Delivering Telegenetics Services: Review and Synthesis of Best Practices.

Introduction: Before the COVID-19 public health emergency, few genetics providers used telehealth. As a response to this, many genetics providers began conducting telehealth care, referred to as telegenetics, usually with guidance from their institutions but without specific guidance related to the uniqueness of genetic services. Objectives: The Telegenetics Workgroup of the National Coordinating Center for Regional Genetics Networks convened a panel of experts in the fields of telemedicine, genetics, and genomics to review the existing literature on telegenetics and synthesize best operating practices for medical geneticists, genetic counselors, and metabolic dietitians providing telegenetics services. Methods: The group searched PubMed using the terms "telegenetics," "telemedicine + genetics," and "telehealth + genetics." The group also reviewed the Northeast Telehealth Resource Center's telegenetics webliography. Websites were searched, including the American Telemedicine Association's website, Center for Connected Health Policy, and National Telehealth Resource Center for position statements, standards documents, and guidelines. The group met frequently by videoconference and discussed the literature, and using expert consensus, the group determined best practices in providing telegenetics services. Results: These telegenetics best practices cover important aspects of telegenetics services, including, but not limited to, ongoing delivery of telegenetics services, use of special technology, legal and regulatory requirements, and considerations regarding special settings and circumstances in which telegenetics may be conducted. Conclusions: Recognizing the growing use of telegenetics and a future in which telegenetics continues to be part of the regular practice of genetics, this guide informs genetics providers of best practices for delivering telegenetics services to patients.

Pegvaliase for the treatment of phenylketonuria: Final results of a long-term phase 3 clinical trial program.

Phenylketonuria (PKU) is a genetic disorder caused by deficiency of the enzyme phenylalanine hydroxylase (PAH), which results in phenylalanine (Phe) accumulation in the blood and brain, and requires lifelong treatment to keep blood Phe in a safe range. Pegvaliase is an enzyme-substitution therapy approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 µmol/L) despite prior management. Aggregated results from the PRISM clinical trials demonstrated substantial and sustained reductions in blood Phe with a manageable safety profile, but also noted individual variation in time to and dose needed for a first response. This analysis reports longer-term aggregate findings and characterizes individual participant responses to pegvaliase using final data from the randomized trials PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862), and the open-label extension study 165-304 (NCT03694353). In 261 adult participants with a mean of 36.6 months of pegvaliase treatment, 71.3%, 65.1%, and 59.4% achieved clinically significant blood Phe levels of ≤600, ≤360, and ≤ 120 µmol/L, respectively. Some participants achieved blood Phe reductions with <20 mg/day pegvaliase, although most required higher doses. Based on Kaplan-Meier analysis, median (minimum, maximum) time to first achievement of a blood Phe threshold of ≤600, ≤360, or ≤ 120 µmol/L was 4.4 (0.0, 54.0), 8.0 (0.0, 57.0), and 11.6 (0.0, 66.0) months, respectively. Once achieved, blood Phe levels remained below clinical threshold in most participants. Sustained Phe response (SPR), a new method described within for measuring durability of blood Phe response, was achieved by 85.5%, 84.7%, and 78.1% of blood Phe responders at blood Phe thresholds of ≤600, ≤360, or ≤ 120 µmol/L, respectively. Longer-term safety data were consistent with previous reports, with the most common adverse events (AEs) being arthralgia, injection site reactions, headache, and injection site erythema. The incidence of most AEs, including hypersensitivity AEs, was higher during the early treatment phase (≤6 months) than later during treatment. In conclusion, using data from three key pegvaliase clinical trials, participants treated with pegvaliase were able to reach clinically significant blood Phe reductions to clinical thresholds of ≤600, ≤360, or ≤ 120 µmol/L during early treatment, with safety profiles improving from early to sustained treatment. This study also supports the use of participant-level data and new ways of looking at durable blood Phe responses to better characterize patients' individual PKU treatment journeys.

Risk Factors for Non-Healing Wounds-A Single-Centre Study.

