A framework for implementing Patient and Public Involvement in mental health research: The PATHWAY research programme benchmarked against NIHR standards.

BACKGROUND: Patient and Public Involvement (PPI) in research has become a key component recommended by research commissioners, grant award bodies and specified in government policies. Despite the increased call for PPI, few studies have demonstrated how to implement PPI within large-scale research studies. OBJECTIVE: The aim of the current study was to provide a case example of the implementation of a patient advisory group in a large-scale mental health research programme (PATHWAY) and to benchmark this against UK standards. METHOD: A PPI group was incorporated throughout the PATHWAY research programme, from grant development to dissemination. The group attended regular meetings and supported participant recruitment, evaluated patient-facing documents, supported the piloting of the research intervention and co-developed the dissemination and impact strategy. The implementation of PPI throughout the project was benchmarked against the UK standards for PPI. RESULTS: The inclusion of PPI in the PATHWAY project provided tangible changes to the research project (i.e., improving study documents, co-developing dissemination materials) but also proved to be a beneficial experience to PPI members through the development of new skills and the opportunity to provide a patient voice in research. We show how PPI was involved across seven study phases and provide examples of implementation of the six UK standards. The study did not include PPI in data analysis but met all the UK standards for PPI. Challenges regarding practical components (i.e., meeting frequency, language use), increasing diversity and PPI members' knowledge of research were highlighted as areas for further improvement. CONCLUSIONS: We provide a case example of how PPI can be implemented throughout a research lifecycle and we note the barriers faced and make suggestions for PPI in future implementation and research. PATIENT AND PUBLIC CONTRIBUTION: PPI members were involved throughout the lifecycle of the research programme. The PPI lead was a co-author on the manuscript and contributed to report writing.

Female Soccer Periodization on Anaerobic Power/Capacity.

ABSTRACT: Purdom, TM, Levers, KS, Ryan, GA, Brown, L, Giles, J, and McPherson, C. Female soccer periodization on anaerobic power/capacity. J Strength Cond Res 37(12): 2405-2410, 2023-The purpose of this study was to observe changes in anaerobic power and capacity (resistance to fatigue) over an annual training cycle (ATC) in 14 Division I female soccer athletes (19.4 ± 1.0 years, 60.8 ± 5.4 kg, 164.9 ± 6.2 cm, 19.5 ± 3.2% body fat, and 48.9 ± 3.9 kg fat free mass). All subjects were evaluated across the ATC at 5 testing blocks (B1-B5) representing seasonal transitions: postcompetition I (B1), prespring (B2), postspring training (B3), precompetition (B4), and postcompetition II (B5) using 3 tests: countermovement vertical jump to measure peak vertical power (PVP), 40-yard sprint to measure peak horizontal power (PHP), and 35-m running anaerobic sprint test to measure anaerobic capacity via fatigue index (FI). Repeated measures analysis of variance was used with the Bonferroni post hoc test when relevant along with Cohen's d to evaluate effect size. Data are represented as mean ± SD ; significance set to p < 0.05. Significant performance increases were observed from postseason I to spring season training (B1-B3) in PVP (6.61 ± 3.18 and 7.71 ± 3.20; p < 0.01, d = 1.12) while changes occurred from prespring season to postspring season (B2-B3) in PVP (6.84 ± 3.15 and 7.71 ± 3.20; p = 0.03, d = 0.93) and PHP (6.65 ± 0.97 and 7.55 ± 1.26; p < 0.01, d = 1.06) with no change in body composition. No other significant changes were observed across the ATC ( p > 0.05). Increases in PHP and PVP occurred with directed training after B3 and then declined remaining so across the competitive season. Peak horizontal power and PVP may be more sensitive to coaching style and seasonal transition compared with FI and body composition changes.

p47 licenses activation of the immune deficiency pathway in the tick Ixodes scapularis.

