Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma.

BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).

Plain language summary of the FOENIX-CCA2 study: futibatinib for people with advanced bile duct cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their second treatment. This study included people whose cancer had grown/spread after one or more chemotherapy treatments. The aims of the study were to see if futibatinib could shrink the size of tumors and stop the cancer from growing/spreading and to see how long people lived when treated with futibatinib. Clinicians also looked at side effects from taking futibatinib and at how it affected people's quality of life. WHAT WERE THE RESULTS?: Futibatinib treatment shrank tumors in over 80% of people who received treatment. Tumors shrank by at least 30% in 42% of people. Futibatinib stopped tumors from growing/spreading for a median of 9.7 months. People who took the medicine lived for a median of 21.7 months, and 72% of people were still alive after 1 year. Side effects from taking futibatinib were like those reported for similar medicines, and clinicians considered the side effects to be manageable by adjusting the dose of futibatinib or treating the side effects. Most people reported that their quality of life stayed the same or improved during the first 9 months of taking futibatinib. WHAT DO THE RESULTS MEAN?: The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene.Clinical Trial Registration: NCT02052778 (FOENIX-CCA2).

Motivational and Cognitive Factors in Pathways to Offending Amongst Women who Have Sexually Offended.

Data-driven models, addressing the internal motivations, pathways to offending, and supportive cognitions amongst women who have sexually offended have emerged in recent years, with significant consequences for understanding risk factors and developing treatment programmes. In the current research, recent empirically based models were explored in a national sample consisting of all women who had committed sexual offences and were assessed over a 12-year period (n = 28). The utility of the motivational and cognitive models tested was supported, although not all cases could be easily coded, and new categories are suggested in order to better characterize the unique aspects of sex offending amongst women who have sexually offended. Key findings included fewer women than expected who reported being coerced by a male partner, frequent conjunction between sex and intimacy needs, and a lack of a clear relationship between offence-related cognitions and motivational pathways. The results support the importance of integrating and further developing gender-specific clinical factors within a gender-neutral treatment paradigm.

Compaction of very thin corneas from ultraviolet A riboflavin-vitamin E transepithelial cross-linking.

The purpose of the study was to determine the decrease in pachymetry of very thin corneas with advanced keratoconus due to corneal compaction from the ultraviolet-A (UV-A) irradiation phase of transepithelial (epi-on) cross-linking. Twenty removed corneal buttons were obtained from patients who underwent penetrating keratoplasty for advanced keratoconus. Removed corneal buttons selected from among the post-surgical specimens for this study had intact epithelium, no scarring or surgical cautery, endothelial cell density >2500 cells/mm2, and average pachymetry over the measured points of below 400 µm. Corneas were mounted in a Franz chamber. Each epithelial surface was soaked in isotonic riboflavin and D-alpha-tocopheryl polyethylene glycol 1000 succinate (Ribocross® IROMED Group, Italy) for 15 min. Pachymetry was measured at three points over both the shielded and unshielded corneal halves for each corneal button. Surfaces were then washed in saline to remove the Ribocross®. Shields from UV-A irradiation over half of each cornea were then fixed to stand 5 mm above the test corneas. UV-A irradiation using the custom fast cross-linking (CF-CXL) protocol was then performed for the typical 10 ± 1.5 min, for a total energy of 1.08 ± 0.6 J/cm2 after which pachymetry was re-measured. The average percent change in pachymetry was -0.43% ± 0.38% (maximum -1.06%) in the shielded half. Pachymetry change was -6.2% ± 2.2% (maximum 12%) in the cross-linked halves. In conclusion, we estimate that the change in corneal thickness from corneal compaction due to the cross-linking reaction itself was -5.8% ± 2.2%. Scanning electron microscopy of cross-linked corneal segments showed stromal fiber contraction.

Real-world use and outcomes of hypomethylating agent therapy in higher-risk myelodysplastic syndromes: why are we not achieving the promise of clinical trials?