Background: Chronic wounds present a significant clinical, social, and economic challenge. This study aimed to objectify the risk factors of healing outcomes and the duration of chronic wounds from various etiologies. Methods: Patients treated for non-healing wounds at the surgical outpatient clinic of the Olomouc Military Hospital were involved. Data from patients treated between 8/2021 and 9/2023 were selected. Patients were mostly treated as outpatients, with microbiological follow-up indicated in cases of advanced signs of inflammation. Results: There were 149 patients who met our selection criteria (the mean age was 64.4 years). Predominant causes of wounds involved diabetes (30.9%), post-trauma (25.5%), pressure ulcers (14.8%), surgical site infections (14.8%), and vascular ulcers (14.1%). Patient outcomes included wound resolution in 77.2% of patients (with a mean healing time of 110.9 days), amputation in 14.1%, and wound-related death in 8.7% of patients. Non-healing cases (amputation/death) were predicted by several local factors including an initial depth greater than 1 cm, wound secretion, inflammatory base, and a maximum wound size. Systemic factors included most strongly clinically manifested atherosclerosis and its risk factors. Of the 110 swabs performed, 103 identified at least 1 bacterial genus. The dominant risk factor for a prolonged healing duration was bacterial infection. Wounds contaminated by Proteus or Pseudomonas had prolonged healing times of 87 days (p = 0.02) and 72 days (p = 0.045), respectively. Conclusions: The early identification of local and systemic risk factors contributes to the successful resolution of chronic wounds and a reduced duration of healing.

'Being and becoming a practice educator': An AHP online programme.

BACKGROUND: Five higher education institutions (HEIs) in Scotland with qualifying allied health professional (AHP) programmes developed an online programme in practice education. This paper focuses on the design, development and evaluation of this programme. APPROACH: The programme was developed using the ADDIE approach for instructional design and was launched on TURAS (NHS e-learning platform) in November 2020. In November 2021, an online questionnaire was distributed to evaluate the e-learning programme and AHPs' preferences for future practice education training. EVALUATION: Of the 407 responses, 95% (n = 388) were working in the NHS. There was no preference for online or face-to-face format of training. For the majority, having flexibility of time and place was deemed to be important to manage learning particularly given high workloads and staff shortages. Out of the 29% (n = 118) who answered questions regarding the programme, more than 60% (n > 75) of respondents reported it was well organised, the content relevant and would support their learning. Free text comments suggested a desire for networking opportunities to discuss learning. IMPLICATIONS: An e-learning programme for new and existing AHP practice educators in Scotland was developed and launched in November 2020. Key feedback from participants was that they wanted to have opportunities for interaction with other learners to discuss and share their learning whether this was online or face-to-face. The programme now forms the foundation education in practice education for AHPs in Scotland and is supplemented with networking opportunities through synchronous online training with HEIs and via NHS Education for Scotland's virtual community.

Efficacy and safety of a synthetic biotic for treatment of phenylketonuria: a phase 2 clinical trial.

Despite available treatment options, many patients with phenylketonuria (PKU) cannot achieve target plasma phenylalanine (Phe) levels1. We previously modified Escherichia coli Nissle 1917 to metabolize Phe in the gut after oral administration (SYNB1618) and designed a second strain (SYNB1934) with enhanced activity of phenylalanine ammonia lyase2,3. In a 14-day open-label dose-escalation study (Synpheny-1, NCT04534842 ), we test a primary endpoint of change from baseline in labeled Phe (D5-Phe AUC0-24; D5-Phe area under the curve (AUC) over 24 hours after D5-Phe administration) in plasma after D5-Phe challenge in adult participants with screening Phe of greater than 600 µM. Secondary endpoints were the change from baseline in fasting plasma Phe and the incidence of treatment-emergent adverse events. A total of 20 participants (ten male and ten female) were enrolled and 15 completed the study treatment. Here, we show that both strains lower Phe levels in participants with PKU: D5-Phe AUC0-24 was reduced by 43% from baseline with SYNB1934 and by 34% from baseline with SYNB1618. SYNB1934 led to a decrease in fasting plasma Phe of 40% (95% CI, -52, -24). There were no serious adverse events or infections. Four participants discontinued because of adverse events, and one withdrew during the baseline period. We show that synthetic biotics can metabolize Phe in the gut, lower post-prandial plasma Phe levels and lower fasting plasma Phe in patients with PKU.

Smoking reduction among homeless smokers in a randomized controlled trial targeting cessation.

