavírus , Vacinas contra COVID-19/administração & dosagem
7.
BMJ Case Rep ; 17(1)2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38176753

RESUMO

We discuss the use of an inpatient multi-day continuous intravenous ketamine infusion for the treatment of opioid-induced hyperalgesia (OIH) and high fentanyl requirements in the case of a patient with a background of fibromyalgia/central sensitisation syndrome who underwent a complicated post-operative course following a right below-knee amputation for high-grade myxoid fibrosarcoma. The patient was successfully tapered off a total fentanyl patch dose of 162 mcg/hour every 72 hours (morphine equivalent dose of 389 mg/day) to short-acting hydromorphone 2 mg orally two times per day as needed (equivalent of 8 mg morphine sustained-release twice per day) during a 2-week admission with only mild withdrawal symptoms. We discuss the pharmacology of ketamine and its possible application in the treatment of OIH.


Assuntos
Analgésicos Opioides , Ketamina , Humanos , Amputação Cirúrgica , Analgésicos Opioides/efeitos adversos , Fentanila , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Ketamina/administração & dosagem , Ketamina/uso terapêutico , Morfina
8.
BMC Res Notes ; 17(1): 38, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38273327

RESUMO

OBJECTIVES: Urinary tract infections (UTIs) are very common infections in humans, and Escherichia coli (E. coli) is the commonest pathogen leading to UTIs. The generation of beta-lactamase enzymes in this bacterium results in its resistance against many antibiotics. This study compares three doses of amikacin on alternate days with a daily dose of meropenem in the same period for the treatment of UTIs with E. coli in a double-blind clinical trial. METHODS: The current double-blind clinical trial compares three doses of amikacin on alternate days with a daily dose of meropenem in the same period for the treatment of UTIs with E. coli. The patients were assigned to two groups: Intervention (receiving a single dose of amikacin once a day at 48-h intervals for a week, three doses) and control (receiving meropenem for 1/TDS for a week). RESULTS: The E. coli infection frequency was 61 (21 cases of non-ESBL and 40 cases of ESBL-positive infections) and the frequency of the other infections was 52 (46%). In the patients with ESBL E. coli infection, ciprofloxacin (21; 70%) showed the highest antibiotic resistance, and nitrofurantoin (33; 91.7%) showed the highest sensitivity. The baseline variables between the control and intervention groups indicated no significant difference (p > 0.05). The frequency of signs and symptoms showed no significant difference between the amikacin and meropenem groups in the first 24 h and the first week. In the second week of follow-up, no clinical signs or symptoms were observed in the two groups. CONCLUSION: The results of this study showed that treatment with amikacin, 1 g q48h, for one week (three doses) has the same result as meropenem, 1 g q8h, for one week (21 doses). The results are the same for the treatment of UTIs with ESBL positive and ESBL negative. Amikacin can be used once every 48 h to treat UTIs, is less expensive and can be administered on an outpatient basis. TRIAL REGISTRATION: This study was registered in the Iranian Registry of Clinical Trials (IRCT) with ID number: IRCT20170417033483N2 on the date 2018-02-13.


Assuntos
Infecções por Escherichia coli , Infecções Urinárias , Humanos , Amicacina/administração & dosagem , Antibacterianos/administração & dosagem , beta-Lactamases , Método Duplo-Cego , Escherichia coli , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Irã (Geográfico) , Meropeném/administração & dosagem , Testes de Sensibilidade Microbiana , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia
9.
Health Rep ; 35(1): 14-24, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38232409

RESUMO

Background: Immunization against vaccine-preventable diseases such as shingles and pneumococcal disease is especially pertinent among older Canadians. However, vaccine uptake remains low. Data and methods: Data from the Canadian Health Survey on Seniors (CHSS) - 2019/2020 were used to examine receipt of shingles and pneumococcal vaccines among Canadians aged 65 and older living in the community. Multivariable logistic regression was used to identify individual predisposing, enabling and needs-related factors associated with receipt of each type of vaccination. Reasons reported for not getting vaccinated were also examined. Results: Based on the 2019/2020 CHSS, an estimated 36.3% of Canadians aged 65 and older (2.3 million people) had received the shingles vaccine, while 51.1% (3.1 million) had received the pneumococcal vaccine. Being a woman, having higher socioeconomic status, having had the flu shot and having a regular health care provider were associated with increased odds of vaccination. Being an immigrant, living outside large population centres, and belonging to South Asian or Chinese population groups were associated with lower odds of vaccination. Over one-third of unvaccinated people did not think the shingles vaccine (39.7%) or the pneumococcal vaccine (36.6%) was necessary. Other frequently reported reasons for non-vaccination were not having heard of the vaccine or the doctor not mentioning it; for the shingles vaccine, 12% cited cost as a reason. Interpretation: Understanding factors associated with uptake of vaccines and reasons for not obtaining them among older Canadians will help to inform policy and programs aimed at preventing the burden of these diseases.


