The smallest functional antibody fragment: Ultralong CDR H3 antibody knob regions potently neutralize SARS-CoV-2.

Cows produce antibodies with a disulfide-bonded antigen-binding domain embedded within ultralong heavy chain third complementarity determining regions. This "knob" domain is analogous to natural cysteine-rich peptides such as knottins in that it is small and stable but can accommodate diverse loops and disulfide bonding patterns. We immunized cattle with SARS-CoV-2 spike and found ultralong CDR H3 antibodies that could neutralize several viral variants at picomolar IC50 potencies in vitro and could protect from disease in vivo. The independent CDR H3 peptide knobs were expressed and maintained the properties of the parent antibodies. The knob interaction with SARS-CoV-2 spike was revealed by electron microscopy, X-ray crystallography, NMR spectroscopy, and mass spectrometry and established ultralong CDR H3-derived knobs as the smallest known recombinant independent antigen-binding fragment. Unlike other vertebrate antibody fragments, these knobs are not reliant on the immunoglobulin domain and have potential as a new class of therapeutics.

Accelerating the development of genetically engineered cellular therapies: a framework for extrapolating data across related products.

BACKGROUND: Significant advancements have been made in the field of cellular therapy as anti-cancer treatments, with the approval of chimeric antigen receptor (CAR)-T cell therapies and the development of other genetically engineered cellular therapies. CAR-T cell therapies have demonstrated remarkable clinical outcomes in various hematological malignancies, establishing their potential to change the current cancer treatment paradigm. Due to the increasing importance of genetically engineered cellular therapies in the oncology treatment landscape, implementing strategies to expedite development and evidence generation for the next generation of cellular therapy products can have a positive impact on patients. METHODS: We outline a risk-based methodology and assessment aid for the data extrapolation approach across related genetically engineered cellular therapy products. This systematic data extrapolation approach has applicability beyond CAR-T cells and can influence clinical development strategies for a variety of immune therapies such as T cell receptor (TCR) or genetically engineered and other cell-based therapies (e.g., tumor infiltrating lymphocytes, natural killer cells and macrophages). RESULTS: By analyzing commonalities in manufacturing processes, clinical trial designs, and regulatory considerations, key learnings were identified. These insights support optimization of the development and regulatory approval of novel cellular therapies. CONCLUSIONS: The field of cellular therapy holds immense promise in safely and effectively treating cancer. The ability to extrapolate data across related products presents opportunities to streamline the development process and accelerate the delivery of novel therapies to patients.

Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose.

BACKGROUND: Anti-myelin-associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti-MAG neuropathy. METHODS: This phase 1b, open-label, single-arm, dose-finding trial was conducted from 2019 through 2022. The original design included a dose-escalation/extension phase followed by a dose-expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. RESULTS: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58-77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1-40 years). The study terminated early due to higher-than-expected non-dose-limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ-5D (-0.95, 95% CI -1.81 to -0.09) and total IgM (-162 mg/dL, 95% CI -298 to -26) showed signs of improvement by month 12. CONCLUSIONS: Lenalidomide was associated with higher-than-expected VTE events in anti-MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti-MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. TRIAL REGISTRATION: Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019.

Homologous Recombination Deficiency: Concepts, Definitions, and Assays.

BACKGROUND: Homologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. Loss-of-function genes involved in this pathway can sensitize tumors to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. However, to identify patients with these tumors, it is vital to understand how to best measure homologous repair (HR) status and to characterize the level of alignment in these measurements across different diagnostic platforms. A key current challenge is that there is no standardized method to define, measure, and report HR status using diagnostics in the clinical setting. METHODS: Friends of Cancer Research convened a consortium of project partners from key healthcare sectors to address concerns about the lack of consistency in the way HRD is defined and methods for measuring HR status. RESULTS: This publication provides findings from the group's discussions that identified opportunities to align the definition of HRD and the parameters that contribute to the determination of HR status. The consortium proposed recommendations and best practices to benefit the broader cancer community. CONCLUSION: Overall, this publication provides additional perspectives for scientist, physician, laboratory, and patient communities to contextualize the definition of HRD and various platforms that are used to measure HRD in tumors.

