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.

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.

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.

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.

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.

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.

Evidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria.

PURPOSE: Phenylketonuria (PKU) is a rare metabolic disorder that requires life-long management to reduce phenylalanine (Phe) concentrations within the recommended range. The availability of pegvaliase (PALYNZIQ™, an enzyme that can metabolize Phe) as a new therapy necessitates the provision of guidance for its use. METHODS: A Steering Committee comprising 17 health-care professionals with experience in using pegvaliase through the clinical development program drafted guidance statements during a series of face-to-face meetings. A modified Delphi methodology was used to demonstrate consensus among a wider group of health-care professionals with experience in using pegvaliase. RESULTS: Guidance statements were developed for four categories: (1) treatment goals and considerations prior to initiating therapy, (2) dosing considerations, (3) considerations for dietary management, and (4) best approaches to optimize medical management. A total of 34 guidance statements were included in the modified Delphi voting and consensus was reached on all after two rounds of voting. CONCLUSION: Here we describe evidence- and consensus-based recommendations for the use of pegvaliase in adults with PKU. The manuscript was evaluated against the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument and is intended for use by health-care professionals who will prescribe pegvaliase and those who will treat patients receiving pegvaliase.

Biomarkers of oxidative stress, inflammation, and vascular dysfunction in inherited cystathionine ß-synthase deficient homocystinuria and the impact of taurine treatment in a phase 1/2 human clinical trial.

STUDY OBJECTIVE: A phase 1/2 clinical trial was performed in individuals with cystathionine ß synthase (CBS) deficient homocystinuria with aims to: (a) assess pharmacokinetics and safety of taurine therapy, (b) evaluate oxidative stress, inflammation, and vascular function in CBS deficiency, and (c) evaluate the impact of short-term taurine treatment. METHODS: Individuals with pyridoxine-nonresponsive CBS deficiency with homocysteine >50 µM, without inflammatory disorder or on antioxidant therapy were enrolled. Biomarkers of oxidative stress and inflammation, endothelial function (brachial artery flow-mediated dilation [FMD]), and disease-related metabolites obtained at baseline were compared to normal values. While maintaining current treatment, patients were treated with 75 mg/kg taurine twice daily, and treatment response assessed after 4 hours and 4 days. RESULTS: Fourteen patients (8-35 years; 8 males, 6 females) were enrolled with baseline homocysteine levels 161 ± 67 µM. The study found high-dose taurine to be safe when excluding preexisting hypertriglyceridemia. Taurine pharmacokinetics showed a rapid peak level returning to near normal levels at 12 hours, but had slow accumulation and elevated predosing levels after 4 days of treatment. Only a single parameter of oxidative stress, 2,3-dinor-8-isoprostaglandin-F2α, was elevated at baseline, with no elevated inflammatory parameters, and no change in FMD values overall. Taurine had no effect on any of these parameters. However, the effect of taurine was strongly related to pretreatment FMD values; and taurine significantly improved FMD in the subset of individuals with pretreatment FMD values <10% and in individuals with homocysteine levels >125 µM, pertinent to endothelial function. CONCLUSION: Taurine improves endothelial function in CBS-deficient homocystinuria in patients with preexisting reduced function.

"It's a hard thing to manage when you're homeless": the impact of the social environment on smoking cessation for smokers experiencing homelessness.

BACKGROUND: Up to 80% of the adult homeless population use tobacco, and smoking cessation programs could offer an important opportunity to address preventable mortality and morbidity for this population. This population faces serious challenges to smoking cessation, including the impact of the social environment. METHODS: Forty participants (11 female; 29 male) from an ongoing smoking cessation randomized clinical trial conducted at 2 urban homeless shelters in the Upper Midwest were invited to take part in semi-structured interviews in 2016-2017. An interviewer used a semi-structured interview guide asking participants to describe their experience of how the social environment impacted their attempt to quit smoking. RESULTS: Participants described feeling pressure to smoke and drink in and around shelters, and that this pressure had led some to start smoking or resume smoking, along with making it very challenging to quit. Participants described being motivated to quit, and seeing smoking cessation as positively impacting the time and focus they felt they had for finding housing. However many felt more interested in reducing their smoking, rather than quitting. CONCLUSIONS: Addressing smoking cessation for people experiencing homelessness is both an important public health opportunity, and a challenge. There is a need to consider cessation in the context of the social and environmental factors impacting smokers who are experiencing homelessness. In particular, there is a need to address the collective value placed on smoking in social interactions. Despite these challenges, there are high levels of motivation and interest in addressing smoking. TRIAL REGISTRATION: NCT01932996 . Date of registration 30th August 2013. Prospectively registered.

