Real-world evidence in lung and hematologic oncology health technology appraisals: a review of six assessment agencies.

Aim: To assess the use and acceptability of real-world evidence (RWE) in lung and hematologic cancer appraisals. Materials & methods: A review of appraisals published by National Institute for Health and Care Excellence (NICE) in the UK was conducted. A total of 20 case studies employing RWE were identified and compared across five additional health technology assessment agencies: Scottish Medicines Consortium (SMC) (Scotland), CADTH (Canada), INESSS (Quebec), HAS (France) and IQWiG (Germany). Results: Of 80 RWE references from 20 case studies from NICE, 67 were identified in the respective CADTH submissions, 46 in IQWiG, 37 in INESSS, 37 in HAS, and 33 in SMC. NICE had the highest RWE acceptance rate (90%), followed by HAS (88%), SMC (82%), INESSS (73%), IQWiG (68%) and CADTH (67%). Conclusion: RWE was generally accepted by respective committees, allowing improved access to innovative treatments.

Use of real-world evidence for assessing the value of cancer treatments Health technology assessment (HTA) is a process used to decide whether a drug works well enough to be worth paying for. Most drugs have data showing how well they work from special studies called clinical trials. Sometimes a manufacturer also has evidence of a drug or disease that is not from a clinical trial but from the real world. This review discusses how real-world evidence (RWE) is being used for HTAs of new lung and blood cancer therapies. We reviewed twenty HTA submissions for new therapies. All twenty were submitted to these agencies: National Institute for HealthCare and Excellence (NICE; UK), Scottish Medicines Consortium (SMC; Scotland), Canadian Agency for Drugs and Technologies in Health (CADTH; Canada), National Institute of Excellence in Health and Social Services (INESSS; Quebec), French National Authority for Health (HAS; France) and Institute for Quality and Efficiency in HealthCare (IQWiG; Germany). RWE was often used to describe the type of patient that needs the new therapy. RWE was also used to show the cost of the treatment and how well the treatment worked in relation to its cost. It was also used to show how well the new therapy works compared with other treatments. Most of the RWE was accepted by the agencies. High-quality RWE in relevant patients helped support access to new treatments.

Indirect comparisons of brigatinib and alectinib for front-line ALK-positive non-small-cell lung cancer.

Aim: To conduct an indirect treatment comparison (ITC) of the relative efficacy of brigatinib and alectinib for progression-free survival in people with tyrosine kinase inhibitor (TKI)-naive ALK-positive non-small-cell lung cancer (NSCLC). Methods: Final aggregate and patient-level data from the ALTA-1L trial comparing brigatinib to crizotinib and published aggregate data from ALEX (comparing alectinib to crizotinib) were contrasted using Bucher ITC and matching-adjusted indirect comparisons (MAICs). Results: No statistically significant differences were identified between brigatinib and alectinib in reducing the risk of disease progression overall and in patients with baseline central nervous system metastases. Conclusion: Brigatinib appeared similar to alectinib in reducing risk of disease progression for people with TKI-naive ALK-positive NSCLC.

Patients with advanced non-small-cell lung cancer (NSCLC) who have a genetic marker called rearrangement in the anaplastic lymphoma kinase, or ALK-positive disease, are treated with targeted medications taken by mouth. Two medications, alectinib and brigatinib, are both considered first-line treatment for these patients but have not been compared head-to-head. Recently, updated clinical trial results were published for these medications. The present study utilized these updated results and advanced statistical tests to indirectly compare the effectiveness of the two treatments to help guide clinical treatment choices. Results showed brigatinib and alectinib have a similar magnitude of effect in decreasing the risk of a patient with ALK-positive NSCLC developing worsening disease.

The panic triangle: onset of panic in scuba divers.

Panic arising from physical or psychological stress is a common issue in reported incidents and accidents in scuba diving. Due to its effect on perception, thinking and diver behavior, the panic reaction is often a significant factor in the generation or escalation of problems, potentially leading to injuries and fatalities. The instinctive behaviors associated with panic are incompatible with the constraints of scuba diving (e.g., flight response to threat, leading to rapid ascent). Although the dangers are well known, the psychological mechanisms of panic and the implications for prevention/risk reduction are not sufficiently highlighted to recreational divers. In applied psychology, there are grounded theoretical models which describe the onset and maintenance of anxiety and panic, and an evidence base for approaches to anxiety management. For example, these models are used within structured psychological approaches for people experiencing anxiety disorders; and panic attacks are resolvable. Based on these models and underlying theory, this article proposes a new, accessible model for panic in divers. The potential uses of the model are to: (1) provide a simple framework for divers to understand the onset of panic; (2) promote the need for adequate training; (3) describe the importance of staying within training standards, qualifications and personal limitations; (4) support diver and dive educator understanding of individual factors in panic reactions (e.g. psychiatric conditions) placing greater emphasis on psychological fitness to dive; and (5) draw attention to approaches to improved regulation of emotion and promote individual responsibility.