Need for aligning the definition and reporting of cytokine release syndrome (CRS) in immuno-oncology clinical trials.

As cancer immunotherapies continue to expand across all areas of oncology, it is imperative to establish a standardized approach for defining and capturing clinically important toxicities, such as cytokine release syndrome (CRS). In this paper, we provide considerations for categorizing the variety of adverse events that may accompany CRS and for recognizing that presentations of CRS may differ among various immunotherapies (e.g., monoclonal antibodies, CAR T cell therapies and T cell engagers, which can include bispecific antibodies and other constructs). The goals of this paper are to ensure accurate and consistent identification of CRS in patients receiving immunotherapies in clinical studies to aid in reporting; enable more precise evaluation of the therapeutic risk-benefit profile and cross-study analyses; support evidence-based monitoring and management of important toxicities related to cancer immunotherapies; and improve patient care and outcomes. These efforts will become more important as the number and variety of molecular targets for immunotherapies broaden and as therapies with novel mechanisms continue to be developed.

Testing the Validity of the Pathways Model: A Latent Class Analysis of Potential Pathological Gambling Subtypes in a Non-Treatment Sample.

Latent class analysis (LCA) was used to test the validity of the Pathways Model in 285 subjects with DSM-IV pathological gambling (PG). In addition to identifying three subtypes that roughly correspond with those described in the model (Behaviorally Conditioned, or BC, Emotionally Vulnerable, or EV, Antisocial-Impulsivist, or AI), LCA identified a fourth class, termed the Antisocial Drinker, or AD, characterized by high rates of antisociality, conduct disorder, and alcohol use disorder. BC gamblers comprised 45% of the sample, followed by EV (24%), AD (22%), and AI (9%) gamblers. Women were more likely to be EV gamblers (OR = 1.89) and less likely to be AD gamblers (OR = 0.46). Those who had attempted suicide were more likely to be EV (OR = 3.06) or AI (OR = 3.05) gamblers and less likely to be BC (OR = 0.37) or AD gamblers (OR = 0.50). Greater childhood maltreatment was associated with AD (standardized OR = 1.81) and AI (standardized OR = 1.43) gamblers. Individuals with later PG onset were less likely to be AI gamblers (standardized OR = 0.48). Individuals who preferred slots were more likely to be EV gamblers (OR = 1.83) and less likely to be AD gamblers (OR = 0.33). The BC subtype was associated with better health outcomes, better social functioning, less childhood maltreatment, and less severe PG. The AI subtype was associated with worse health outcomes, worse social functioning, and higher PG severity. The findings provide a better understanding PG heterogeneity that could be relevant to clinical management.

Accelerating Advances in Cancer Care Research: A Lookback at the 21st Century Cures Act in 2020.

The 21st Century Cures Act (Cures Act), signed into law in 2016, was designed to advance new therapies by modernizing clinical trials, funding research initiatives, and accelerating the development and use of health information technology. To analyze the current issues in cancer care related to the implementation and impact of the Cures Act, NCCN convened a multistakeholder working group. Participants discussed the legislation's impact on the oncology community since enactment and identified the remaining gaps and challenges as experienced by stakeholders. In June 2020, the policy recommendations of the working group were presented at the virtual NCCN Policy Summit: Accelerating Advances in Cancer Care Research: A Lookback at the 21st Century Cures Act in 2020. The summit consisted of informative discussions and a multistakeholder panel to explore the recommendations and the future of the Cures Act. This article explores identified policy recommendations from the NCCN Working Group and the NCCN Policy Summit, and analyzes opportunities to advance innovative cancer care and patient access to data.

An Exploratory Analysis of Predictors of Course in Older and Younger Adults with Pathological Gambling: A Non-Treatment Sample.