Induction, titration, and maintenance dosing regimen in a phase 2 study of pegvaliase for control of blood phenylalanine in adults with phenylketonuria.

BACKGROUND: Phenylketonuria (PKU) is caused by a deficiency in phenylalanine hydroxylase enzyme activity that leads to phenylalanine (Phe) accumulation in the blood and brain. Elevated blood Phe levels are associated with complications in adults, including neurological, psychiatric, and cognitive issues. Even with nutrition and pharmacological management, the majority of adults with PKU do not maintain blood Phe levels at or below guideline recommended levels. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is an investigational enzyme substitution therapy to lower blood Phe in adults with PKU. METHODS: Pegvaliase was administered using an induction, titration, and maintenance dosing regimen in adults with PKU naïve to pegvaliase treatment. Doses were gradually increased until blood Phe ≤ 600 µmol/L was achieved. The maintenance dose was the dose at which participants achieved and sustained blood Phe ≤ 600 µmol/L for at least 4 weeks without dose modification. Analyses were performed for participants who achieved (Group A, n = 11) and did not achieve (Group B, n = 13) maintenance dose during the first 24 weeks of study treatment. RESULTS: Baseline mean blood Phe for Group A and Group B were 1135 µmol/L and 1198 µmol/L, respectively. Mean blood Phe ≤ 600 µmol/L was achieved for Group A by Week 11 (mean blood Phe of 508 ±â€¯483 µmol/L) and for Group B by Week 48 (mean blood Phe of 557 ±â€¯389 µmol/L). The most common adverse events involved hypersensitivity reactions, which were mostly mild to moderate in severity and decreased over time. One participant in Group B had four acute systemic hypersensitivity events of anaphylaxis consistent with clinical National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria; all events were non-IgE mediated and resolved without sequelae, with pegvaliase dosing discontinued after the fourth event. The incidence and titers of anti-drug antibodies were generally lower in Group A compared to Group B. CONCLUSIONS: Pegvaliase administered with an induction, titration, and maintenance dosing regimen demonstrated substantial efficacy at reducing blood Phe in both Group A and Group B by Week 48, with a manageable safety profile in most participants. Blood Phe reduction due to pegvaliase appears to be related to dose, treatment duration, and individual immune response; given additional time on treatment and dose titration, later Phe responders (Group B) achieved benefit similar to early Phe responders (Group A), with similar long-term safety profiles.

Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM).

BACKGROUND: Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency that results in phenylalanine (Phe) accumulation. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is a potential enzyme substitution therapy to lower blood Phe in adults with PKU. METHODS: Two Phase 3 studies, PRISM-1 and PRISM-2, evaluated the efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU. In PRISM-1, pegvaliase-naïve participants with blood Phe >600 µmol/L were randomized 1:1 to a maintenance dose of 20 mg/day or 40 mg/day of pegvaliase. Participants in PRISM-1 continued pegvaliase treatment in PRISM-2, a 4-part clinical trial that includes an ongoing, open-label, long-term extension study of pegvaliase doses of 5 mg/day to 60 mg/day. RESULTS: Of 261 participants who received pegvaliase treatment, 72.0% and 32.6% reached ≥12 months and ≥ 24 months of study treatment, respectively, and 65% are still actively receiving treatment. Mean (SD) blood Phe was 1232.7 (386.4) µmol/L at baseline, 564.5 (531.2) µmol/L at 12 months, and 311.4 (427) µmol/L at 24 months, a decrease from baseline of 51.1% and 68.7%, respectively. Within 24 months, 68.4% of participants achieved blood Phe ≤600 µmol/L, 60.7% of participants achieved blood Phe ≤360 µmol/L, below the upper limit recommended in the American College of Medical Genetics and Genomics PKU management guidelines, and 51.2% achieved blood Phe ≤120 µmol/L, below the upper limit of normal in the unaffected population. Improvements in neuropsychiatric outcomes were associated with reductions in blood Phe and were sustained with long-term pegvaliase treatment. Adverse events (AEs) were more frequent in the first 6 months of exposure (early treatment phase) than after 6 months of exposure (late treatment phase); 99% of AEs were mild or moderate in severity and 96% resolved without dose interruption or reduction. The most common AEs were arthralgia (70.5%), injection-site reaction (62.1%), injection-site erythema (47.9%), and headache (47.1%). Acute systemic hypersensitivity events consistent with clinical National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network anaphylaxis criteria were observed in 12 participants (17 events); of these, 6 participants remained on treatment. Acute systemic hypersensitivity events including potential events of anaphylaxis were not associated with immunoglobulin E, and all events resolved without sequelae. CONCLUSION: Results from the PRISM Phase 3 program support the efficacy of pegvaliase for the treatment of adults with PKU, with a manageable safety profile in most participants. The PRISM-2 extension study will continue to assess the long-term effects of pegvaliase treatment.