Myelodysplastic syndromes are hematological malignancies characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Hypomethylating agents (HMAs), azacitidine and decitabine, are standard of care therapy for higher-risk myelodysplastic syndromes. However, outcomes reported for real-world studies fall short of those achieved in clinical trials. We conducted a targeted literature review exploring real-world utilization, persistence and outcomes with intravenous and subcutaneous HMA therapies to better understand barriers to achieving optimal outcomes in clinical practice. The potential benefits of oral HMA therapy were also explored. Underutilization and poor persistence with HMA therapy are associated with suboptimal outcomes, highlighting the need for approaches to improve utilization and persistence, so that patients achieve the optimum benefit from HMA therapy.

Lay abstract Myelodysplastic syndromes (MDS) are bone marrow disorders affecting the production of blood cells. In some patients, MDS can progress to acute myeloid leukemia (AML), an aggressive blood cancer with poor prognosis. Patients with higher-risk MDS are often treated with a type of chemotherapy called hypomethylating agents (HMAs). Studies conducted in real-world clinical practice have shown HMAs to be less effective than has been found in clinical trials. We reviewed available studies exploring real-world utilization, persistence and outcomes with current HMA therapies to better understand any barriers to patients achieving the best outcomes. Two important factors were found to be the underuse of HMAs and poor persistence with HMA therapy, highlighting the need for approaches to improve HMA utilization and persistence.

Factors Associated With Potential Progressive Course of Primary Biliary Cholangitis: Data From Real-world US Database.

BACKGROUND AND AIMS: Although relatively, primary biliary cholangitis (PBC) is an important cause of nonalcoholic chronic liver disease which may lead to liver transplantation. PBC patients with alkaline phosphatase (ALP) ≥1.5× the upper limit of normal (ULN) tend to have a more aggressive course. The study was designed to identify factors associated with ALP≥1.5×ULN or cirrhosis in PBC and to evaluate concomitant health care resource utilization. METHODS: We used a large real-world database that contained comprehensive and continuous electronic medical recored/claims data from over 500 health care practices or systems from the United States. RESULTS: Of 195 million patients included in the database, 36,317 were adults with PBC. After applying exclusion criteria, 15,875 patients comprised the final PBC cohort (63.0±13.5 y, 78% female, 71% privately insured, 5% covered by Medicaid, 57% with other autoimmune diseases, 46% with cirrhosis); 6083 (38%) had ALP≥1.5×ULN. Patients with ALP≥1.5×ULN were more frequently female, less covered by Medicaid, had more pruritus, cirrhosis, and other autoimmune diseases (P<0.05). In multivariate analysis, older age, female gender, the presence of other autoimmune diseases, and having compensated or decompensated cirrhosis were independently associated with having ALP≥1.5×ULN in PBC (P<0.05). In contrast, being male was associated with higher risk of cirrhosis in PBC [odds ratio 2.3 (95% confidence interval, 2.1-2.5)]. Patients with ALP≥1.5×ULN and/or with cirrhosis also incurred substantially more health care resource utilization (P<0.05). CONCLUSIONS: Many clinical, sociodemographic, and economic factors are associated with a potentially more aggressive profile of PBC with elevated ALP. These data may inform clinicians to implement management strategies to optimize care of these patients.

Estimates of Non-Heterosexual Prevalence: The Roles of Anonymity and Privacy in Survey Methodology.

When do people feel comfortable enough to provide honest answers to sensitive questions? Focusing specifically on sexual orientation prevalence-a measure that is sensitive to the pressures of heteronormativity-the present study was conducted to examine the variability in U.S. estimates of non-heterosexual identity prevalence and to determine how comfortable people are with answering questions about their sexual orientation when asked through commonly used survey modes. We found that estimates of non-heterosexual prevalence in the U.S. increased as the privacy and anonymity of the survey increased. Utilizing an online questionnaire, we rank-ordered 16 survey modes by asking people to rate their level of comfort with each mode in the context of being asked questions about their sexual orientation. A demographically diverse sample of 652 individuals in the U.S. rated each mode on a scale from -5 (very uncomfortable) to +5 (very comfortable). Modes included anonymous (name not required) and non-anonymous (name required) versions of questions, as well as self-administered and interviewer-administered versions. Subjects reported significantly higher mean comfort levels with anonymous modes than with non-anonymous modes and significantly higher mean comfort levels with self-administered modes than with interviewer-administered modes. Subjects reported the highest mean comfort level with anonymous online surveys and the lowest with non-anonymous personal interviews that included a video recording. Compared with the estimate produced by an online survey with a nationally representative sample, surveys utilizing more intrusive methodologies may have underestimated non-heterosexual prevalence in the U.S. by between 50 and 414%. Implications for public policy are discussed.