We examined the association of baseline social, demographic, and clinical predictor variables with course in 48 older (≥ 60 years) and 57 younger (< 40 years) subjects with pathological gambling (PG) in a prospective follow-up study. Weekly gambling activity was tracked and used to categorize PG course. Generalized estimating equation models were used to examine predictors of disordered (i.e., level 2 or 3) gambling. Interaction tests were used to test for differential relationships for older and younger subjects. Predictors of disordered gambling during follow-up included greater severity of PG symptoms, greater severity of depressive symptoms, self-reported childhood neglect, cognitive distortions related to games of chance, and more role limitations due to physical health. Interaction tests showed that the relationships between some risk factors and disordered gambling varied for older and younger adults. Understanding these interrelationships could allow clinicians to more effectively monitor and manage their patients with PG.

Are Comorbid Disorders Associated with Changes in Gambling Activity? A Longitudinal Study of Younger and Older Subjects with DSM-IV Pathological Gambling.

This study investigates the association of comorbid disorders with gambling activity in a longitudinal follow-up study of younger and older adult subjects with DSM-IV pathological gambling (PG). The subjects included 57 younger adults with PG (≥ 18/ < 40 years) and 48 older adults with PG (≥ 60 years). Subjects were assessed at baseline and every 6 months for a mean (SD) of 31.4 (13.1) months. Comorbidity was assessed using a modification of the Longitudinal Interval Follow-up Evaluation (LIFE). During follow-up, rates of problem severity were highest for anxiety disorders, mood disorders, and impulse control disorders. Among all subjects with PG, greater severity of depression or posttraumatic stress disorder was associated with increased gambling activity. In older subjects, greater severity of agoraphobia and social phobia were associated with lowered gambling activity. In younger subjects, greater severity of any substance use disorder, an alcohol use disorder, or compulsive computer use were associated with lowered gambling activity. The latter findings provide presumptive evidence for the substitute addiction hypothesis. We conclude that increased severity of several comorbid disorders could serve as triggers for increased gambling or predict lowered gambling activity. On the other hand, certain comorbid disorders could be triggered by increased gambling activity. Knowing these interrelationships is important to gaining a better understanding of PG and its clinical management.

Accelerating the development of innovative cellular therapy products for the treatment of cancer.

The field of cell therapy is rapidly emerging as a priority area for oncology research and drug development. Currently, two chimeric antigen receptor T-cell therapies are approved by the US Food and Drug Administration and other agencies worldwide for two types of hematologic cancers. To facilitate the development of these therapies for patients with life-threatening cancers with limited or no therapeutic options, science- and risk-based approaches will be critical to mitigating and balancing any potential risk associated with either early clinical research or more flexible manufacturing paradigms. Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy convened an expert group of stakeholders to develop specific strategies and proposals for regulatory opportunities to accelerate the development of cell therapies as promising new therapeutics. This meeting took place in Washington, DC on May 17, 2019. As academia and industry expand research efforts and cellular product development pipelines, this report summarizes opportunities to accelerate entry into the clinic for exploratory studies and optimization of cell products through manufacturing improvements for these promising new therapies.

Rituximab in refractory chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a disorder in which early effective treatment is important to minimize disability from axonal degeneration. It has been suggested that some patients with CIDP may benefit from rituximab therapy, but there is no definitive evidence for this. METHODS: Baseline and post-rituximab-therapy neuromuscular Medical Research Council (MRC) sum scores, Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, and functional status were assessed in 11 patients with refactory CIDP. RESULTS: The MRC sum score, INCAT disability score, and functional status improved in all patients after rituximab therapy. DISCUSSION: Our study provides evidence of the efficacy of rituximab therapy in at least some patients with CIDP. A placebo-controlled study to assess the effectiveness of rituximab therapy in CIDP with and without nodal antibodies is required to identify disease markers that predict responsiveness.

Sex differences and normative data for the m-CTSIB and sensory integration on baseline concussion assessment in collegiate athletes.

Primary objective: To investigate sex differences on baseline m-CTSIB and sensory integration function between male and female collegiate athletes and develop preliminary normative data for this population.Methods and procedures: Baseline data were retrospectively analyzed for 591 National Collegiate Athletic Association (NCAA) athletes between 2015 and 2018 on the modified Clinical Test for Sensory Interaction and Balance (m-CTSIB). A series of Mann-Whitney U tests were conducted to determine sex differences on m-CTSIB and individual sensory integration performance.Main outcomes and results: Female athletes performed significantly better than male athletes on baseline m-CTSIB composite scores (p < .001). Females also performed better on the eyes open-firm surface (p < .001), eyes closed-firm surface (p = .001), eyes open-foam surface (p < .001), and eyes closed-foam surface (p = .001) tasks as compared to male athletes.Conclusions: Male and female athletes exhibit differences on baseline m-CTSIB and sensory integration test performance. The m-CTSIB normative data are presented for the total sample and by sex. These normative data provide a frame of reference for interpreting m-CTSIB performance in collegiate athletes as part of concussion assessment.