The E3 ubiquitin ligase X-linked inhibitor of apoptosis (XIAP) acts as a molecular rheostat for the immune deficiency (IMD) pathway of the tick Ixodes scapularis How XIAP activates the IMD pathway in response to microbial infection remains ill defined. Here, we identified the XIAP enzymatic substrate p47 as a positive regulator of the I. scapularis IMD network. XIAP polyubiquitylates p47 in a lysine 63-dependent manner and interacts with the p47 ubiquitin-like (UBX) module. p47 also binds to Kenny (IKKγ/NEMO), the regulatory subunit of the inhibitor of nuclear factor (NF)- κB kinase complex. Replacement of the amino acid lysine to arginine within the p47 linker region completely abrogated molecular interactions with Kenny. Furthermore, mitigation of p47 transcription levels through RNA interference in I. scapularis limited Kenny accumulation, reduced phosphorylation of IKKß (IRD5), and impaired cleavage of the NF-κB molecule Relish. Accordingly, disruption of p47 expression increased microbial colonization by the Lyme disease spirochete Borrelia burgdorferi and the rickettsial agent Anaplasma phagocytophilum Collectively, we highlight the importance of ticks for the elucidation of paradigms in arthropod immunology. Manipulating immune signaling cascades within I. scapularis may lead to innovative approaches to reducing the burden of tick-borne diseases.

A dual-feedback loop model of the mammalian circadian clock for multi-input control of circadian phase.

The molecular circadian clock is driven by interlocked transcriptional-translational feedback loops, producing oscillations in the expressions of genes and proteins to coordinate the timing of biological processes throughout the body. Modeling this system gives insight into the underlying processes driving oscillations in an activator-repressor architecture and allows us to make predictions about how to manipulate these oscillations. The knockdown or upregulation of different cellular components using small molecules can disrupt these rhythms, causing a phase shift, and we aim to determine the dosing of such molecules with a model-based control strategy. Mathematical models allow us to predict the phase response of the circadian clock to these interventions and time them appropriately but only if the model has enough physiological detail to describe these responses while maintaining enough simplicity for online optimization. We build a control-relevant, physiologically-based model of the two main feedback loops of the mammalian molecular clock, which provides sufficient detail to consider multi-input control. Our model captures experimentally observed peak to trough ratios, relative abundances, and phase differences in the model species, and we independently validate this model by showing that the in silico model reproduces much of the behavior that is observed in vitro under genetic knockout conditions. Because our model produces valid phase responses, it can be used in a model predictive control algorithm to determine inputs to shift phase. Our model allows us to consider multi-input control through small molecules that act on both feedback loops, and we find that changes to the parameters of the negative feedback loop are much stronger inputs for shifting phase. The strongest inputs predicted by this model provide targets for new experimental small molecules and suggest that the function of the positive feedback loop is to stabilize the oscillations while linking the circadian system to other clock-controlled processes.

A classification approach to estimating human circadian phase under circadian alignment from actigraphy and photometry data.

The time of dim light melatonin onset (DLMO) is the gold standard for circadian phase assessment in humans, but collection of samples for DLMO is time and resource-intensive. Numerous studies have attempted to estimate circadian phase from actigraphy data, but most of these studies have involved individuals on controlled and stable sleep-wake schedules, with mean errors reported between 0.5 and 1 hour. We found that such algorithms are less successful in estimating DLMO in a population of college students with more irregular schedules: Mean errors in estimating the time of DLMO are approximately 1.5-1.6 hours. We reframed the problem as a classification problem and estimated whether an individual's current phase was before or after DLMO. Using a neural network, we found high classification accuracy of about 90%, which decreased the mean error in DLMO estimation-identifying the time at which the switch in classification occurs-to approximately 1.3 hours. To test whether this classification approach was valid when activity and circadian rhythms are decoupled, we applied the same neural network to data from inpatient forced desynchrony studies in which participants are scheduled to sleep and wake at all circadian phases (rather than their habitual schedules). In participants on forced desynchrony protocols, overall classification accuracy dropped to 55%-65% with a range of 20%-80% for a given day; this accuracy was highly dependent upon the phase angle (ie, time) between DLMO and sleep onset, with the highest accuracy at phase angles associated with nighttime sleep. Circadian patterns in activity, therefore, should be included when developing and testing actigraphy-based approaches to circadian phase estimation. Our novel algorithm may be a promising approach for estimating the onset of melatonin in some conditions and could be generalized to other hormones.

Preoperative Depression Is Negatively Associated With Function and Predicts Poorer Outcomes After Hip Arthroscopy for Femoroacetabular Impingement.