Analysis of self-report and biochemically verified tobacco abstinence outcomes with missing data: a sensitivity analysis using two-stage imputation.

BACKGROUND: Missing data are common in tobacco studies. It is well known that from the observed data alone, it is impossible to distinguish between missing mechanisms such as missing at random (MAR) and missing not at random (MNAR). In this paper, we propose a sensitivity analysis method to accommodate different missing mechanisms in cessation outcomes determined by self-report and urine validation results. METHODS: We propose a two-stage imputation procedure, allowing survey and urine data to be missing under different mechanisms. The motivating data were from a tobacco cessation trial examining the effects of the extended vs. standard Quit and Win contests and counseling vs. no counseling under a 2-by-2 factorial design. The primary outcome was 6-month biochemically verified tobacco abstinence. RESULTS: Our proposed method covers a wide spectrum of missing scenarios, including the widely adopted "missing = smoking" imputation by assuming a perfect smoking-missing correlation (an extreme case of MNAR), the MAR case by assuming a zero smoking-missing correlation, and many more in between. The analysis of the data example shows that the estimated effects of the studied interventions are sensitive to the different missing assumptions on the survey and urine data. CONCLUSIONS: Sensitivity analysis has played a crucial role in assessing the robustness of the findings in clinical trials with missing data. The proposed method provides an effective tool for analyzing missing data introduced at two different stages of outcome assessment, the self-report and validation time. Our methods are applicable to trials studying biochemically verified abstinence from alcohol and other substances.

Comparison between MRI and pathology in the assessment of tumour regression grade in rectal cancer.

BACKGROUND: Limited data exist regarding the correlation between MRI tumour regression grade (mrTRG) and pathological TRG (pTRG) in rectal cancer. METHODS: mrTRG and pTRG were compared in rectal cancer patients from two phase II trials (EXPERT and EXPERT-C). The agreement between radiologist and pathologist was assessed with the weighted κ test while the Kaplan-Meier method was used to estimate survival outcomes. RESULTS: One hundred ninety-one patients were included. Median time from completion of neoadjuvant treatment to pre-operative MRI and surgery was 4.1 weeks (interquartile range (IQR): 3.7-4.7) and 6.6 weeks (IQR: 5.9-7.6), respectively. Fair agreement was found between mrTRG and pTRG when regression was classified according to standard five-tier systems (κ=0.24) or modified three-tier systems (κ=0.25). Sensitivity and specificity of mrTRG 1-2 (complete/good radiological regression) for the prediction of pathological complete response was 74.4% (95% CI: 58.8-86.5) and 62.8% (95% CI: 54.5-70.6), respectively. Survival outcomes of patients with intermediate pathological regression (pTRG 2) were numerically better if complete/good regression was also observed on imaging (mrTRG 1-2) compared to poor regression (mrTRG 3-5) (5-year recurrence-free survival 76.9% vs 65.9%, P=0.18; 5-year overall survival 80.6% vs 68.8%, P=0.22). CONCLUSIONS: The agreement between mrTRG and pTRG is low and mrTRG cannot be used as a surrogate of pTRG. Further studies are warranted to assess the ability of mrTRG to identify pathological complete responders for the adoption of non-operative management strategies and to provide complementary prognostic information to pTRG for better risk-stratification after surgery.

Proactive tobacco treatment offering free nicotine replacement therapy and telephone counselling for socioeconomically disadvantaged smokers: a randomised clinical trial.