The search engine manipulation effect (SEME) and its possible impact on the outcomes of elections.

Internet search rankings have a significant impact on consumer choices, mainly because users trust and choose higher-ranked results more than lower-ranked results. Given the apparent power of search rankings, we asked whether they could be manipulated to alter the preferences of undecided voters in democratic elections. Here we report the results of five relevant double-blind, randomized controlled experiments, using a total of 4,556 undecided voters representing diverse demographic characteristics of the voting populations of the United States and India. The fifth experiment is especially notable in that it was conducted with eligible voters throughout India in the midst of India's 2014 Lok Sabha elections just before the final votes were cast. The results of these experiments demonstrate that (i) biased search rankings can shift the voting preferences of undecided voters by 20% or more, (ii) the shift can be much higher in some demographic groups, and (iii) search ranking bias can be masked so that people show no awareness of the manipulation. We call this type of influence, which might be applicable to a variety of attitudes and beliefs, the search engine manipulation effect. Given that many elections are won by small margins, our results suggest that a search engine company has the power to influence the results of a substantial number of elections with impunity. The impact of such manipulations would be especially large in countries dominated by a single search engine company.

Pharmacoepidemiology of Clinically Relevant Hypothyroidism and Hypertension from Sunitinib and Sorafenib.

BACKGROUND: Thyroid dysfunction and hypertension (HTN) have been sporadically reported with sunitinib (SUN) and sorafenib (SOR). Determination of the side effect incidence will enhance monitoring and management recommendations. METHODS: An observational cohort study was performed using deidentified pharmacy claims data from a 3-year period to evaluate patients prescribed SUN, SOR, or capecitabine (CAP; comparison group). The primary outcome was time to first prescription for thyroid replacement or HTN treatment. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by Cox proportional hazards models. RESULTS: A total of 20,061 patients were eligible for evaluation of thyroid replacement therapy, which was initiated in 11.6% of those receiving SUN (HR, 16.77; 95% CI, 13.54-20.76), 2.6% of those receiving SOR (HR, 3.47; 95% CI, 2.46-4.98), and 1% of those receiving CAP, with median time to initiation of 4 months (range, 1-35 months). A total of 14,468 patients were eligible for evaluation of HTN therapy, which was initiated in 21% of SUN recipients (HR, 4.91; 95% CI, 4.19-5.74), 14% of SOR recipients (HR, 3.25; 95% CI, 2.69-3.91), and 5% of CAP recipients, with median time to initiation of 1 month (range, 1-18 months) for SOR and 2 months (range, 1-25 months) for SUN. CONCLUSION: SUN and SOR significantly increased the risk for clinically relevant hypothyroidism; the risk was at least 4 times greater with SUN than with SOR. Patients receiving SUN and SOR had a similar elevated risk for clinically relevant HTN. These data provide robust measures of the incidence and time to onset of these clinically actionable adverse events. The Oncologist 2017;22:208-212Implications for Practice: The side effect profiles for novel therapies are typically used to create monitoring and management recommendations using clinical trial data from patient populations that may not represent those seen in standard clinical practice. This analysis using a large pharmacy claims database better reflects typical patients treated with sorafenib or sunitinib outside of a clinical trial. The findings of increased need for thyroid replacement in patients receiving sunitinib compared with sorafenib and a similar increase in need for hypertension therapy with both agents can be used to form clinically relevant monitoring recommendations for these agents.

The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell Transplantation for Patients with Acute Leukemia.