PURPOSE: (1) To determine the prevalence of depression in patients undergoing hip arthroscopy for the treatment of femoroacetabular impingement (FAI) syndrome and (2) to determine whether depression has a statistically significant and clinically relevant effect on preoperative and postoperative patient-reported outcome scores. METHODS: Consecutive subjects undergoing hip arthroscopy for FAI syndrome were retrospectively reviewed. The Beck Depression Inventory-II (BDI-II), Hip Outcome Score (HOS), and 33-item International Hip Outcome Tool (iHOT-33) were administered preoperatively and postoperatively. Clinically relevant differences were defined by the minimal clinically important difference, substantial clinical benefit, and patient acceptable symptom state. Comparisons between preoperative and postoperative scores were completed. The Spearman correlation coefficient (r) was used to determine the degree of correlation between the BDI-II score, HOS, and iHOT-33 score preoperatively and postoperatively. RESULTS: We analyzed 77 patients (72.7% female patients; mean age, 35.2 ± 12.5 years). Depressive symptoms were reported as minimal (75.3%), mild (11.7%), moderate (6.5%), or severe (6.5%). Patients with minimal or mild depression had a superior HOS Activities of Daily Living (Δ17.3 preoperatively [P < .001] and Δ37.8 postoperatively [P < .001]), HOS Sport-Specific Subscore (Δ12.8 preoperatively [P = .002] and Δ52.1 postoperatively [P < .0001]), and iHOT-33 score (Δ15.4 preoperatively [P < .0001] and Δ51.3 postoperatively [P < .0001]) compared with patients with moderate or severe depression. There was a weak to moderate negative correlation between the BDI-II score and iHOT-33 score (r = -0.4614, P < .0001 preoperatively; r = -0.327, P < .0001 at 1 year), HOS Activities of Daily Living (r = -0.531, P < .0001 preoperatively), and HOS Sport-Specific Subscore (r = -0.379, P < .0017 at 1 year). CONCLUSIONS: Most patients undergoing hip arthroscopy for FAI have minimal depressive symptoms with the overall prevalence higher than the general population. Patients with minimal or mild depressive symptoms have statistically and clinically better preoperative and postoperative patient-reported outcomes, are more likely to obtain substantial clinical benefit from surgery, and are more likely to reach a patient acceptable symptom state after surgery than patients with moderate to severe depressive symptoms. LEVEL OF EVIDENCE: Level III, case-control study.

Pyruvate oxidase of Streptococcus pneumoniae contributes to pneumolysin release.

BACKGROUND: Streptococcus pneumoniae is one of the leading causes of community acquired pneumonia and acute otitis media. Certain aspects of S. pneumoniae's virulence are dependent upon expression and release of the protein toxin pneumolysin (PLY) and upon the activity of the peroxide-producing enzyme, pyruvate oxidase (SpxB). We investigated the possible synergy of these two proteins and identified that release of PLY is enhanced by expression of SpxB prior to stationary phase growth. RESULTS: Mutants lacking the spxB gene were defective in PLY release and complementation of spxB restored PLY release. This was demonstrated by cytotoxic effects of sterile filtered supernatants upon epithelial cells and red blood cells. Additionally, peroxide production appeared to contribute to the mechanism of PLY release since a significant correlation was found between peroxide production and PLY release among a panel of clinical isolates. Exogenous addition of H2O2 failed to induce PLY release and catalase supplementation prevented PLY release in some strains, indicating peroxide may exert its effect intracellularly or in a strain-dependent manner. SpxB expression did not trigger bacterial cell death or LytA-dependent autolysis, but did predispose cells to deoxycholate lysis. CONCLUSIONS: Here we demonstrate a novel link between spxB expression and PLY release. These findings link liberation of PLY toxin to oxygen availability and pneumococcal metabolism.

Young people's views about consenting to data linkage: findings from the PEARL qualitative study.