Heart Rate Variability in College Football Players throughout Preseason Camp in the Heat.

We aimed to characterize cardiac-autonomic responses to a 13-day preseason camp in the heat among an American college football team. Players were categorized as linemen (n=10) and non-linemen (n=18). RHR, natural logarithm of the root-mean square of successive differences multiplied by twenty (LnRMSSD), and subjective wellbeing (LnWellness) were acquired daily. Effect sizes±90% confidence interval showed that for linemen, LnRMSSD decreased (moderate) on day 2 (71.2±10.4) and increased (moderate) on day 12 (87.1±11.2) relative to day 1 (77.9±11.2) while RHR decreased (small-moderate) on days 6, 7, and 12 (67.7±9.3-70.4±5.5 b∙min-1) relative to day 1 (77.1±10.1 b∙min-1). For non-linemen, LnRMSSD increased (small-large) on days 3-5, 7, 12, and 13 (83.4±6.8-87.6±8.5) relative to day 1 (80.0±6.5) while RHR decreased (small-large) on days 3-9, 12, and 13 (62.1±5.2-67.9±8.1 b∙min-1) relative to day 1 (70.8±6.2 b∙min-1). Decrements in LnWellness were observed on days 4-10 and 13 for linemen (moderate) and on days 6-9, 12, and 13 for non-linemen (small-moderate). Despite reductions in LnWellness, cardiac-autonomic parameters demonstrated responses consistent with heat-acclimation, which possibly attenuated fatigue-related decrements.

Cardiac-Autonomic Responses to In-Season Training Among Division-1 College Football Players.

Flatt, AA, Esco, MR, Allen, JR, Robinson, JB, Bragg, A, Keith, CM, Fedewa, MV, and Earley, RL. Cardiac-autonomic responses to in-season training among Division-1 college football players. J Strength Cond Res 34(6): 1649-1656, 2020-Despite having to endure a rigorous in-season training schedule, research evaluating daily physiological recovery status markers among American football players is limited. The purpose of this study was to determine whether recovery of cardiac-autonomic activity to resting values occurs between consecutive-day, in-season training sessions among college football players. Subjects (n = 29) were divided into groups based on position: receivers and defensive backs (SKILL, n = 10); running backs, linebackers, and tight-ends (MID-SKILL, n = 11) and linemen (LINEMEN, n = 8). Resting heart rate (RHR) and the natural logarithm of the root mean square of successive differences multiplied by 20 (LnRMSSD) were acquired at rest in the seated position before Tuesday and Wednesday training sessions and repeated over 3 weeks during the first month of the competitive season. A position × time interaction was observed for LnRMSSD (p = 0.04), but not for the RHR (p = 0.33). No differences in LnRMSSD between days was observed for SKILL (Tuesday = 82.8 ± 9.3, Wednesday = 81.9 ± 8.7, p > 0.05). Small reductions in LnRMSSD were observed for MID-SKILL (Tuesday = 79.2 ± 9.4, Wednesday = 76.2 ± 9.5, p ≤ 0.05) and LINEMEN (Tuesday = 79.4 ± 10.5, Wednesday = 74.5 ± 11.5, p ≤ 0.05). The individually averaged changes in LnRMSSD from Tuesday to Wednesday were related to PlayerLoad (r = 0.46, p = 0.02) and body mass (r = -0.39, p = 0.04). Cardiac-parasympathetic activity did not return to resting values for LINEMEN or MID-SKILL before the next training session. Larger reductions in LnRMSSD tended to occur in players with greater body mass despite having performed lower workloads, although some individual variability was observed. These findings may have implications for how coaches and support staff address training and recovery interventions for players demonstrating inadequate cardiovascular recovery between sessions.

