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Importance There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George’s Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was –124.6 mL (95% CI, −178.0 to −71.2 mL) with 600 mg of ziritaxestat vs –147.3 mL (95% CI, −199.8 to −94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, −52.3 to 97.6 mL]), and –173.9 mL (95% CI, −225.7 to −122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, −26.7 mL [95% CI, −100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was –173.8 mL (95% CI, −209.2 to −138.4 mL) with 600 mg of ziritaxestat vs –176.6 mL (95% CI, −211.4 to −141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, −46.9 to 52.4 mL]) and –174.9 mL (95% CI, −209.5 to −140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, −47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444

This study continues our assessment of agreement and disagreement among 25 Chinese and 20 US orthodontists in the ranking for facial attractiveness of end-of-treatment photographs of randomly sampled growing Chinese and white orthodontic patients. The main aims of this article were to (1) measure the overall pattern of agreement between the mean rankings of US and Chinese orthodontists, and (2) measure the strength of agreement between the rankings of the US and Chinese orthodontists for each patient.Each judge independently ranked standard clinical sets of profile, frontal, and frontal-smiling photographs of 43 US patients and 48 Chinese patients. For each patient, a separate mean rank was computed from the responses of each group of judges. Pearson correlations between the mean ranks of the 2 groups of judges were used to measure their overall agreement. Paired and unpaired t tests were used to measure the agreement between the judges of the 2 groups for each patient.The overall agreement between the mean rankings of the US and Chinese judges was very high. For the US patients, the correlation between the Chinese and US judges means was r = 0.92, P0.0001. For the Chinese patients, the analogous value was r = 0.86, P0.0001. Agreement between the 2 groups of judges concerning each patient was also generally strong. For two thirds of the patients, the mean ranks of the US and Chinese judges differed by less than 1 unit in a scale of 12. However, for 6 patients considered individually (5 Chinese and 1 US), the assessment of the 2 groups of judges was statistically significantly different at P values ranging from 0.02 to less than 0.0001, even after the Bonferroni correction.These findings demonstrate that orthodontic clinicians can reliably identify and rank subtle differences between patients, and that differences between judges and between patients can be distinguished at a high level of statistical significance, given appropriate study designs. However, the reasons clinicians give for the differences in their judgments are more difficult to investigate and will require further study.

Orthodontists typically make judgments of facial attractiveness by examining groupings of profile, full-face, and smiling photographs considered together as a "triplet." The primary objective of this study was to determine the relative contributions of the 3 photographs-each considered separately-to the overall judgment a clinician forms by examining the combination of the 3.End-of-treatment triplet orthodontic photographs of 45 randomly selected orthodontic patients were duplicated. Copies of the profile, full-face, and smiling images were generated, and the images were separated and then pooled by image type for all subjects. Ten judges ranked the 45 photographs of each image type for facial attractiveness in groups of 9 to 12, from "most attractive" to "least attractive." Each judge also ranked the triplet groupings for the same 45 subjects. The mean attractiveness rankings for each type of photograph were then correlated with the mean rankings of each other and the triplets.The rankings of the 3 image types correlated highly with each other and the rankings of the triplets (P.0001). The rankings of the smiling photographs were most predictive of the rankings of the triplets (r = 0.93); those of the profile photographs were the least predictive (r = 0.76). The difference between these correlations was highly statistically significant (P = .0003). It was also possible to test the extent to which the judges' rankings were influenced by sex, original Angle classification, and extraction status of each patient. No statistically significant preferences were found for sex or Angle classification, and only 1 marginally significant preference was found for extraction pattern.Clinician judges demonstrated a high level of agreement in ranking the facial attractiveness of profile, full-face, and smiling photographs of a group of orthodontically treated patients whose actual differences in physical dimensions were relatively small. The judges' rankings of the smiling photographs were significantly better predictors of their rankings of the triplet of each patient than were their rankings of the profile photographs.

When characterizing the processes that shape ecosystems, ecologists increasingly use the unique perspective offered by repeat observations of remotely sensed imagery. However, the concept of change embodied in much of the traditional remote-sensing literature was primarily limited to capturing large or extreme changes occurring in natural systems, omitting many more subtle processes of interest to ecologists. Recent technical advances have led to a fundamental shift toward an ecological view of change. Although this conceptual shift began with coarser-scale global imagery, it has now reached users of Landsat imagery, since these datasets have temporal and spatial characteristics appropriate to many ecological questions. We argue that this ecologically relevant perspective of change allows the novel characterization of important dynamic processes, including disturbances, long-term trends, cyclical functions, and feedbacks, and that these improvements are already facilitating our understanding of critical driving forces, such as climate change, ecological interactions, and economic pressures.

Background In the absence of a functional dermatophyte-specific polymerase chain reaction (PCR), current diagnosis of dermatophytoses, which constitute the commonest communicable diseases worldwide, relies on microscopy and culture. This combination of techniques is time-consuming and notoriously low in sensitivity. Objectives Recent dermatophyte gene sequence records were used to design a real-time PCR assay for detection and identification of dermatophytes in clinical specimens in less than 24 h. Patients and methods Two assays based on amplification of ribosomal internal transcribed spacer regions and on the use of probes specific to relevant species and species-complexes were designed, optimised and clinically evaluated. One assay was for detecting the Trichophyton mentagrophytes species complex plus T. tonsurans and T. violaceum. The second assayed for the T. rubrum species complex, Microsporum canis and M. audouinii. Results The analytical sensitivity of both assays was 0.1 pg DNA per reaction, corresponding to 2.5-3.3 genomes per sample. The protocol was clinically evaluated over 6 months by testing 92 skin, nail and hair specimens from 67 patients with suspected dermatophytosis. Real-time PCR detected and correctly identified the causal agent in specimens from which T. rubrum, T. interdigitale, M. audouinii or T. violaceum grew in culture, and also identified a dermatophyte species in an additional seven specimens that were negative in microscopy and culture. Conclusions This highly sensitive assay also proved to have high positive and negative predictive values (95.7% and 100%), facilitating the accurate, rapid diagnosis conducive to targeted rather than empirical therapy for dermatophytoses.

Followup data on 90 of 177 patients with Peyronie’s disease seen from January 1, 1950 to April 1, 1970 revealed that the ultimate outcome of the disease when not treated was no different from that following orthovoltage radiotherapy. The real benefit derived from orthovoltage radiotherapy appears to be that it hastens symptomatic improvement by 3 to 7 months. In 21 per cent of the patients there was an associated inflammatory joint or tendon disease, an association not previously reported.