Limited clinical data are available to assess whether the sequencing of cyclophosphamide (Cy) and total body irradiation (TBI) changes outcomes. We evaluated the sequence in 1769 (CyTBI, n = 948; TBICy, n = 821) recipients of related or unrelated hematopoietic cell transplantation who received TBI (1200 to 1500 cGY) for acute leukemia from 2003 to 2010. The 2 cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Philadelphia chromosome-positive acute lymphoblastic leukemia, HLA-matched siblings, stem cell source, antithymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect transplantation-related mortality (24% versus 23% at 3 years, P = .67; relative risk, 1.01; P = .91), leukemia relapse (27% versus 29% at 3 years, P = .34; relative risk, .89, P = .18), leukemia-free survival (49% versus 48% at 3 years, P = .27; relative risk, .93; P = .29), chronic GVHD (45% versus 47% at 1 year, P = .39; relative risk, .9; P = .11), or overall survival (53% versus 52% at 3 years, P = .62; relative risk, .96; P = .57) for CyTBI and TBICy, respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (P = .08), respectively. This study demonstrates that the sequence of Cy and TBI does not impact transplantation outcomes and complications in patients with acute leukemia undergoing hematopoietic cell transplantation with myeloablative conditioning.

Patient-Focused Drug Development: A New Direction for Collaboration.

CONTEXT: Patient-Focused Drug Development (PFDD) is a new initiative from the Food and Drug Administration (FDA) intended to bring patient perspectives into an earlier stage of product development. The goal is that patients will be able to provide context for benefit-risk assessments and input to review divisions, and also aid in the development of new assessment tools, study endpoints, and risk communications. This paper provides a summary on what is known to date about FDA's PFDD initiative and describes implications for patients, researchers, payers, and the biopharmaceutical industry. It also provides a roadmap for stakeholders to consider in defining their role in and in shaping PFDD's direction, and for expanding PFDD principles to conditions beyond the current 20 under FDA consideration. METHODS: A search was conducted of the peer-reviewed and gray literature using PubMed and Google. This included laws, FDA guidance documents, the peer-reviewed literature, and FDA presentations for content relevant to the search term "patient-focused drug development." FINDINGS: Currently, FDA activities within PFDD are limited to gaining patient insights through 20 disease-specific meetings. However, many stakeholders see the initiative much more generally as representing a broad shift toward patient centeredness in biopharmaceutical product development. CONCLUSIONS: Depending upon the trajectory taken and whether or not all PFDD aims are eventually addressed, the initiative has the potential to change product development in fundamental ways. Further research should explore how patient input on disease manifestation and treatment options is best ascertained from patients and documented before initiating and during drug development.

Characterizing genetic variants for clinical action.

Genome-wide association studies, DNA sequencing studies, and other genomic studies are finding an increasing number of genetic variants associated with clinical phenotypes that may be useful in developing diagnostic, preventive, and treatment strategies for individual patients. However, few variants have been integrated into routine clinical practice. The reasons for this are several, but two of the most significant are limited evidence about the clinical implications of the variants and a lack of a comprehensive knowledge base that captures genetic variants, their phenotypic associations, and other pertinent phenotypic information that is openly accessible to clinical groups attempting to interpret sequencing data. As the field of medicine begins to incorporate genome-scale analysis into clinical care, approaches need to be developed for collecting and characterizing data on the clinical implications of variants, developing consensus on their actionability, and making this information available for clinical use. The National Human Genome Research Institute (NHGRI) and the Wellcome Trust thus convened a workshop to consider the processes and resources needed to: (1) identify clinically valid genetic variants; (2) decide whether they are actionable and what the action should be; and (3) provide this information for clinical use. This commentary outlines the key discussion points and recommendations from the workshop.

Humeral stress edema: an injury in overhead athletes quarterback with humeral "shin" splints-a case report.

Stress injury to the distal humerus has been reported as a cause of chronic arm pain among competitive tennis players. As the serve is technically similar to an overhead throwing motion, it is conceivable that this injury could occur in other overhead athletes. Overuse injuries, including rotator cuff tears, ulnar collateral ligament injuries, and joint sprains have routinely been reported in quarterbacks, but there are few reported cases of upper extremity bony stress injuries in these athletes. Magnetic resonance imaging aids in the diagnostic evaluation of an upper extremity injury as it can identify numerous structural injuries and early stress changes within bone. Accurately diagnosing stress reactions helps prevent progression toward stress fracture, which is possible if conservative measures are initiated early in the rehabilitation period. In this article, we report the case of an elite college quarterback who presented with localized elbow pain while throwing.