Religiosity and Chance Beliefs in Persons with DSM-IV Pathological Gambling Enrolled in a Longitudinal Follow-Up Study.

This study investigates the association of public, private and intrinsic religiosity and chance beliefs (superstition, illusion of control) with gambling behavior in a longitudinal follow-up study of younger and older adult subjects with DSM-IV pathological gambling (PG) and an older adult comparison group without PG. One-hundred sixty-three subjects were enrolled including 60 younger adults with PG (≥ 18/< 40 years), 53 older adults with PG (≥ 60 years), and 50 older adults without PG (≥ 60). Subjects were assessed at baseline and every 6 months thereafter. The Duke University Religion Index for Religious Assessment and the Drake Beliefs About Chance scales were administered at baseline. Follow-up was a mean (SD) of 2.6 (1.4) years. Older adults with PG scored lower on measures of public and intrinsic aspects of religiosity than older adults without PG, and scored higher on superstition and illusion of control. Older adults with PG also scored higher than younger adults with PG on private and intrinsic religiosity, but not public religiosity. Superstition predicted intrinsic, but not other aspects of religiosity. Importantly, during follow-up, higher levels of public and intrinsic religiosity were protective against problematic (levels 2, 3) gambling; were protective against chronic PG; and were predictive of PG remission status. Lower illusion of control ratings were protective against problematic gambling and chronic PG; lower superstition ratings were predictive of remission. We conclude that higher levels of public and intrinsic religiosity and lower levels of chance beliefs are associated with a more benign PG course.

Does response to the STEPPS program differ by sex, age, or race in offenders with borderline personality disorder?

Systems Training for Emotional Predictability and Problem Solving (STEPPS) is an evidence-based group treatment program for ambulatory patients with borderline personality disorder (BPD). The program was introduced to the Iowa correctional system in 2005, and groups have been ongoing ever since. In this analysis, we examine whether response to the STEPPS program differs based on sex, age (<40/≥40 years), or race/ethnicity (minority/non-minority) using data collected in Iowa prisons and in community corrections. Subjects were recruited and assessed by correctional staff. Offenders with BPD were offered the opportunity to participate in the STEPPS program. The presence of BPD was assessed using a module from the Structured Interview for DSM-IV Personality. Efficacy assessments included the Borderline Evaluation of Severity Over Time Scale, the Beck Depression Inventory, and the Positive and Negative Affectivity Scale. The Client Satisfaction Questionnaire-8 assessed program satisfaction. Data on 77 offenders were analyzed. All participated in the STEPPS program and 53% completed all 20 weeks. The analysis showed that there were no significant differences in response to STEPPS in terms of sex, age, or race/ethnicity on any of the three efficacy measures. Women expressed greater satisfaction than men, but there were no differences with regard to age or race/ethnicity. The implications of the findings are discussed.

Heart Rate Variability and Training Load Among National Collegiate Athletic Association Division 1 College Football Players Throughout Spring Camp.

Flatt, AA, Esco, MR, Allen, JR, Robinson, JB, Earley, RL, Fedewa, MV, Bragg, A, Keith, CM, and Wingo, JE. Heart rate variability and training load among National Collegiate Athletic Association Division 1 college football players throughout spring camp. J Strength Cond Res 32(11): 3127-3134, 2018-The purpose of this study was to determine whether recovery of cardiac-autonomic activity to baseline occurs between consecutive-day training sessions among positional groups of a collegiate football team during Spring camp. A secondary aim was to evaluate relationships between chronic (i.e., 4-week) heart rate variability (HRV) and training load parameters. Baseline HRV (lnRMSSD_BL) was compared with HRV after ∼20 hours of recovery before next-day training (lnRMSSDpost20) among positional groups composed of SKILL (n = 11), MID-SKILL (n = 9), and LINEMEN (n = 5) with a linear mixed model and effect sizes (ES). Pearson and partial correlations were used to quantify relationships between chronic mean and coefficient of variation (CV) of lnRMSSD (lnRMSSD_chronic and lnRMSSDcv, respectively) with the mean and CV of PlayerLoad (PL_chronic and PL_cv, respectively). A position × time interaction was observed for lnRMSSD (p = 0.01). lnRMSSD_BL was higher than lnRMSSDpost20 for LINEMEN (p < 0.01; ES = large), whereas differences for SKILL and MID-SKILL were not statistically different (p > 0.05). Players with greater body mass experienced larger reductions in lnRMSSD (r = -0.62, p < 0.01). Longitudinally, lnRMSSDcv was significantly related to body mass (r = 0.48) and PL_chronic (r = -0.60). After adjusting for body mass, lnRMSSDcv and PL_chronic remained significantly related (r = -0.43). The ∼20-hour recovery time between training sessions on consecutive days may not be adequate for restoration of cardiac-parasympathetic activity to baseline among LINEMEN. Players with a lower chronic training load throughout camp experienced greater fluctuation in lnRMSSD (i.e., lnRMSSDcv) and vice versa. Thus, a capacity for greater chronic workloads may be protective against perturbations in cardiac-autonomic homeostasis among American college football players.