BACKGROUND: Evidenced-based tobacco cessation treatments are underused, especially by socioeconomically disadvantaged smokers. This contributes to widening socioeconomic disparities in tobacco-related morbidity and mortality. METHODS: The Offering Proactive Treatment Intervention trial tested the effects of a proactive outreach tobacco treatment intervention on population-level smoking abstinence and tobacco treatment use among a population-based sample of socioeconomically disadvantaged smokers. Current smokers (n=2406), regardless of interest in quitting, who were enrolled in the Minnesota Health Care Programs, the state's publicly funded healthcare programmes for low-income populations, were randomly assigned to proactive outreach or usual care. The intervention comprised proactive outreach (tailored mailings and telephone calls) and free cessation treatment (nicotine replacement therapy and intensive, telephone counselling). Usual care comprised access to a primary care physician, insurance coverage of Food and Drug Administration-approved smoking cessation medications, and the state's telephone quitline. The primary outcome was self-reported 6-month prolonged smoking abstinence at 1 year and was assessed by follow-up survey. FINDINGS: The proactive intervention group had a higher prolonged abstinence rate at 1 year than usual care (16.5% vs 12.1%, OR 1.47, 95% CI 1.12 to 1.93). The effect of the proactive intervention on prolonged abstinence persisted in selection models accounting for non-response. In analysis of secondary outcomes, use of evidence-based tobacco cessation treatments were significantly greater among proactive outreach participants compared with usual care, particularly combination counselling and medications (17.4% vs 3.6%, OR 5.69, 95% CI 3.85 to 8.40). INTERPRETATION: Population-based proactive tobacco treatment increases engagement in evidence-based treatment and is effective in long-term smoking cessation among socioeconomically disadvantaged smokers. Findings suggest that dissemination of population-based proactive treatment approaches is an effective strategy to reduce the prevalence of smoking and socioeconomic disparities in tobacco use. TRIAL REGISTRATION NUMBER: NCT01123967.

Retention of Homeless Smokers in the Power to Quit Study.

INTRODUCTION: Concerns about retention are a major barrier to conducting studies enrolling homeless individuals. Since smoking is a major problem in homeless communities and research on effective methods of promoting smoking cessation is needed, we describe strategies used to increase retention and participant characteristics associated with retention in smoking cessation study enrolling homeless adults. METHODS: The parent study was a 2-group randomized controlled trial with 26-week follow-up enrolling 430 homeless smokers from emergency shelters and transitional housing units in Minneapolis/Saint Paul, MN, USA. Multiple strategies were used to increase retention, including conducting visits at convenient locations for participants, collecting several forms of contact information from participants, using a schedule that was flexible and included frequent low-intensity visits, and providing incentives. Participant demographics as well as characteristics related to tobacco and drug use and health status were analyzed for associations with retention using univariate and multivariate analysis. RESULTS: Overall retention was 75% at 26 weeks. Factors associated with increased retention included greater age; having healthcare coverage; history of multiple homeless episodes, lower stress level; and higher PHQ-9 (Patient Health Questionnaire-9) score. A history of excessive drinking and drug use were associated with decreased retention. CONCLUSIONS: It is possible to successfully retain homeless individuals in a smoking cessation study if the study is designed with participants' needs in mind.

Thirdhand tobacco smoke: a tobacco-specific lung carcinogen on surfaces in smokers' homes.

INTRODUCTION: Thirdhand tobacco smoke consists of substances remaining on the surfaces or in the dust of areas where people have smoked. While previous studies have demonstrated the presence of nicotine and various other constituents of tobacco smoke on surfaces in smokers' homes, none has investigated the presence of tobacco-specific carcinogens. METHODS: We used liquid chromatography-tandem mass spectrometry to analyze surface dust samples from both the homes of smokers and nonsmokers for the powerful tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). RESULTS: We positively identified NNK on surfaces in 33 of 37 smokers' homes (700±788 pg/100cm(2) [range, not detected-3,500 pg/100cm(2)]), but only in 3 of 19 nonsmokers' homes (235±176 pg/100cm(2) in the homes where NNK was detected [range, not detected-435 pg/100cm(2)]). The differences in occurrence and levels of NNK in the homes of smokers and nonsmokers were significant (p < .0001). CONCLUSIONS: The powerful tobacco-specific lung carcinogen NNK is present on surfaces in most homes occupied by smokers. Potential renters or buyers of apartments or homes should be notified if previous residents were smokers in order to avoid unnecessary exposure of their families to a potent lung carcinogen.

Cotinine and tobacco-specific carcinogen exposure among nondaily smokers in a multiethnic sample.