Can biased search results change people's opinions about anything at all? a close replication of the Search Engine Manipulation Effect (SEME).

In previous experiments we have conducted on the Search Engine Manipulation Effect (SEME), we have focused on the ability of biased search results to shift voting preferences. In three new experiments with a total of 1,137 US residents (mean age = 33.2), we sought to determine whether biased search rankings could shift people's opinions on topics that do not involve candidates or elections. Each of the new experiments looked at a different topic, and participants were pre-screened to make sure they didn't have strong opinions about these topics. The topics were: Is artificial intelligence useful or dangerous? Is fracking helpful or dangerous? And: Are people born gay or do they choose to be gay? All participants were first asked various demographic questions, then shown brief summaries of the "pro" and "anti" views on each topic, and then asked their opinions about each topic. Next, participants were allowed to conduct an online search using our mock search engine (Kadoodle) lasting up to 15 minutes. In each experiment, one-third of the participants saw biased search results favoring one perspective; one-third saw biased search results favoring the opposing perspective; and one-third (the control group) saw mixed search results. After completing their search, participants were again asked for their opinions about the topic. Our primary dependent variable was Manipulation Power (MP), the percentage increase in the number of participants favoring one viewpoint after having viewed search rankings favoring that viewpoint. The MPs in the three experiments were 25.0%, 30.9%, and 17.8%, respectively. Corresponding shifts were also found for how persuasive participants found each viewpoint to be and for how much they trusted each viewpoint. We conclude that search rankings favoring one viewpoint on a wide range of topics might be able to cause people who have not yet formulated a strong opinion on such topics to adopt the favored perspective. If our findings prove to be robust, we are exposing what might be considered an unforeseen consequence of the creation of search engines, namely that even without human interference, search algorithms will inevitably alter the thinking and behavior of billions of people worldwide on perhaps any topic for which they have not yet formed strong opinions.

Patients' perspectives on oral decitabine/cedazuridine for the treatment of myelodysplastic syndromes/neoplasms.

Background: Hypomethylating agents (HMAs) are guideline-recommended treatment for higher-risk myelodysplastic syndromes/neoplasms (MDS). However, a prior survey of patients with MDS reported challenges with intravenous (IV) and subcutaneous (SC) HMA therapies, including pain related to treatment administration and interference with daily activities; most patients also indicated a preference to switch to an oral therapy if one were available. Objectives: This study evaluated the perspectives of US patients with MDS receiving oral decitabine/cedazuridine (DEC-C), an alternative to IV/SC HMAs. Methods: An online survey was conducted among adult patients with MDS in the United States (10 November 2022 to 5 December 2022) who had filled a prescription for oral DEC-C between 2021 and 2022. Results: A total of 150 patients completed the survey; 61% were aged ⩾60 years and 63% were male. Of these, 123 (82%) were still receiving oral DEC-C, and 27 (18%) had stopped oral DEC-C treatment. Half (50%) of patients had received oral DEC-C for ⩾6 months. The majority reported that treatment was convenient (83%) and that they were satisfied with treatment (86%). Most patients also reported very little/no interference with regular daily activities (82%), social activities (78%), and productivity (78%). When queried about negative impacts on quality of life (QOL), treatment side effects were the most commonly reported (30% of respondents). Among patients who had previously received IV/SC HMAs (n = 91), most agreed that oral DEC-C interfered less with daily life (91%) and had experienced improvement in QOL (85%) compared with previous treatment; 91% reported that oral DEC-C reduced the number of times they needed to travel to a healthcare facility. Conclusion: Survey results suggest very little/no impact on regular daily activities and improved QOL with oral DEC-C relative to IV/SC HMAs, highlighting the potential for oral DEC-C to reduce the treatment burden associated with parenteral HMA therapy.

A rank ordering and analysis of four cognitive-behavioral stress-management competencies suggests that proactive stress management is especially valuable.