Assuntos
Vacina contra Herpes Zoster , Herpes Zoster , População norte-americana , Vacinas Pneumocócicas , Idoso , Feminino , Humanos , Canadá/epidemiologia , Herpes Zoster/epidemiologia , Herpes Zoster/prevenção & controle , Vacina contra Herpes Zoster/administração & dosagem , Vacinas contra Influenza/administração & dosagem , Vacinas Pneumocócicas/administração & dosagem , Vacinação/estatística & dados numéricos , Masculino
10.
West J Emerg Med ; 25(1): 22-27, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38205981

RESUMO

Background: Providing adequate paralysis and appropriate sedation is challenging in patients with obesity during rapid sequence intubation (RSI). Pharmacokinetic parameters play an important role in dosing of rocuronium due to low lipophilicity. Rocuronium may be dosed based on ideal body weight (IBW). Current guidelines do not offer recommendations for dosing in the setting of obesity. Dosing depends on clinician preference based on total body weight (TBW) or IBW. Objective: In this study we performed non-inferiority analysis to compare the intubation conditions, duration of paralysis, and incidence of new-onset tachycardia or hypertension after intubation in obese patients requiring RSI in the emergency department (ED). Methods: This was a single-center, prospective, observational study. Eligible for enrollment were adult patients with a TBW ≥30% IBW or body mass index ≥30 kilograms per meters squared who presented to the ED requiring RSI with the use of rocuronium. Rocuronium was dosed according to intubating physicians' preference. Physicians completed a survey assessing intubation conditions. Height and weight used for the calculation of the dose, the dose of rocuronium, time of administration, and time of muscle function recovery were recorded. Endpoints assessed included grading of view during laryngoscopy, first-past success, and duration of paralysis. Results: In total, 96 patients were included, 54 in TBW and 42 in IBW. The TBW cohort received a mean of 1 milligram per kilogram (mg/kg) compared to 0.71 mg/kg in the IBW group. Excellent intubation conditions were observed in 68.5% in the TBW group and 73.8% in the IBW group. The non-inferiority analysis for relative risk of excellent intubation was 1.12 (P = 0.12, [90% CI 0.80-1.50]). Conclusion: Non-inferiority analysis suggests that IBW dosing provides similar optimal intubation conditions when compared to TBW dosing, but the noninferiority comparison did not reach statistical significance. This study was unable to show statistical non-inferiority for IBW dosing.


Assuntos
Intubação , Obesidade , Rocurônio , Adulto , Humanos , Índice de Massa Corporal , Obesidade/complicações , Estudos Prospectivos , Rocurônio/administração & dosagem , Fármacos Neuromusculares não Despolarizantes/administração & dosagem , Sedação Profunda
11.
JAMA ; 331(2): 147-157, 2024 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-38193957

RESUMO

Importance: Age-related macular degeneration (AMD) affects approximately 20 million people in the US and 196 million people worldwide. AMD is a leading cause of severe vision impairment in older people and is expected to affect approximately 288 million people worldwide by 2040. Observations: Older age, genetic factors, and environmental factors, such as cigarette smoking, are associated with development of AMD. AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision. The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD. The annual incidence of AMD ranges from 0.3 per 1000 in people who are aged 55 to 59 years to 36.7 per 1000 in people aged 90 years or older. The estimated heritability of late-stage AMD is approximately 71% (95% CI, 18%-88%). Long-term prospective cohort studies show a significantly higher AMD incidence in people who smoke more than 20 cigarettes per day compared with people who never smoked. AMD is diagnosed primarily with clinical examination that includes a special lens that focuses light of the slit lamp through the pupil. Exudative neovascular AMD is best identified using angiography and by optical coherence tomography. Individuals with AMD who take nutritional supplements consisting of high-dose vitamin C, vitamin E, carotenoids, and zinc have a 20% probability to progress to late-stage AMD at 5 years vs a 28% probability for those taking a placebo. In exudative neovascular AMD, 94.6% of patients receiving monthly intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections experience less than a 15-letter visual acuity loss after 12 months compared with 62.2% receiving sham treatment. Conclusions and Relevance: The prevalence of AMD is anticipated to increase worldwide to 288 million individuals by 2040. Intravitreally administered anti-VEGF treatment is first-line therapy for exudative neovascular AMD.