The Role of the Cardiac Surgery Patient in Pain Management: The Patient Perspective.

One and a half million cardiac surgeries are completed worldwide each year where undertreated postoperative pain increases the risk of patient morbidity and mortality. Patient-centered pain management is recommended to improve patient outcomes but there is insufficient information regarding how the patient views their role. The objective of this study is to explore cardiac surgery patients' perspectives on their role in postoperative pain management. This study used an interpretive phenomenological design and convenience sampling. Six participants who had undergone cardiac surgery were recruited from a cardiac rehabilitation program in Western Canada. The first author conducted semi-structured digitally recorded interviews. Sociodemographic characteristics and measures of anxiety and depression were also collected. Emergent thematic analysis of the qualitative data generated three themes: attitude, coping and care, and communication. The findings of this study address a gap in the literature with regard to patients' perceived roles in pain management. There is a complex relationship between patient attitude, coping and care, and communication which, in turn, influences how patients view their role within the pain management continuum. These themes contribute to the development of the patient role within the pain management continuum and form an integrated feedback loop. The patient's attitude contributes to their ability to cope with pain and participate in pain assessment and management. Furthermore, their ability to cope and desire to participate influences the development of their attitude. These findings may enhance providers' understanding of the patient's perspective and improve pain management outcomes.

The ethics of hastening death during terminal weaning.

PURPOSE OF REVIEW: Withdrawal of life-sustaining medical treatment (LSMT) is under scrutiny as next-of-kin challenge medical decision-making in the courts and established end-of-life pathways are withdrawn in the face of public criticism. With persistent lobbying for medically assisted dying as the other side of the coin, and professional advice that doctors distance themselves from this activity, the fine line between defensible palliative care and hastening a death needs to be unambiguously defined, particularly with additional confounders such as transplantation initiatives. RECENT FINDINGS: The medical literature in this domain is dominated by ethical debate on euthanasia and medically assisted dying rather than defensibility within intensive care at the point of withdrawal of LSMT. SUMMARY: The process and, therefore, the timing of dying is open to manipulation by intensivists, families, other hospital physicians, courts of law and extraneous influences such as organ donation. Intensivists faced with these challenging processes need to consider some key principles to help them navigate the management of dying. They need to demonstrate transparency in order to engender trust, be responsive to the dynamically evolving needs of patient and family, avoid ambiguity, show consistency and predictability and, finally, they need to conform with society's expectations and professional standards to achieve defensibility for their actions. Adherence to these principles is likely to minimize conflict, maximize patient benefit, maintain public confidence and avoid professional jeopardy.

Surgery patients' perspectives of their role in postoperative pain: A scoping review.

Background: Post-operative pain is a major factor in surgical recovery. There is evidence that pain remains undermanaged. Complications related to the undermanagement of acute pain can increase length of stay and contribute to readmission and the development of chronic pain. It is well acknowledged that pain assessment is critical to pain management and that self-report of pain is the gold standard. As a result, patients play a central role in their own pain management. A preliminary review of the literature failed to provide a clear or consistent description of this key patient role. Objective: A scoping review was conducted with the objective of reviewing literature that described adult patients' perspectives or highlighted the adult patient's role in post-operative pain management, including assessment. Understanding patients' attitudes toward their roles in pain management through a scoping review of the current literature is critical for informing research and improvements in post-operative pain management. Design: Scoping review. Methods: The databases searched for the review included CINAHL, MEDLINE, PubMed, and SCOPUS (ending May 2022). Thematic analysis, using the methodology of Arksey and O'Malley, was applied to the records identified. Results: Of the 106 abstracts initially identified, 26 papers were included in the final analysis. Two major themes identified through thematic analysis were attitudes toward pain and pain management, with the subthemes of patient expectations and beliefs and desire to treat; and care and communication, with the subthemes of pain assessment and education. Conclusions: This paper provides one of the first known comprehensive scoping reviews of surgical patients' perspectives of their role in pain management, including assessment, and offers an important global awareness of this patient role. The findings suggest that improved understanding of patients' perspectives of their roles in pain assessment and treatment is critical to improving post-operative pain management. Engaging patients as partners in their care can facilitate enhanced communication and improving congruence in pain assessment and treatment decisions. The complex nature of patients' beliefs, expectations, and subjective experiences of pain present challenges for health care practitioners. These challenges can be met with enhanced education for patients, respect for patients' beliefs and expectations, and the provision of dignified care.

Supporting Perinatal Mental Health and Wellbeing during COVID-19.