BACKGROUND: Nondaily smoking has increased among current U.S. smokers during the past decade and is practiced by a significant percentage of smokers. Although research in nondaily smoking has grown, little is known about levels of exposure to tobacco toxicants among nondaily smokers and their variation across ethnic groups. METHODS: We examined urinary levels of cotinine and a tobacco-specific nitrosamine (NNAL) in community participants. Associations between the biomarker data and smoking characteristics were evaluated with Spearman's correlation analysis. RESULTS: Participants included 28 Blacks, 4 Latinos, and 25 Whites who smoked at least 1 cigarette on 4-24 days in the past 30 days. Participants averaged 3.3 (SD = 2.1) cigarettes per day (cpd) on days smoked, they smoked an average of 13.0 (SD = 5.4) days in the past month, and they smoked nondaily for 10.5 (SD = 10.5) years. Median levels of creatinine-normalized cotinine and NNAL were 490.9 ng/mg and 140.7 pg/mg, respectively. NNAL and cotinine were highly correlated (r = .84); NNAL and cotinine were modestly correlated with cpd (r = .39 and r = .34; all p values <.05). The number of days smoked per month was not associated with any biomarker levels. CONCLUSIONS: Our findings demonstrate that nondaily smokers are, on average, exposed to significant levels of nicotine and carcinogenic nitrosamines, with exposures of 40%-50% of those seen in daily smokers. This level of exposure suggests a significant health risk. Nicotine and carcinogen exposure is most closely related to number of cigarettes smoked per day but not to number of days per month of smoking.

Proactive tobacco treatment for low income smokers: study protocol of a randomized controlled trial.

BACKGROUND: There is a high prevalence of smoking and high burden of tobacco-related diseases among low-income populations. Effective, evidenced-based smoking cessation treatments are available, but low-income smokers are less likely than higher-income smokers to use these treatments, especially the most comprehensive forms that include a combination of pharmacotherapy and intensive behavioral counseling. METHODS/DESIGN: The primary objectives of this randomized controlled trial are to compare the effects of a proactive tobacco treatment intervention compared to usual care on population-level smoking abstinence rates and tobacco treatment utilization rates among a diverse population of low-income smokers, and to determine the cost-effectiveness of proactive tobacco treatment intervention. The proactive care intervention systematically offers low-income smokers free and easy access to evidence-based treatments and has two primary components: (1) proactive outreach to current smokers in the form of mailed invitation materials and telephone calls containing targeted health messages, and (2) facilitated access to free, comprehensive, evidence-based tobacco cessation treatments in the form of NRT and intensive, telephone-based behavioral counseling. The study aims to include a population-based sample (N = 2500) of adult smokers enrolled in the Minnesota Health Care Programs (MHCP), a state-funded health insurance plan for low-income persons. Baseline data is obtained from MHCP administrative databases and a participant survey that is conducted prior to randomization. Outcome data is collected from a follow-up survey conducted 12 months after randomization and MHCP administrative data. The primary outcome is six-month prolonged smoking abstinence at one year and is assessed at the population level. All randomized individuals are asked to complete the follow-up survey, regardless of whether they participated in tobacco treatment. Data analysis of the primary aims will follow intent-to-treat methodology. DISCUSSION: There is a critical need to increase access to effective tobacco dependence treatments. This randomized trial evaluates the effects of proactive outreach coupled with free NRT and telephone counseling on the population impact of tobacco dependence treatment. If proven to be effective and cost-effective, national dissemination of proactive treatment approaches would reduce tobacco-related morbidity, mortality, and health care costs for low income Americans. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT01123967.

Disciplinary supervision following ethics complaints: goals, tasks, and ethical dimensions.

Clinical supervision is considered an integral component of the training of psychologists, and most of the professional literature is focused on this type of supervision. But psychologists also may supervise fully credentialed colleagues in other circumstances. One such context occurs when licensing boards mandate supervision as part of a disciplinary order. When supervision is provided in disciplinary cases, there are significant implications for the ethical dimensions of the supervisory relationship and concomitant ethical challenges for supervisors. Not only are the goals, objectives, and supervisory tasks of disciplinary supervision distinct from other types of supervision, but the supervisor's ethical responsibilities also encompass unique dimensions. Competence, informed consent, boundaries, confidentiality, and documentation are examined. Recommendations for reports to licensing boards include a statement of the clinical or ethical problems instigating discipline, description of how these problems have been addressed, and an assessment of the supervisee's current practices and ability to perform competently.