Assuntos
Inibidores da Angiogênese , Degeneração Macular , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Injeções Intravítreas , Degeneração Macular/diagnóstico , Degeneração Macular/tratamento farmacológico , Degeneração Macular/epidemiologia , Degeneração Macular/etiologia , Estudos Prospectivos , Retina/efeitos dos fármacos , Retina/patologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual , Degeneração Macular Exsudativa/diagnóstico , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/epidemiologia
12.
Epidemiol Infect ; 152: e7, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38174436

RESUMO

This study aimed to understand rural-urban differences in the uptake of COVID-19 vaccinations during the peak period of the national vaccination roll-out in Aotearoa New Zealand (NZ). Using a linked national dataset of health service users aged 12+ years and COVID-19 immunization records, age-standardized rates of vaccination uptake were calculated at fortnightly intervals, between June and December 2021, by rurality, ethnicity, and region. Rate ratios were calculated for each rurality category with the most urban areas (U1) used as the reference. Overall, rural vaccination rates lagged behind urban rates, despite early rapid rural uptake. By December 2021, a rural-urban gradient developed, with age-standardized coverage for R3 areas (most rural) at 77%, R2 81%, R1 83%, U2 85%, and U1 (most urban) 89%. Age-based assessments illustrate the rural-urban vaccination uptake gap was widest for those aged 12-44 years, with older people (65+) having broadly consistent levels of uptake regardless of rurality. Variations from national trends are observable by ethnicity. Early in the roll-out, Indigenous Maori residing in R3 areas had a higher uptake than Maori in U1, and Pacific peoples in R1 had a higher uptake than those in U1. The extent of differences in rural-urban vaccine uptake also varied by region.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Vacinação , Idoso , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Nova Zelândia/epidemiologia , Vacinação/estatística & dados numéricos , População Rural , População Urbana , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade
13.
JAMA ; 331(3): 201-211, 2024 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-38227033

RESUMO

Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. Design, Setting, and Participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. Main Outcomes and Measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. Conclusions and Relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT04158440.


Assuntos
Anticorpos Monoclonais Humanizados , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Compostos de Platina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Antineoplásicos/uso terapêutico , Terapia Combinada , Compostos de Platina/administração & dosagem , Compostos de Platina/uso terapêutico , Idoso
14.
N Engl J Med ; 390(3): 221-229, 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38231623

RESUMO

BACKGROUND: Mass distribution of azithromycin to children 1 to 59 months of age has been shown to reduce childhood all-cause mortality in some sub-Saharan African regions, with the largest reduction seen among infants younger than 12 months of age. Whether the administration of azithromycin at routine health care visits for infants would be effective in preventing death is unclear. METHODS: We conducted a randomized, placebo-controlled trial of a single dose of azithromycin (20 mg per kilogram of body weight) as compared with placebo, administered during infancy (5 to 12 weeks of age). The primary end point was death before 6 months of age. Infants were recruited at routine vaccination or other well-child visits in clinics and through community outreach in three regions of Burkina Faso. Vital status was assessed at 6 months of age. RESULTS: Of the 32,877 infants enrolled from September 2019 through October 2022, a total of 16,416 infants were randomly assigned to azithromycin and 16,461 to placebo. Eighty-two infants in the azithromycin group and 75 infants in the placebo group died before 6 months of age (hazard ratio, 1.09; 95% confidence interval [CI], 0.80 to 1.49; P = 0.58); the absolute difference in mortality was 0.04 percentage points (95% CI, -0.10 to 0.21). There was no evidence of an effect of azithromycin on mortality in any of the prespecified subgroups, including subgroups defined according to age, sex, and baseline weight, and no evidence of a difference between the two trial groups in the incidence of adverse events. CONCLUSIONS: In this trial conducted in Burkina Faso, we found that administration of azithromycin to infants through the existing health care system did not prevent death. (Funded by the Bill and Melinda Gates Foundation; CHAT ClinicalTrials.gov number, NCT03676764.).