INTRODUCTION: Homeless populations have high rates of smoking and unique barriers to quitting. General cessation strategies have been unsuccessful in this population. Smoking reduction may be a good intermediate goal. We conducted a secondary analysis to identify predictors of smoking reduction in a cohort of homeless smokers enrolled in a 26-week randomized clinical trial (RCT) targeting smoking cessation. METHODS: Data are from an RCT comparing motivational interviewing counseling plus nicotine replacement therapy (NRT) to brief advice to quit (standard care) plus NRT among homeless smokers. Using bivariate analyses and multinomial logistic regression, we compared demographics, health and psychosocial variables, tobacco use, substance use, and NRT adherence among those who reported: quitting; reducing smoking by 50-99%; and not reducing smoking by 50%. RESULTS: Of 324 participants who completed 26-week follow-up, 18.8% and 63.9% self-reported quitting and reducing, respectively. Compared to those who did not reduce smoking, participants reporting reducing indicated higher baseline cigarette use (OR=1.08; CI:1.04-1.12) and menthol use (OR=2.24; CI:1.05-4.77). Compared to participants who reduced, participants reporting quitting were more likely to be male (OR=1.998; CI:1.00-3.98), experience more housing instability (OR=1.97; CI:1.08-3.59), indicate higher importance of quitting (OR=1.27; CI:1.041.55), have higher NRT adherence (OR=1.75; CI:1.00-3.06), and lower odds of reported illicit drug use (OR=0.48; CI:0.24-0.95). CONCLUSIONS: Over half of participants reduced smoking by at least 50%, indicating reduction is feasible among homeless smokers. Further research is required to understand the impact of reduction on future cessation attempts in homeless smokers. This study shows that reduction is achievable and may be a valid intermediate goal.

The implementation of a smoking cessation and alcohol abstinence intervention for people experiencing homelessness.

BACKGROUND: In the United States, eighty percent of the adult homeless population smokes cigarettes compared to 15 percent of the general population. In 2017 Power to Quit 2 (PTQ2), a randomized clinical trial, was implemented in two urban homeless shelters in the Upper Midwest to address concurrent smoking cessation and alcohol treatment among people experiencing homelessness. A subset of this study population were interviewed to assess their experiences of study intervention. The objective of this study was to use participants' experiences with the intervention to inform future implementation efforts of combined smoking cessation and alcohol abstinence interventions, guided by the Consolidated Framework for Implementation Research (CFIR). METHODS: Qualitative semi-structured interviews were conducted with 40 PTQ2 participants between 2016-2017 and analyzed in 2019. Interviews were audio-recorded, transcribed, and analyzed using a socially constructivist approach to grounded theory. RESULTS: Participants described the PTQ2 intervention in positive terms. Participants valued the opportunity to obtain both counseling and nicotine-replacement therapy products (intervention characteristics) and described forming a bond with the PTQ2 staff and reliance on them for emotional support and encouragement (characteristics of individuals). However, the culture of alcohol use and cigarette smoking around the shelter environment presented a serious challenge (outer setting). The study setting and the multiple competing needs of participants were reported as the most challenging barriers to implementation (implementation process). CONCLUSION: There are unique challenges in addressing smoking cessation with people experiencing homelessness. For those in shelters there can be the difficulty of pro-smoking norms in and around the shelter itself. Considering pairing cessation with policy level interventions targeting smoke-free spaces, or pairing cessation with housing support efforts may be worthwhile.. Participants described a discord in their personal goals of reduction compared with the study goals of complete abstinence, which may pose a challenge to the ways in which success is defined for people experiencing homelessness. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01932996 , registered 08/30/2013.

A Bayesian hierarchical model for individual participant data meta-analysis of demand curves.

Individual participant data meta-analysis is a frequently used method to combine and contrast data from multiple independent studies. Bayesian hierarchical models are increasingly used to appropriately take into account potential heterogeneity between studies. In this paper, we propose a Bayesian hierarchical model for individual participant data generated from the Cigarette Purchase Task (CPT). Data from the CPT details how demand for cigarettes varies as a function of price, which is usually described as an exponential demand curve. As opposed to the conventional random-effects meta-analysis methods, Bayesian hierarchical models are able to estimate both the study-specific and population-level parameters simultaneously without relying on the normality assumptions. We applied the proposed model to a meta-analysis with baseline CPT data from six studies and compared the results from the proposed model and a two-step conventional random-effects meta-analysis approach. We conducted extensive simulation studies to investigate the performance of the proposed approach and discussed the benefits of using the Bayesian hierarchical model for individual participant data meta-analysis of demand curves.

Colorblind Racial Ideology and Physician Use of Race in Medical Decision-Making.

