Expanding the US Food and Drug Administration–approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events ...(irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%–12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, improving outcomes in patients with advanced malignancies. The use of ICIs in clinical practice, and the number of ICI ...clinical trials, are rapidly increasing. The use of ICIs in combination with other forms of cancer therapy, such as chemotherapy, radiotherapy, or targeted therapy, is also expanding. However, immune-related adverse events (irAEs) can be serious in up to a third of patients. Critical questions remain surrounding the characteristics and outcomes of irAEs, and how they may affect the overall risk–benefit relationship for combination therapies. This article proposes a framework for irAE classification and reporting, and identifies limitations in the capture and sharing of data on irAEs from current clinical trial and real-world data. We outline key gaps and suggestions for clinicians, clinical investigators, drug sponsors, patients, and other stakeholders to make these critical data more available to researchers for pooled analysis, to advance contemporary understanding of irAEs, and ultimately improve the efficacy of ICIs.
A randomized, clinical trial was conducted to evaluate the spermicidal agent nonoxynol 9 as prophylaxis for sexually transmitted diseases. Eight hundred eighteen women using birth control who ...attended a sexually transmitted disease clinic were evaluated monthly for trichomoniasis, candidiasis, and bacterial vaginosis for 6 months. Women using the active spermicide experienced a somewhat lower incidence rate of trichomoniasis (relative rate 0.83; 95% confidence interval 0.61 to 1.12) and bacterial vaginosis (relative rate 0.86; 95% confidence interval 0.69 to 1.12) as compared with placebo users. The rate of candidiasis was nearly identical for spermicide and placebo users (relative rate 1.02; 95% confidence interval 0.77 to 1.35). The number of sexual partners during the preceding month was related directly to the occurrence of trichomoniasis (p = 0.047) and bacterial vaginosis (p = 0.009) but not candidiasis (p = 0.99). Subjects using oral contraceptives experienced a statistically significant lower rate of trichomoniasis than did women using an intrauterine contraceptive device or who had had a tubal ligation (relative rate 0.56; 95% confidence interval 0.39 to 0.81).
A randomized, double-blind, placebo-controlled trial was conducted to evaluate the spermicidal agent nonoxynol-9 as prophylaxis for cervical infections caused by Chlamydia trachomatis and Neisseria ...gonorrhoeae. Eight hundred eighteen women were recruited from a sexually transmitted disease clinic. Only subjects who were using reliable birth control methods (oral contraceptives, intrauterine device, or sterilization) were eligible. Subjects were randomly assigned to use either a commercially available spermicidal agent containing nonoxynol-9 or a placebo preparation. Subjects were followed up for six months; specimens were collected monthly for culture of the two pathogens. Women assigned to the nonoxynol-9 group were less likely to become infected with N. gonorrhoeae (relative rate, 0.75; 90% confidence limits, 0.58 and 0.96) and C. trachomatis (relative rate, 0.79; 90% confidence limits, 0.64 and 0.97). Among women who used their assigned gel for the majority of coital episodes, a stronger protective effect was observed.
A case-control study was done to evaluate the effectiveness of vaginal spermicides as a prophylaxis against gonorrhea. The subjects included 735 women with gonorrhea and 958 controls seen in a ...sexually transmitted disease clinic. The relative risk (RR) of gonorrhea for spermicide users compared with nonusers was 0.67 with 90% confidence limits, 0.44 to 1.0. This RR was 0.47 (90% confidence limits, 0.25 to 0.87) after the exclusion of women using oral contraceptives, an intrauterine device, or with a tubal ligation. The protective effect of spermicides was confined largely to women who had also used diaphragms or whose partners had used condoms. The RR of gonorrhea for spermicide and condom users relative to nonusers of spermicides, condoms, and diaphragms was 0.41 (90% confidence limits, 0.21 to 0.79), while for spermicide and diaphragm users, this RR was 0.45 (90% confidence limits, 0.15 to 1.3). These results suggest that a woman can appreciably decrease her risk of contracting gonorrhea if she uses spermicides in conjunction with either the diaphragm or the condom.
A nested case-control study, also known as an ambidirectional study, is a case-control study within a cohort study. Although distortion by competing risks is well-recognized in follow-up studies, the ...problem has not been as widely appreciated in nested case-control studies. This paper extends previous work concerning the bias associated with competing risks for nested case-control studies. Specifically, the distorting effect of competing risks is illustrated for three methods of control selection. Assuming the proportional hazards model, the authors derived formulas for the bias of the odds ratio when competing risks cannot be ignored. Examples illustrate the magnitude of bias that occurs when the exposure of interest is associated with competing causes of death or withdrawal.
Oral contraceptive users were compared with nonusers with respect to the rate of cervical infections by Chlamydia trachomatis and Neisseria gonorrhoeae. The comparison was adjusted for differences in ...demographic and behavioral characteristics between the two groups. The rates of infection among oral contraceptive users were increased by approximately 70% (statistically significant) for both pathogens. Cervical ectopy was implicated in the increased rate of chlamydia but not gonorrhea. Rates of gonorrheal infection differed significantly among oral contraceptive formulations; rates were higher for formulations containing more androgenic progestins.
Combining One-Sided Binomial Tests Louv, William C.; Littell, Ramon C.
Journal of the American Statistical Association,
06/1986, Letnik:
81, Številka:
394
Journal Article
Recenzirano
Six methods of combining k independent binomial test statistics are compared with respect to their median significance levels, asymptotic relative efficiencies, and accuracy of null distribution ...approximations. The test statistics considered are the minimum significance level, Fisher's omnibus test, the likelihood ratio, an approximate likelihood ratio, the Mantel-Haenszel statistic, and the sum of chis. Fisher's test and the likelihood ratio perform relatively well for all alternative hypotheses. The Mantel-Haenszel procedure performs well when departures from the null hypotheses are similar for all tests. The minimum is sensitive to the situation in which most of the parameters assume the null value. The sum-of-chis procedure tends to assign too much weight to individual binomial statistics with large standard errors, whereas the approximate likelihood ratio assigns too much weight to statistics with small standard errors.
Risk factors for and sérologie evidence of hepatitis virus (HBV) infection were analyzed among 557 women. Study subjects were attending a clinic for sexually transmitted diseases and enrolled in a ...clinical trial of nonoxynol-9 prevention of gonococcal and chlamydial infections. Seventy-eight (14%) showed sérologie evidence of past HBV infection. Only age at time of serum collection was significantly associated with HBV marker prevalence (P = 0.04). None of the four measures of sexual activity taken (number of sex partners per month, frequency of sexual intercourse, number of documented episodes of sexually transmitted diseases, and lifetime number of sexual partners) were significantly related to the presence of HBV markers. For each measure, however, differences observed between HBV positive and negative subjects were consistent with what would be expected if these factors did contribute to HBV infection risk. These results support the role of heterosexual transmission of HBV infection in women and are consistent with recommendations for hepatitis immunization of heterosexually active persons with multiple sexual partners.
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