The Plasmodium falciparum Cell-Traversal Protein for Ookinetes and Sporozoites as a Candidate for Preerythrocytic and Transmission-Blocking Vaccines.

Recent studies have shown that immune responses against the cell-traversal protein for Plasmodium ookinetes and sporozoites (CelTOS) can inhibit parasite infection. While these studies provide important evidence toward the development of vaccines targeting this protein, it remains unknown whether these responses could engage the Plasmodium falciparum CelTOS in vivo Using a newly developed rodent malaria chimeric parasite expressing the P. falciparum CelTOS (PfCelTOS), we evaluated the protective effect of in vivo immune responses elicited by vaccination and assessed the neutralizing capacity of monoclonal antibodies specific against PfCelTOS. Mice immunized with recombinant P. falciparum CelTOS in combination with the glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE) or glucopyranosyl lipid adjuvant-liposome-QS21 (GLA-LSQ) adjuvant system significantly inhibited sporozoite hepatocyte infection. Notably, monoclonal antibodies against PfCelTOS strongly inhibited oocyst development of P. falciparum and Plasmodium berghei expressing PfCelTOS in Anopheles gambiae mosquitoes. Taken together, our results demonstrate that anti-CelTOS responses elicited by vaccination or passive immunization can inhibit sporozoite and ookinete infection and impair vector transmission.

The Value of Addressing Patient Preferences.

Recent scientific progress is, in some cases, leading to transformative new medicines for diseases that previously had marginal or even no treatment options. This offers great promise for people affected by these diseases, but it has also placed stress on the health care system in terms of the growing cost associated with some new interventions. Effort has been taken to create tools to help patients and health care providers assess the value of new medical innovations. These tools may also provide the basis for assessing the price associated with new medical products. Given the growing expenditures in health care, value frameworks present an opportunity to evaluate new therapeutic options in the context of other treatments and potentially lead to a more economically sustainable health care system. In summary, the contribution to meaningful improvements in health outcomes is the primary focus of any assessment of the value of a new intervention. A component of such evaluations, however, should factor in timely access to new products that address an unmet medical need, as well as the magnitude of that beneficial impact. To achieve these goals, value assessment tools should allow for flexibility in clinical end points and trial designs, incorporate patient preferences, and continually evolve as new evidence, practice patterns, and medical progress advance.

Relating psychological and social factors to academic performance: A longitudinal investigation of high-poverty middle school students.

We investigated the relations between middle school students' psychological factors (academic commitment and emotional control), social perceptions (family involvement and school climate), and academic performance over time. Gender differences in these relations were also examined. Based on a two-year longitudinal data set of 942 middle-school students from a high-poverty district in the United States, we found that all four factors measured in 6th grade were predictive of GPA at the end of the 7th grade above and beyond gender, race, and home intellectual materials. Among these factors, emotional control had the strongest relation with GPA, and the importance of family involvement increased over time, especially for female students. The results also revealed the indirect effects of the social factors on GPA through the psychological factors, and mostly through emotional control. These findings highlight the complex relation between the social-emotional factors and academic outcomes in early adolescence.