Assuntos
Antibacterianos , Azitromicina , Mortalidade Infantil , Criança , Humanos , Lactente , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Azitromicina/administração & dosagem , Azitromicina/uso terapêutico , Mortalidade Infantil/tendências , Administração Massiva de Medicamentos/métodos , Administração Massiva de Medicamentos/mortalidade , Administração Massiva de Medicamentos/estatística & dados numéricos , Burkina Faso/epidemiologia
15.
N Engl J Med ; 390(3): 230-241, 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38231624

RESUMO

BACKGROUND: Simnotrelvir is an oral 3-chymotrypsin-like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy in a phase 1B trial. METHODS: In this phase 2-3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the absence of 11 Covid-19-related symptoms for 2 consecutive days. Safety and changes in viral load were also assessed. RESULTS: A total of 1208 patients were enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, -35.8 hours [95% CI, -60.1 to -12.4]; P = 0.006 by Peto-Prentice test). On day 5, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], -1.51±0.14 log10 copies per milliliter; 95% CI, -1.79 to -1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate. CONCLUSIONS: Early administration of simnotrelvir plus ritonavir shortened the time to the resolution of symptoms among adult patients with Covid-19, without evident safety concerns. (Funded by Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.).


Assuntos
COVID-19 , Inibidores de Protease de Coronavírus , Adulto , Humanos , Administração Oral , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacologia , Antivirais/uso terapêutico , China , Proteínas M de Coronavírus/antagonistas & inibidores , Proteínas M de Coronavírus/metabolismo , Inibidores de Protease de Coronavírus/administração & dosagem , Inibidores de Protease de Coronavírus/efeitos adversos , Inibidores de Protease de Coronavírus/farmacologia , Inibidores de Protease de Coronavírus/uso terapêutico , COVID-19/metabolismo , COVID-19/terapia , Tratamento Farmacológico da COVID-19/métodos , Método Duplo-Cego , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Ritonavir/farmacologia , Ritonavir/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Fatores de Tempo , Combinação de Medicamentos
16.
N Engl J Med ; 390(3): 203-211, 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38231621

RESUMO

BACKGROUND: Testosterone treatment in men with hypogonadism improves bone density and quality, but trials with a sufficiently large sample and a sufficiently long duration to determine the effect of testosterone on the incidence of fractures are needed. METHODS: In a subtrial of a double-blind, randomized, placebo-controlled trial that assessed the cardiovascular safety of testosterone treatment in middle-aged and older men with hypogonadism, we examined the risk of clinical fracture in a time-to-event analysis. Eligible men were 45 to 80 years of age with preexisting, or high risk of, cardiovascular disease; one or more symptoms of hypogonadism; and two morning testosterone concentrations of less than 300 ng per deciliter (10.4 nmol per liter), in fasting plasma samples obtained at least 48 hours apart. Participants were randomly assigned to apply a testosterone or placebo gel daily. At every visit, participants were asked if they had had a fracture since the previous visit. If they had, medical records were obtained and adjudicated. RESULTS: The full-analysis population included 5204 participants (2601 in the testosterone group and 2603 in the placebo group). After a median follow-up of 3.19 years, a clinical fracture had occurred in 91 participants (3.50%) in the testosterone group and 64 participants (2.46%) in the placebo group (hazard ratio, 1.43; 95% confidence interval, 1.04 to 1.97). The fracture incidence also appeared to be higher in the testosterone group for all other fracture end points. CONCLUSIONS: Among middle-aged and older men with hypogonadism, testosterone treatment did not result in a lower incidence of clinical fracture than placebo. The fracture incidence was numerically higher among men who received testosterone than among those who received placebo. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034.).