BACKGROUND: Electronic administrative data exist in several domains which, if linked, are potentially useful for research. However, benefits from data linkage should be considered alongside risks such as the threat to privacy. Avon Longitudinal Study of Parents and Children (ALSPAC) is a birth cohort study. The Project to Enhance ALSPAC through Record Linkage (PEARL) was established to enrich the ALSPAC resource through linkage between ALSPAC participants and routine sources of health and social data. Qualitative research was incorporated in the PEARL study to examine participants' views about data linkage and inform approaches to information sharing. This paper focusses on issues of consent. METHODS: Digitally recorded interviews were conducted with 55 participants aged 17-19 years. Terms and processes relating to consent, anonymization and data linkage were explained to interviewees. Scenarios were used to prompt consideration of linking different sources of data, and whether consent should be requested. Interview recordings were fully transcribed. Thematic analysis was undertaken using the Framework approach. RESULTS: Participant views on data linkage appeared to be most influenced by: considerations around the social sensitivity of the research question, and; the possibility of tangible health benefits in the public interest. Some participants appeared unsure about the effectiveness of anonymization, or did not always view effective anonymization as making consent unnecessary. This was related to notions of ownership of personal information and etiquette around asking permission for secondary use. Despite different consent procedures being explained, participants tended to equate consent with 'opt-in' consent through which participants are 'asked' if their data can be used for a specific study. Participants raising similar concerns came to differing conclusions about whether consent was needed. Views changed when presented with different scenarios, and were sometimes inconsistent. CONCLUSIONS: Findings from this study question the validity of 'informed consent' as a cornerstone of good governance, and the extent to which potential research participants understand different types of consent and what they are consenting, or not consenting, to. Pragmatic, imaginative and flexible approaches are needed if research using data linkage is to successfully realise its potential for public good without undermining public trust in the research process.

Young people's views about the purpose and composition of research ethics committees: findings from the PEARL qualitative study.

BACKGROUND: Avon Longitudinal Study of Parents and Children (ALSPAC) is a birth cohort study within which the Project to Enhance ALSPAC through Record Linkage (PEARL) was established to enrich the ALSPAC resource through linkage between ALSPAC participants and routine sources of health and social data. PEARL incorporated qualitative research to seek the views of young people about data linkage, including their opinions about appropriate safeguards and research governance. In this paper we focus on views expressed about the purpose and composition of research ethics committees. METHODS: Digitally recorded interviews were conducted with 48 participants aged 17-19 years. Participants were asked about whether medical research should be monitored and controlled, their knowledge of research ethics committees, who should sit on these committees and what their role should be. Interview recordings were fully transcribed and anonymised. Thematic analysis was undertaken, assisted by the Framework approach to data management. RESULTS: The majority of interviewees had little or no specific knowledge of ethics committees. Once given basic information about research ethics committees, only three respondents suggested there was no need for such bodies to scrutinise research. The key tasks of ethics committees were identified as monitoring the research process and protecting research participants. The difficulty of balancing the potential to inhibit research against the need to protect research participants was acknowledged. The importance of relevant research and professional expertise was identified but it was also considered important to represent wider public opinion, and to counter the bias potentially associated with self-selection possibly through a selection process similar to 'jury duty'. CONCLUSIONS: There is a need for more education and public awareness about the role and composition of research ethics committees. Despite an initial lack of knowledge, interviewees were able to contribute their ideas and balance the rights of individuals with the wider benefits from research. The suggestion that public opinion should be represented through random selection similar to jury duty may be worth pursuing in the light of the need to ensure diversity of opinion and establish trust amongst the general public about the use of 'big data' for the wider public good.

A randomised controlled trial comparing opt-in and opt-out home visits for tracing lost participants in a prospective birth cohort study.

BACKGROUND: Attrition is an important problem in cohort studies. Tracing cohort members who have moved or otherwise lost contact with the study is vital. There is some debate about the acceptability and relative effectiveness of opt-in versus opt-out methods of contacting cohort members to re-engage them in this context. We conducted a randomised controlled trial to compare the two approaches in terms of effectiveness (tracing to confirm address and consenting to continue in the study), cost-effectiveness and acceptability. METHODS: Participants in this trial were individuals (young people and mothers) recruited to the Avon Longitudinal Study of Parents and Children (ALSPAC), who had not engaged with the study in the previous 5 years and for whom mail had been returned from their last known address. The sampling frame was restricted to those for whom database searching led to a potential new address being found in the Bristol area. 300 participants were randomly selected and assigned using stratified randomisation to the opt-in or opt-out arm. A tailored letter was sent to the potential new address, either asking participants to opt in to a home visit, or giving them the option to opt out of a home visit. Fieldworkers from Ipsos MORI conducted home visits to confirm address details. RESULTS: The proportion who were traced was higher in the opt-out arm (77/150 = 51 %) than the opt-in arm (6/150 = 4 %), as was the proportion who consented to continue in ALSPAC (46/150 = 31 % v 4/150 = 3 %). The mean cost per participant was £8.14 in the opt-in arm and £71.93 in the opt-out arm. There was no evidence of a difference in acceptability between the opt-in and opt-out approaches. CONCLUSION: Since the opt-in approach yielded very low response rates, and there were no differences in terms of acceptability, we conclude that the opt-out approach is the most effective method of tracing disengaged study members. The gains made in contacting participants must be weighed against the increase in cost using this methodology.