BACKGROUND: Colorblindness is a racial ideology that minimizes the role of systemic racism in shaping outcomes for racial minorities. Physicians who embrace colorblindness may be less likely to interrogate the role of racism in generating health disparities and less likely to challenge race-based treatment. This study evaluates the association between physician colorblindness and the use of race in medical decision-making. METHODS: This is a cross-sectional survey study, conducted in September 2019, of members of the Minnesota Academy of Family Physicians. The survey included demographic and practice questions and two measures: Color-blind Racial Attitudes Scale (CoBRAS; measuring unawareness of racial privilege, institutional discrimination, and blatant racial issues) and Racial Attributes in Clinical Evaluation (RACE; measuring the use of race in medical decision-making). Multivariable regression analyses assessed the relationship between CoBRAS and RACE. RESULTS: Our response rate was 17% (267/1595). In a multivariable analysis controlling for physician demographic and practice characteristics, CoBRAS scores were positively associated with RACE (ß = 0.05, p = 0.02). When CoBRAS subscales were used in place of the overall CoBRAS score, only unawareness of institutional discrimination was positively associated with RACE (ß = 0.18, p = 0.01). CONCLUSIONS: Physicians who adhere to a color blind racial ideology, particularly those who deny institutional racism, are more likely to use race in medical decision-making. As the use of race may be due to a colorblind racial ideology, and therefore due to a poor understanding of how systemic racism affects health, more physician education about racism as a health risk is needed.

Knowledge, Attitudes, and Beliefs about Relapse Prevention Research Involving Bupropion among Current and Former Pregnant Individuals Who Smoke.

Introduction: While many individuals quit smoking during pregnancy, most relapse within one year postpartum. Research into methods to decrease smoking relapse postpartum has been hampered by difficulties with recruitment. Method: We conducted individual interviews with pregnant women (N = 22) who were interested in quitting smoking while pregnant about their attitudes regarding smoking and quitting during pregnancy, clinical trial participation, and smoking cessation medication use. Results: Participants were aware of the risks of smoking while pregnant. Many wanted to quit smoking before delivery. Few used empirically supported treatments to quit. While research was viewed positively, interest in taking on new commitments postpartum and taking a medication to prevent relapse was low. Medication concerns were evident among most participants, especially among those planning to breastfeed. Further, several women noted medication was unnecessary, as they did not believe they would relapse postpartum. Financial incentives, childcare, and fewer and/or remote visits were identified as facilitators to participating in research. However, these factors did not outweigh women's concerns about medication use and time commitments. Conclusions: Women are aware that quitting smoking during pregnancy and remaining smoke-free postpartum are important. However, beliefs that personal relapse risk is low and that medications are dangerous reduced enthusiasm for taking medication for postpartum relapse prevention. Future medication trials should educate women about the high likelihood of relapse, prepare to answer detailed questions about risks of cessation medications, and connect with participants' clinicians. For new mothers, studies conducted remotely with few scheduled appointments would reduce barriers to participation.

A non-interventional observational study to identify and validate clinical outcome assessments for adults with phenylketonuria for use in clinical trials.

INTRODUCTION: Current clinical outcome assessments (COAs) are not effectively capturing the complex array of symptoms of adults with phenylketonuria (PKU). This study aimed to identify concepts of interest relevant to adults with PKU. Based on these concepts, COAs for patient-reported outcomes (PROs), observer-reported outcomes (ObsROs), and clinician-reported outcomes (ClinROs) were selected or developed and content validity was assessed. MATERIALS AND METHODS: Concept-elicitation interviews were conducted with an international cohort of adults with PKU (n = 30), family member observers (n = 14), and clinical experts (n = 8). Observers and clinical experts were included to overcome the risk of lack of self-awareness among adults with PKU. The concepts of interests endorsed by ≥30% of patients, observers, and/or clinical experts were selected, mapped to items in existing COAs, and used to develop global impression items for patients, observers, and clinicians. Next, the content validity of the COAs and global impression items was evaluated by cognitive interviews with patients (n = 22), observers (n = 11), and clinical experts (n = 8). All patients were categorized according to blood phenylalanine (Phe) levels (i.e., <600 µmol/L, 600-1200 µmol/L, and >1200 µmol/L). RESULTS: Concepts of interests were identified across four domains: emotional, cognitive, physical, and behavioral. After mapping, eight existing COAs were selected based on the concept coverage (six PROs, one ObsRO, and one ClinRO). The six PRO measures were considered as potentially fit-for-purpose. The ObsRO measure was not deemed relevant for use in observers of adults with PKU and only a subscale of the ClinRO measure was considered valid for assessing adults with PKU by clinicians. Due to the lack of existing COAs covering all concepts of interests, global impression items for symptom severity and change in symptoms were developed, which were limited to one question covering in total 14 concepts. Upon validation, some of the patient and observer global impression items were excluded as they were subject to lack of insight or could not be reported by observers. Due to the limited interaction time between clinician and patient, use of the clinician global impression items was not supported. CONCLUSION: Existing COAs relevant to adults with PKU were selected and PKU-specific global impression items were developed by mapping the most frequently identified concepts of interests from internationally-conducted in-depth interviews. Future studies should address the appropriateness of the selected COAs and global impression items to assess if these can be used as efficacy endpoints in PKU clinical trials.