Assuntos
Fraturas Ósseas , Hipogonadismo , Testosterona , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Densidade Óssea/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Método Duplo-Cego , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Hipogonadismo/sangue , Hipogonadismo/complicações , Hipogonadismo/tratamento farmacológico , Testosterona/administração & dosagem , Testosterona/efeitos adversos , Testosterona/sangue , Testosterona/farmacologia , Géis , Administração Tópica
19.
N Engl J Med ; 390(5): 409-420, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38294973

RESUMO

BACKGROUND: Studies evaluating surgical-site infection have had conflicting results with respect to the use of alcohol solutions containing iodine povacrylex or chlorhexidine gluconate as skin antisepsis before surgery to repair a fractured limb (i.e., an extremity fracture). METHODS: In a cluster-randomized, crossover trial at 25 hospitals in the United States and Canada, we randomly assigned hospitals to use a solution of 0.7% iodine povacrylex in 74% isopropyl alcohol (iodine group) or 2% chlorhexidine gluconate in 70% isopropyl alcohol (chlorhexidine group) as preoperative antisepsis for surgical procedures to repair extremity fractures. Every 2 months, the hospitals alternated interventions. Separate populations of patients with either open or closed fractures were enrolled and included in the analysis. The primary outcome was surgical-site infection, which included superficial incisional infection within 30 days or deep incisional or organ-space infection within 90 days. The secondary outcome was unplanned reoperation for fracture-healing complications. RESULTS: A total of 6785 patients with a closed fracture and 1700 patients with an open fracture were included in the trial. In the closed-fracture population, surgical-site infection occurred in 77 patients (2.4%) in the iodine group and in 108 patients (3.3%) in the chlorhexidine group (odds ratio, 0.74; 95% confidence interval [CI], 0.55 to 1.00; P = 0.049). In the open-fracture population, surgical-site infection occurred in 54 patients (6.5%) in the iodine group and in 60 patients (7.3%) in the chlorhexidine group (odd ratio, 0.86; 95% CI, 0.58 to 1.27; P = 0.45). The frequencies of unplanned reoperation, 1-year outcomes, and serious adverse events were similar in the two groups. CONCLUSIONS: Among patients with closed extremity fractures, skin antisepsis with iodine povacrylex in alcohol resulted in fewer surgical-site infections than antisepsis with chlorhexidine gluconate in alcohol. In patients with open fractures, the results were similar in the two groups. (Funded by the Patient-Centered Outcomes Research Institute and the Canadian Institutes of Health Research; PREPARE ClinicalTrials.gov number, NCT03523962.).


Assuntos
Anti-Infecciosos Locais , Clorexidina , Fixação de Fratura , Fraturas Ósseas , Iodo , Infecção da Ferida Cirúrgica , Humanos , 2-Propanol/administração & dosagem , 2-Propanol/efeitos adversos , 2-Propanol/uso terapêutico , Anti-Infecciosos Locais/administração & dosagem , Anti-Infecciosos Locais/efeitos adversos , Anti-Infecciosos Locais/uso terapêutico , Antissepsia/métodos , Canadá , Clorexidina/administração & dosagem , Clorexidina/efeitos adversos , Clorexidina/uso terapêutico , Etanol , Extremidades/lesões , Extremidades/microbiologia , Extremidades/cirurgia , Iodo/administração & dosagem , Iodo/efeitos adversos , Iodo/uso terapêutico , Cuidados Pré-Operatórios/efeitos adversos , Cuidados Pré-Operatórios/métodos , Pele/microbiologia , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Fraturas Ósseas/cirurgia , Estudos Cross-Over , Estados Unidos
20.
N Engl J Med ; 390(5): 421-431, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38294974

RESUMO

BACKGROUND: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C. METHODS: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo. RESULTS: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred. CONCLUSIONS: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).


Assuntos
Fármacos do Sistema Nervoso Central , Doença de Niemann-Pick Tipo C , Humanos , Coleta de Dados , Método Duplo-Cego , Leucina/análogos & derivados , Leucina/uso terapêutico , Doença de Niemann-Pick Tipo C/complicações , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Doença de Niemann-Pick Tipo C/genética , Resultado do Tratamento , Estudos Cross-Over , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Fármacos do Sistema Nervoso Central/administração & dosagem , Fármacos do Sistema Nervoso Central/uso terapêutico
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