The tick salivary protein sialostatin L2 inhibits caspase-1-mediated inflammation during Anaplasma phagocytophilum infection.

Saliva from arthropod vectors facilitates blood feeding by altering host inflammation. Whether arthropod saliva counters inflammasome signaling, a protein scaffold that regulates the activity of caspase-1 and cleavage of interleukin-1ß (IL-1ß) and IL-18 into mature molecules, remains elusive. In this study, we provide evidence that a tick salivary protein, sialostatin L2, inhibits inflammasome formation during pathogen infection. We show that sialostatin L2 targets caspase-1 activity during host stimulation with the rickettsial agent Anaplasma phagocytophilum. A. phagocytophilum causes macrophage activation and hemophagocytic syndrome features. The effect of sialostatin L2 in macrophages was not due to direct caspase-1 enzymatic inhibition, and it did not rely on nuclear factor κB or cathepsin L signaling. Reactive oxygen species from NADPH oxidase and the Loop2 domain of sialostatin L2 were important for the regulatory process. Altogether, our data expand the knowledge of immunoregulatory pathways of tick salivary proteins and unveil an important finding in inflammasome biology.

Using S-adenosyl-L-homocysteine capture compounds to characterize S-adenosyl-L-methionine and S-adenosyl-L-homocysteine binding proteins.

S-Adenosyl-l-methionine (SAM) is recognized as an important cofactor in a variety of biochemical reactions. As more proteins and pathways that require SAM are discovered, it is important to establish a method to quickly identify and characterize SAM binding proteins. The affinity of S-adenosyl-l-homocysteine (SAH) for SAM binding proteins was used to design two SAH-derived capture compounds (CCs). We demonstrate interactions of the proteins COMT and SAHH with SAH-CC with biotin used in conjunction with streptavidin-horseradish peroxidase. After demonstrating SAH-dependent photo-crosslinking of the CC to these proteins, we used a CC labeled with a fluorescein tag to measure binding affinity via fluorescence anisotropy. We then used this approach to show and characterize binding of SAM to the PR domain of PRDM2, a lysine methyltransferase with putative tumor suppressor activity. We calculated the Kd values for COMT, SAHH, and PRDM2 (24.1 ± 2.2 µM, 6.0 ± 2.9 µM, and 10.06 ± 2.87 µM, respectively) and found them to be close to previously established Kd values of other SAM binding proteins. Here, we present new methods to discover and characterize SAM and SAH binding proteins using fluorescent CCs.

'Getting it write' in a new era of patient online access to primary care health records.

AIM: To explore how to help make online consultation notes easier for patient audiences to understand. BACKGROUND: Most patients in England will soon be able to access all new prospective entries (including free-text) within their online primary care health record via the NHS App or other online services. METHOD: We conducted interviews and focus group discussions with 26 patients from underserved communities. Participants responded to vignettes about fictional patient consultation scenarios and assessed the clarity of corresponding simulated records. Participants were then asked to identify potential comprehension issues, offensive content, or anxiety triggers. RESULTS: Most participants struggled to understand a large proportion of simulated notes, particularly medical acronyms, clinician shorthand, and non-clinical abbreviations. Participants also identified issues that may cause unintended offence or additional anxiety. Participants considered that most patients will struggle to fully understand the content of their consultation notes in their current format. They made a number of suggestions about how this service may be improved to meet the needs of patient audiences and maintain positive patient-clinician relationships. CONCLUSION: Opening up online record access to include patient audiences necessitates a significant cultural shift in the way that consultation notes are written and used. To maximise NHS investment in this policy and avoid worsening health inequalities, it is essential to ensure that all patients can understand and access the benefits of online access to their notes. To do this, clinicians need to be supported to manage the challenges of writing for patient audiences, while continuing to maintain effective clinical care.