Falls efficacy: Extending the understanding of self-efficacy in older adults towards managing falls.

Falls efficacy is a widely studied construct. The understanding of falls efficacy has evolved over time. Falls efficacy was initially perceived to be suitably used as a measure of fear of falling. However, further research suggested that falls efficacy and fear of falling are distinct constructs, and therefore, would be inappropriate to be used as a proxy. Instead, some researchers posited that falls efficacy is synonymous with balance confidence. Falls efficacy has been conventionally understood as the perceived ability of individuals to perform activities without losing balance or falling. A recently conducted systematic review by the authors on existing falls efficacy related measures had revealed a fresh perspective of recognising falls efficacy as a perceived ability to manage a threat of a fall. Falls efficacy, with a broadened interpreted construct, relates to the individual's perceived self-efficacy of performing necessary actions needed in different scenarios, including pre-fall, near-fall, fall-landing and completed fall. The conventional interpretation of falls efficacy needs a rethinking of perspective. An extended understanding of falls efficacy would provide an integral approach towards improving the agency of individual to deal with falls and would enhance person-centred care.

Use of pegvaliase in the management of phenylketonuria: Case series of early experience in US clinics.

OBJECTIVE: To present a case series that illustrates real-world use of pegvaliase based on the initial experiences of US healthcare providers. METHODS: Sixteen healthcare providers from 14 centers across the US with substantial clinical experience in treating patients with phenylketonuria (PKU) with pegvaliase in the two-plus years since FDA approval (May 2018) provided cases that exemplified important lessons from their initial experiences treating patients with pegvaliase. Key lessons from each case and takeaway points were discussed in both live and virtual meetings. RESULTS: Fifteen cases of adults with PKU (eight males, seven females), representing a spectrum of age (18 to 53 years), previous PKU care, comorbidities, and socioeconomic situations were reviewed and discussed. Full extended case reports are included in the Supplement. The cases showed that treating patients with a daily injectable can be challenging due to a patient's financial problems, treatment challenges, and neuropsychological and psychiatric comorbidities, which can be identified before starting pegvaliase, but do not prohibit successful treatment. The authors agreed that patient education on adverse events (AEs), time to efficacy, dietary changes, and food preparation is an ongoing process that should start prior to initiating pegvaliase treatment. Treatment goals and planned dietary changes once efficacy is reached should be defined prior to treatment initiation and re-evaluated throughout the course of therapy. Each patient's titration schedule and dietary adjustments are unique, depending on occurrence of AEs and individual goals of treatment. Despite the AE profile of pegvaliase, all but two patients remained motivated to continue treatment and achieved efficacy (except one patient in whom titration was still ongoing). AEs occurring early in the treatment pathway may require prolongation of the titration phase and/or concomitant medication use, but do not seem indicative of future tolerability or eventual efficacy. Close follow-up of patients during titration and maintenance to help with dietary changes is important. CONCLUSION: This case series provides real-world experience on the use of pegvaliase. Until data from registries and independent research become available, the data presented herein can support appropriate management of patients receiving pegvaliase in clinical practice.

REVIEW: Practical strategies to maintain anabolism by intravenous nutritional management in children with inborn metabolic diseases.