The main objective of this study was to determine the relative value of four cognitive-behavioral competencies that have been shown in empirical studies to be associated with effective stress management. Based on a review of relevant psychological literature, we named the competencies as follows: Manages or Reduces Sources of Stress, Manages Thoughts, Plans and Prevents, and Practices Relaxation Techniques. We measured their relative value by examining data obtained from a diverse convenience sample of 18,895 English-speaking participants in 125 countries (65.0% from the U.S. and Canada) who completed a new inventory of stress-management competencies. We assessed their relative value by employing a concurrent study design, which also allowed us to assess the validity of the new instrument. Regression analyses were used to rank order the four competencies according to how well they predicted desirable outcomes. Both regression and factor analyses pointed to the importance of proactive stress-management practices over reactive methods, but we note that the correlational design of our study has no implications for the possible causal effects of these methods. Questionnaire scores were strongly associated with self-reported happiness and also significantly associated with personal success, professional success, and general level of stress. Data were collected between 2007 and 2022, but we found no effect for time. The study supports the value of stress-management training, and it also suggests that moderate levels of stress may not be as beneficial as previously thought.

What would happen if twitter sent consequential messages to only a strategically important subset of users? A quantification of the Targeted Messaging Effect (TME).

The internet has made possible a number of powerful new forms of influence, some of which are invisible to users and leave no paper trails, which makes them especially problematic. Some of these effects are also controlled almost exclusively by a small number of multinational tech monopolies, which means that, for all practical purposes, these effects cannot be counteracted. In this paper, we introduce and quantify an effect we call the Targeted Messaging Effect (TME)-the differential impact of sending a consequential message, such as a link to a damning news story about a political candidate, to members of just one demographic group, such as a group of undecided voters. A targeted message of this sort might be difficult to detect, and, if it had a significant impact on recipients, it could undermine the integrity of the free-and-fair election. We quantify TME in a series of four randomized, controlled, counterbalanced, double-blind experiments with a total of 2,133 eligible US voters. Participants were first given basic information about two candidates who ran for prime minister of Australia in 2019 (this, to assure that our participants were "undecided"). Then they were instructed to search a set of informational tweets on a Twitter simulator to determine which candidate was stronger on a given issue; on balance, these tweets favored neither candidate. In some conditions, however, tweets were occasionally interrupted by targeted messages (TMs)-news alerts from Twitter itself-with some alerts saying that one of the candidates had just been charged with a crime or had been nominated for a prestigious award. In TM groups, opinions shifted significantly toward the candidate favored by the TMs, and voting preferences shifted by as much as 87%, with only 2.1% of participants in the TM groups aware that they had been viewing biased content.

Is everyone a mix of straight and gay? A social pressure theory of sexual orientation, with supporting data from a large global sample.

Sigmund Freud, Alfred Kinsey, E.O. Wilson, and others have suggested that social pressure suppresses natural tendencies for humans to express bisexuality, the apparent norm for one of our two closest genetic relatives, the bonobo. An analysis of data obtained from a new online sample of 1,150,938 people in 215 countries and territories (63.9% from the United States, United Kingdom, and Canada) who completed the English version of a validated questionnaire of sexual orientation lends support to this idea. A histogram of scores from 0 (exclusive opposite-sex inclinations) to 18 (exclusive same-sex inclinations) forms a near-normal distribution. Although this distribution was likely caused to some extent by sampling bias, it may also reflect the unusual honesty people show when taking online tests anonymously, as an increasing body of evidence demonstrates. We present a formal mathematical expression of a social pressure theory of sexual orientation, along with empirical evidence and computational explorations that support the theory. We also present an analysis of the new data set. Among other findings: sexual orientation labels corresponded to broad, skewed, overlapping distributions of scores. Self-labeled gays/lesbians and, to a greater extent, self-labeled straights, reported that the larger the mismatch between their sexual orientation label and their actual sexual inclinations, the more distress they felt regarding their sexual orientation, a finding that is predictable from cognitive dissonance theory. Educating the public about the true nature of sexual orientation might quell the often rancorous public debates on this topic, as well as give comfort to a large number of mislabeled people.

Retrospective Review of Radiographic Imaging of Tibial Bony Stress Injuries in Adolescent Athletes With Positive MRI Findings: A Comparative Study.