Primary care staff's views and experience of patients' online access to their electronic health record: a qualitative exploration.

BACKGROUND: NHS England have announced plans to enable all adult patients to have full prospective access to their primary care record by default. Despite this, little is known about the views and experiences of primary care staff regarding patients' online records access (ORA). AIM: To examine the views and experiences of primary care staff regarding patients having online access to their primary care health record, and how this service could be supported and improved. DESIGN AND SETTING: A qualitative study of a purposive sample of 30 primary care staff in England. METHOD: Online semi-structured interviews with primary care staff were conducted between December 2021 and March 2022. Verbatim transcripts were analysed inductively using thematic analysis. RESULTS: Most staff agreed with the principle of patient access to online health records but had mixed feelings regarding the potential benefits and drawbacks of applying this in practice. Staff identified opportunities for improving patient engagement, health literacy, and efficiencies in some administrative workloads, as well as concerns about maintaining the clinical integrity of patient records and ensuring that staff and patient safety and wellbeing are protected. CONCLUSION: Participants acknowledged that ORA may transform the purpose and function of the record and that ORA has potential to instigate a significant cultural shift in primary care, changing how staff work and relate to patients. This underlines the need for additional staff training and support to expand capability and capacity to adapt practice and enhance patient engagement with, and understanding of, their health records.

Developmental patterning of peptide transcription in the central circadian clock in both sexes.

Introduction: Neuropeptide signaling modulates the function of central clock neurons in the suprachiasmatic nucleus (SCN) during development and adulthood. Arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) are expressed early in SCN development, but the precise timing of transcriptional onset has been difficult to establish due to age-related changes in the rhythmic expression of each peptide. Methods: To provide insight into spatial patterning of peptide transcription during SCN development, we used a transgenic approach to define the onset of Avp and Vip transcription. Avp-Cre or Vip-Cre males were crossed to Ai9+/+ females, producing offspring in which the fluorescent protein tdTomato (tdT) is expressed at the onset of Avp or Vip transcription. Spatial patterning of Avp-tdT and Vip-tdT expression was examined at critical developmental time points spanning mid-embryonic age to adulthood in both sexes. Results: We find that Avp-tdT and Vip-tdT expression is initiated at different developmental time points in spatial subclusters of SCN neurons, with developmental patterning that differs by sex. Conclusions: These data suggest that SCN neurons can be distinguished into further subtypes based on the developmental patterning of neuropeptide expression, which may contribute to regional and/or sex differences in cellular function in adulthood.

Later energy intake relative to mathematically modeled circadian time is associated with higher percentage body fat.

OBJECTIVE: Later circadian timing of energy intake is associated with higher body fat percentage. Current methods for obtaining accurate circadian timing are labor- and cost-intensive, limiting practical application of this relationship. This study investigated whether the timing of energy intake relative to a mathematically modeled circadian time, derived from easily collected ambulatory data, would differ between participants with a lean or overweight/obesity body fat percentage. METHODS: Participants (N = 87) wore a light- and activity-measuring device (actigraph) throughout a cross-sectional 30-day study. For 7 consecutive days within these 30 days, participants used a time-stamped-picture phone application to record energy intake. Body fat percentage was recorded. Circadian time was defined using melatonin onset from in-laboratory collected repeat saliva sampling or using light and activity or activity data alone entered into a mathematical model. RESULTS: Participants with overweight/obesity body fat percentages ate 50% of their daily calories significantly closer to model-predicted melatonin onset from light and activity data (0.61 hours closer) or activity data alone (0.86 hours closer; both log-rank p < 0.05). CONCLUSIONS: Use of mathematically modeled circadian timing resulted in similar relationships between the timing of energy intake and body composition as that observed using in-laboratory collected metrics. These findings may facilitate use of circadian timing in time-based interventions.

Neural circuit models for evidence accumulation through choice-selective sequences.