One of the most vital elements of management for patients with inborn errors of intermediary metabolism is the promotion of anabolism, the state in which the body builds new components, and avoidance of catabolism, the state in which the body breaks down its own stores for energy. Anabolism is maintained through the provision of a sufficient supply of substrates for energy, as well as critical building blocks of essential amino acids, essential fatty acids, and vitamins for synthetic function and growth. Patients with metabolic diseases are at risk for decompensation during prolonged fasting, which often occurs during illnesses in which enteral intake is compromised. During these times, intravenous nutrition must be supplied to fully meet the specific nutritional needs of the patient. We detail our approach to intravenous management for metabolic patients and its underlying rationale. This generally entails a combination of intravenous glucose and lipid as well as early introduction of protein and essential vitamins. We exemplify the utility of our approach in case studies, as well as scenarios and specific disorders which require a more careful administration of nutritional substrates or a modification of macronutrient ratios.

Mixed-methods economic evaluation of the implementation of tobacco treatment programs in National Cancer Institute-designated cancer centers.

BACKGROUND: The Cancer Center Cessation Initiative (C3I) was launched in 2017 as a part of the NCI Cancer Moonshot program to assist NCI-designated cancer centers in developing tobacco treatment programs for oncology patients. Participating centers have implemented varied evidence-based programs that fit their institutional resources and needs, offering a wide range of services including in-person and telephone-based counseling, point of care, interactive voice response systems, referral to the quitline, text- and web-based services, and medications. METHODS: We used a mixed methods comparative case study design to evaluate system-level implementation costs across 15 C3I-funded cancer centers that reported for at least one 6-month period between July 2018 and June 2020. We analyzed operating costs by resource category (e.g., personnel, medications) concurrently with transcripts from semi-structured key-informant interviews conducted during site visits. Personnel salary costs were estimated using Bureau of Labor Statistics wage data adjusted for area and occupation, and non-wage benefits. Qualitative findings provided additional information on intangible resources and contextual factors related to implementation costs. RESULTS: Median total monthly operating costs across funded centers were $11,045 (range: $5129-$20,751). The largest median operating cost category was personnel ($10,307; range: $4122-$19,794), with the highest personnel costs attributable to the provision of in-person program services. Monthly (non-zero) cost ranges for other categories were medications ($17-$573), materials ($6-$435), training ($96-$516), technology ($171-$2759), and equipment ($10-$620). Median cost-per-participant was $466 (range: $70-$2093) and cost-per-quit was $2688 (range: $330-$9628), with sites offering different combinations of program components, ranging from individually-delivered in-person counseling only to one program that offered all components. Site interviews provided context for understanding variations in program components and their cost implications. CONCLUSIONS: Among most centers that have progressed in tobacco treatment program implementation, cost-per-quit was modest relative to other prevention interventions. Although select centers have achieved similar average costs by offering program components of various levels of intensity, they have varied widely in program reach and effectiveness. Evaluating implementation costs of such programs alongside reach and effectiveness is necessary to provide decision makers in oncology settings with the important additional information needed to optimize resource allocation when establishing tobacco treatment programs.

Bupropion for postpartum smoking relapse: A remote protocol for a two-arm, double-blind, placebo-controlled randomized clinical trial.

Cigarette smoking among postpartum women remains a significant public health problem despite known health risks to women and their newborns. It is estimated that over 50% of women quit smoking during pregnancy but 90% relapse by one year. Safe and effective postpartum relapse prevention strategies are urgently needed. In an attempt to address this deficit, we will investigate the efficacy of bupropion vs. placebo as a smoking relapse prevention aid in postpartum women. The objective of this paper is to detail an approach to investigate bupropion's efficacy for preventing postpartum smoking relapse among women who quit smoking during pregnancy. Specifically, we designed a two-arm, double-blind, placebo-controlled randomized trial testing the efficacy of bupropion vs. placebo as a relapse prevention tool. Mothers of healthy infants who quit smoking while pregnant will be stratified based on current or past history of major depressive disorder or persistent depressive disorder and randomized to receive either active (bupropion XL 300 mg/day) or placebo medication for 12 weeks. To respond to safety concerns associated with participant and staff exposure to COVID-19, we revised our original protocol and present procedures which allow our trial to be conducted entirely remotely. Primary and secondary outcomes will be assessed at weeks 12, 24, 36 and 52 post-randomization. The primary outcome is 7-day point prevalence abstinence at 24 weeks. Results of this work have the potential to positively impact women and their children by promoting lifelong cessation, eliminating secondhand smoke exposure, and modelling of abstinence to children.

Pegvaliase for the treatment of phenylketonuria: Results of the phase 2 dose-finding studies with long-term follow-up.