BACKGROUND: It is difficult to diagnose and grade bony stress injury (BSI) in the athletic adolescent population without advanced imaging. Radiographs are recommended as a first imaging modality, but have limited sensitivity and, even when findings are present, advanced imaging is often recommended. HYPOTHESIS: It was hypothesized that the significance of radiographs is underestimated for BSI in the adolescent with positive clinical examination and history findings. STUDY DESIGN: Case series. LEVEL OF EVIDENCE: Level 4. METHODS: A total of 80 adolescent athletes with a history of shin pain underwent clinical examination by an orthopaedic surgeon. On the day of clinical examination, full-length bilateral tibial radiographs and magnetic resonance imaging (MRI) scans were obtained. MRI scans were reviewed using Fredericson grading for BSI. At the completion of the study, radiographic images were re-evaluated by 2 musculoskeletal (MSK) radiologists, blinded to MRI and clinical examination results, who reviewed the radiographs for evidence of BSI. Radiographic results were compared with clinical examination and MRI findings. Sensitivity, specificity, negative predictive value, and positive predictive value were calculated based on comparison with MRI. RESULTS: All radiographs were originally read as normal. Of the tibia studied, 80% (127 of 160) showed evidence of BSI on MRI. None of the original radiographs demonstrated a fracture line on initial review by the orthopaedic surgeons. Retrospective review by 2 MSK radiologists identified 27% of radiographs (34 of 127) with evidence of abnormality, which correlated with clinical examination and significant findings on MRI. Review of radiographs found evidence of new bone on 0 of 28 Fredericson grade 0, 0 of 19 Fredericson grade I, 11 of 80 (13.7%) Fredericson grade II, 18 of 28 (64%) Fredericson grade III, and 5 of 5 (100%) Fredericson grade IV. Sensitivity of radiographs showed evidence of new bone on 27% (34 of 127) of initial radiographs, with presence more common with greater degree of BSI, as 23 of 33 (70%) were higher-grade injuries (III of IV) of BSI. Specificity and positive predictive value were 100%, while negative predictive value was 17%. CONCLUSION: These findings highlight the importance of initial radiographs in identifying high-grade BSI. As radiographs are readily available in most office settings of sports medicine physicians, this information can influence the management of adolescent athletic BSI without the need to delay treatment to obtain an MRI. CLINICAL RELEVANCE: Adolescent athletes with radiographic evidence of BSI should be treated in a timely and more conservative manner, given the likelihood of higher-grade BSI. In addition, clinicians knowledgeable of the radiographic findings of high-grade BSI should feel more confident that a negative initial radiograph is not likely to be a high-grade BSI and can modify their treatment plans accordingly.

Pentacam HR criteria for curvature change in keratoconus and postoperative LASIK ectasia.

PURPOSE: To determine criteria for keratoconus or postoperative LASIK ectasia progression or improvement based on Pentacam HR (Oculus Optikgeräte GmbH) measured steepest corneal curvature. METHODS: Sixty-one eyes from 41 patients with keratoconus or postoperative LASIK ectasia were evaluated. Each eye was measured 5 times with the Pentacam HR during the same clinic visit and the random measurement variations of Rmin(back) and maximal keratometry (Kmax; mathematically linked to Rmin[front]) were statistically analyzed. Confidence levels for diagnosing true curvature change were determined for 3 typical clinical situations differing by the number of available Pentacam measurements. RESULTS: With a single past and single present Pentacam HR measurement available (situation 1+1), the 95% confidence levels of true change for ΔKmax, ΔRmin(front), and ΔRmin(back) were 1.51 diopters (D), 0.162 mm, and 0.290 mm, respectively. With one prior and the average of five present Pentacam measurements (situation 5+1), the 95% confidence levels of true change for ΔKmax, ΔRmin(front), and ΔRmin(back) were 1.17 D, 0.126 mm, and 0.225 mm, respectively. With the average of five past and five present measurements (situation 5+5), the 95% confidence levels of true change for ΔKmax, ΔRmin(front), and ΔRmin(back) were 0.68 D, 0.072 mm, and 0.130 mm, respectively. CONCLUSIONS: Steepest corneal curvature changed with 95% confidence if the difference between single past and present Kmax exceeded 1.51 D. With the advantage of five past and five present measurements, 95% confidence of real Kmax change occurs at a 0.68-D difference.