Decision making is traditionally thought to be mediated by populations of neurons whose firing rates persistently accumulate evidence across time. However, recent decision-making experiments in rodents have observed neurons across the brain that fire sequentially as a function of spatial position or time, rather than persistently, with the subset of neurons in the sequence depending on the animal's choice. We develop two new candidate circuit models, in which evidence is encoded either in the relative firing rates of two competing chains of neurons or in the network location of a stereotyped pattern ("bump") of neural activity. Encoded evidence is then faithfully transferred between neuronal populations representing different positions or times. Neural recordings from four different brain regions during a decision-making task showed that, during the evidence accumulation period, different brain regions displayed tuning curves consistent with different candidate models for evidence accumulation. This work provides mechanistic models and potential neural substrates for how graded-value information may be precisely accumulated within and transferred between neural populations, a set of computations fundamental to many cognitive operations.

An Anticipatory Scheme for the Model Predictive Control of Circadian Phase for Expected Environmental Light Changes.

The circadian system is critical to timing biological functions in anticipation of daily environmental light changes, but much previous work on the development of molecular control inputs to shift the phase of the circadian system has applied model predictive control (MPC) without considering expected environmental light changes. We augment the MPC algorithm to develop an anticipatory control algorithm, which has advantages over MPC in achieving scheduled phase shifts (as occurs with jet lag and shiftwork). We further extend the algorithm in a model switching control scheme to account for changes in the light environment. Taken together, these two enhancements to the standard MPC framework allow for better control of the circadian oscillator in more realistic environments by anticipating environmental light changes.

FDA Approval Summary: Margetuximab plus Chemotherapy for Advanced or Metastatic HER2-Positive Breast Cancer.

On December 16, 2020, the FDA granted regular approval to margetuximab-cmkb (MARGENZA), in combination with chemotherapy, for the treatment of adult patients with HER2-positive (HER2+) metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Approval was based on data from SOPHIA, a multicenter, randomized, open-label, active controlled study comparing margetuximab with trastuzumab, in combination with chemotherapy. The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review. SOPHIA demonstrated a 0.9-month difference in median PFS between the two treatment arms [5.8 vs. 4.9 months, respectively; stratified HR, 0.76 (95% confidence interval: 0.59-0.98; P = 0.0334)]. Overall survival (OS) was immature at the data cut-off date of September 10, 2019. Infusion-related reactions (IRR) are an important safety signal associated with margetuximab plus chemotherapy. In SOPHIA, 13% of patients treated with margetuximab plus chemotherapy reported IRRs, of which 1.5% were grade 3. The most commonly reported adverse drug reactions (>10%) with margetuximab in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, IRR, palmar-plantar erythrodysesthesia, and extremity pain. Overall, the favorable risk-benefit profile for margetuximab when added to chemotherapy supported its approval for the intended indication.

Use of risperidone as augmentation treatment for major depressive disorder.

OBJECTIVE: To review the efficacy and safety of risperidone for augmentation treatment in patients with major depressive disorder who fail to achieve adequate response to antidepressant monotherapy. DATA SOURCES: A search of MEDLINE (1966-August 2010) and EMBASE (1980-August 2010) was conducted, using the terms risperidone and major depressive disorder. In addition, a manual search of the references cited in each publication identified from the database search was conducted to identify relevant articles. STUDY SELECTION AND DATA EXTRACTION: All English-language, peer-reviewed publications identified from the data sources were evaluated. Four clinical trials and 1 subanalysis of a clinical trial were included for analysis. DATA SYNTHESIS: Risperidone is an atypical antipsychotic that displays antidepressant properties due to its activity at various serotonergic and dopaminergic receptors. Studies have demonstrated that risperidone augmentation may be effective and safe when used at low doses. Although several of the studies identified had limited sample sizes, all studies demonstrated improvement on various standardized depressive symptom assessment scales. Study durations ranged from 4 to 24 weeks, with doses ranging from 0.25 to 2 mg/day. The most common adverse effects associated with risperidone therapy were headache, dry mouth, and increased appetite. CONCLUSIONS: Clinical evidence suggests that the use of risperidone as adjunctive therapy for treatment-resistant depression may improve rates of response and remission, but long-term effectiveness and safety cannot be determined at this time. Therefore, an adequate trial of first-line agents from different classes and/or a combination of agents from different classes would be recommended prior to initiation of risperidone. If the decision is made to start risperidone, health-care providers should ensure that patients are educated regarding the potential benefits and adverse effects before initiating risperidone.