BACKGROUND: Phenylketonuria (PKU) is characterized by a deficiency in phenylalanine hydroxylase (PAH) that may lead to elevated blood phenylalanine (Phe) and significant neurocognitive and neuropsychological comorbidities. Pegvaliase (PALYNZIQ®, BioMarin Pharmaceutical Inc.) is a PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), which converts Phe to trans-cinnamic acid and ammonia, and was approved in May 2018 in the United States and in May 2019 in the European Union for decreasing blood Phe levels in adults with PKU with blood Phe levels >600 µmol/L. The efficacy and safety of pegvaliase was assessed in two phase 2 dose-finding studies in adults with PKU (PAL-002, NCT00925054, and PAL-004, NCT01212744). Participants completing these studies could enroll in a long-term extension study (PAL-003, NCT00924703). METHODS: Participants in PAL-002 received pegvaliase 0.001, 0.003, 0.01, 0.03, or 0.1 mg/kg weekly for 8 weeks, then continued treatment for a further 8 weeks with dose and/or frequency adjusted to achieve blood Phe concentrations of 60 to 600 µmol/L. Participants in PAL-004 received pegvaliase 0.001 to 0.4 mg/kg 5 days/week for 13 weeks, with modifications made to the starting dose in response to safety and/or efficacy, followed by 3 additional weeks of follow-up assessments. The maximum allowable daily dose in both studies was 1.0 mg/kg/day (5.0 mg/kg/week). Participants who completed any of the phase 2 studies (PAL-002; PAL-004; or a third phase 2 study, 165-205) were eligible to enroll in an open-label, multicenter, long-term extension study (PAL-003, NCT00924703). RESULTS: Thirty-seven of the 40 enrolled participants completed PAL-002 and 15 of the 16 enrolled participants completed PAL-004. Mean blood Phe at baseline was 1311.0 (standard deviation [SD] 354) µmol/L in PAL-002 and 1482.1 (SD 363.5) µmol/L in PAL-004. Mean blood Phe did not substantially decrease with pegvaliase treatment in PAL-002 (-206.3 [SD 287.1] µmol/L at Week 16) or PAL-004 (-410.8 [SD 653.7] µmol/L at Week 13). In PAL-004, mean blood Phe dropped from baseline by 929.1 µmol/L (SD 691.1) by Week 2; subsequent to dose modifications and interruptions, this early decrease in mean Phe level was not sustained. With increased pegvaliase dose and duration in PAL-003, mean blood Phe levels steadily decreased from baseline, with mean reductions by Week 120 of 68.8% (SD 44.2%) in PAL-002 participants and 75.9% (SD 32.4%) in PAL-004 participants. All participants in PAL-002 and PAL-004 reported ≥1 adverse event (AE), with higher exposure-adjusted event rates in PAL-004. The majority of AEs were mild (87.2% in PAL-002, 86.7% in PAL-004) or moderate (12.4% in PAL-002, 13.3% in PAL-004). The most commonly reported AEs in PAL-002 were injection site reaction (50.0% of participants), headache (42.1%), injection site erythema (36.8%), nausea (34.2%), and arthralgia (29.0%), and in PAL-004 were arthralgia (75.0%), headache (62.5%), dizziness (56.3%), injection site erythema (56.3%), and injection site reaction (50.0%). CONCLUSIONS: In two phase 2 dose-finding studies, pegvaliase did not lead to substantial blood Phe reductions. Higher and more frequent pegvaliase dosing in PAL-004 led to a substantial initial drop in blood Phe, but an increase in the number of hypersensitivity AEs and dose reductions or interruptions. With increased dose and duration of treatment in PAL-003, mean blood Phe reduction was substantial and sustained, and the frequency of hypersensitivity AEs decreased and stabilized. Together, these studies led to the development of an induction-titration-maintenance regimen that has been approved for pegvaliase, with patients starting at a low weekly dose that gradually increases in dose and frequency until they achieve a standard non-weight-based daily maintenance dose. This regimen has been tested in a third phase 2 study, as well as in two successful phase 3 studies of pegvaliase.

Distinguishing Encephaloclastic Lesions Resulting From Primary or Secondary Pyruvate Dehydrogenase Deficiency From Other Neonatal or Infantile Cavitary Brain Lesions.

The central nervous system (CNS) is a highly complex and energy-dependent organ that is subject to a wide variety of metabolic, hypoxic-ischemic, and infectious insults that result in cystic changes. Diagnosis of metabolic defects causing extensive cystic changes is particularly challenging for the pediatric pathologist, due to the rarity of these conditions. Pyruvate dehydrogenase (PDH) deficiency is one of the most common etiologies of congenital lactic acidosis, caused by mutations in subunits of the large mitochondrial matrix complex, and characterized by periventricular cysts, although few detailed reports focusing on neuropathologic findings exist. In addition, rare defects in other mitochondrial enzymes such as short-chain enoyl-CoA hydratase (SCEH, encoded by ECHS1 gene) can cause secondary PDH deficiency and present with neonatal lactic acidosis, but neuropathological findings have never been reported. Nonmetabolic conditions can also produce CNS cystic lesions, primarily in newborns. The pathologist must therefore distinguish between these etiologically disparate conditions which can produce CNS cavitary lesions. Here, we compare and contrast the gross and microscopic findings of cysts associated with cases of PDH and SCEH deficiencies with other neonatal cystic brain diseases including periventricular leukomalacia, neonatal Alexander disease, Canavan disease, and a case of cysts associated with a vascular abnormality. Our studies show that PDH and SCEH deficiencies are not grossly or histologically distinguishable from each other and both are associated with smooth-walled cysts largely limited to the telencephalic germinal matrix. Both show an absence of prominent hemosiderin deposits, Rosenthal fibers, vacuolization of the white matter, and gliosis or axonal damage in the surrounding parenchyma. These features can help distinguish PDH/SCEH deficiency from other pediatric/neonatal cystic CNS disorders, especially those produced by hypoxic ischemic conditions. Cysts, usually bilateral, confined to the telencephalic germinal matrix should elicit metabolic and genetic testing to appropriately diagnose PDH and SCEH and distinguish them from each other.

Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients.

Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis single-strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinicopathological characteristics and treatment outcomes were explored. Of these 269, 210 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43, 9, 4, 9 and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs. 65%, p = 0.04), poor pathological tumour regression (23% vs. 36%, p = 0.05) and a trend toward a worse 5-year progression-free survival (PFS; 60% vs. 74%, HR 1.59, p = 0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5-year PFS than those with TP53/KRAS/NRAS wild-type tumours (54% vs. 72%, HR 1.75, p = 0.02). In univariate analysis, BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20% vs. 73%, HR 3.29, p = 0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis generating and require validation in independent series.

Promoting Smoke-Free Homes Through Biomarker Feedback Documenting Child Exposure to Tobacco Toxins: Protocol for a Randomized Clinical Trial.

BACKGROUND: Exposure to secondhand smoke (SHS) early in life increases the risk of sudden infant death syndrome (SIDS), asthma, and respiratory illnesses. Since children's primary exposure to SHS occurs in the home, these most vulnerable members of our society are not fully protected by recent increases in the adoption of smoking bans in public spaces. Although exposure to SHS is a quickly reversible cause of excess morbidity, few low-income homes strictly enforce smoking restrictions. OBJECTIVE: This study aims to test a novel approach to motivate the adoption of home smoking restrictions and to eliminate child SHS exposure by providing parents with objective data documenting home SHS exposure and "biomarker feedback" of child ingestion of tobacco toxins, that is, objective, laboratory-based results of assays performed on child urine, documenting levels of nicotine; cotinine; and NNAL (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol), which is a metabolite of the known tobacco carcinogen NNK (4-[methylnitro-samino]-1-[3-pyridyl]-1-butanone). METHODS: From 2011 to 2013, 195 low-income, female smokers with children aged ≤10 years residing in their homes were recruited into a two-arm randomized clinical trial. Participants were assigned to one of two groups: biomarker feedback (n=98) and health education (n=97). In-home assessments were administered at baseline, week 16, and week 26. Children's home SHS exposure and nicotine, cotinine, and NNAL levels from urine samples, measured through a passive nicotine dosimeter and a surface sample of residual tobacco smoke (ie, thirdhand smoke), were collected at all three time points. Primary outcome was dosimeter-verified, self-reported complete home smoking restrictions at 6 months after randomization. Secondary outcomes included parental self-report of smoking behavior change and child urine tobacco toxin (biomarker) change. RESULTS: Data collection and analyses are complete, and the results are being interpreted. CONCLUSIONS: The study protocol describes the development of a novel community-based controlled trial designed to examine the efficacy of biomarker feedback documenting home and child exposure to SHS on parental smoking behavior change. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/12654.