Mental health is especially important as women transition into parenthood. The COVID-19 pandemic has necessitated the rapid reconfiguration of maternity services, including perinatal mental healthcare, as offered by Specialist Perinatal Mental Health Midwives, in NHS Trusts in the United Kingdom. This article represents work undertaken in rapid response to the COVID-19 pandemic and aims to document the findings from March 2020 up until May 2021 in literature published on perinatal mental health through the pandemic, as well as to engage in a knowledge mapping exercise across five NHS Trusts in London. In this research, we utilised a critical review methodology which purposefully selects and synthesises materials after extensive literature searching to provide a broad and informed narrative around an issue. For our knowledge mapping exercise, we utilised an inclusive stance to gather, pool, and synthesise data from five NHS Trusts regarding the provisions and reconfigurations of their perinatal mental health services, creating a comparable and translatable snapshot in time. Our rapid, critical review highlighted two themes: 'Increased Perinatal Distress' and 'Inaccessible Services and Support'. Our knowledge mapping exercise produced four themes: 'Retention of Existing Service Provision'; 'Additional Services Provided'; 'Reconfiguration of Service Provision'; 'Additional Provision to Support Staff Wellbeing'. We conclude by offering best practice guidance in order to provide shared learning to aid the transition through para-pandemic circumstances to service delivery in a post-pandemic 'new normal'.

Overall survival indirect treatment comparison between brigatinib and alectinib for the treatment of front-line anaplastic lymphoma kinase-positive non-small cell lung cancer using data from ALEX and final results from ALTA-1L.

BACKGROUND: Second-generation anaplastic lymphoma kinase (ALK) gene targeted tyrosine kinase inhibitors (TKIs) alectinib and brigatinib have shown efficacy as front-line treatments for ALK-positive non-small cell lung cancer (NSCLC). No head-to-head data are currently available for brigatinib vs alectinib in the ALK-TKI-naive population. OBJECTIVE: To estimate the relative overall survival (OS) for brigatinib vs alectinib with indirect treatment comparisons (ITCs) using ALEX and ALTA-1L clinical trial data. METHODS: The latest aggregate data from the ALEX trial and final patient-level data from ALTA-1L were used. ITCs were conducted with/without treatment crossover adjustments to estimate relative OS. Bucher methods, anchored matching-adjusted indirect comparisons (MAICs) and unanchored MAICs were employed in ITCs without treatment crossover adjustments. An inverse probability of censoring weight Cox model, a marginal structure model and rank-preserving structural failure time models (with/without re-censoring) within an anchored MAIC were used in ITCs with treatment crossover adjustments. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. RESULTS: HRs for brigatinib vs alectinib for relative OS generated from ITCs without treatment crossover adjustments ranged from 0.90 (95% CI: 0.59-1.38) in the unanchored MAIC to 1.20 (95% CI: 0.69-2.11) using the Bucher method. Methods employing treatment switching adjustments estimated HRs for relative OS ranging from 0.74 (95% CI: 0.38-1.45) to 1.11 (95% CI: 0.63-1.94). Results from all ITCs did not indicate statistically different survival profiles. CONCLUSION: Regardless of ITC methodology, OS is comparable for brigatinib vs alectinib in patients with ALK+ NSCLC previously untreated with an ALK inhibitor.

Yoga as a complementary approach to healing for adult victims and survivors of interpersonal violence.

PURPOSE: Yoga is increasingly accepted to improve overall health and wellness and is considered a meaningful adjunct treatment for mental and physical health ailments associated with interpersonal violence (IV). This review provides background information about the use of yoga among individuals with IV histories and aims to inform researchers and practitioners about the available evidence on yoga's application and effectiveness. METHODS: Using six databases, we systematically reviewed empirical literature examining yoga among IV survivors. Criteria for study inclusion: yoga included a physical component and was the primary intervention; participants had an IV history; peer-reviewed; and participants were 17 years and older. After review, 10 articles reporting findings from seven independent samples were included. FINDINGS: Yoga demonstrated preliminary, positive implications as a complementary treatment for individuals with an IV history. Synthesizing across articles four themes emerged: (1) acceptability and feasibility, (2) enhancement of mental and physical health, (3) promotion of personal growth, and (4) facilitators and barriers to practice. CONCLUSIONS: The nascent literature indicates potential benefits of integrating yoga into interventions for IV survivors to enhance physical and psychological functioning. The primary barriers to intervention were resources (e.g., access) and incompatibility with spiritual beliefs for select clients. Despite consistent barriers, preliminary findings indicate yoga has many positive implications for individuals with an IV history. Given the small evidence base and insufficient methodology, additional empirical research with diverse samples and sites, and robust designs, could improve the state of knowledge and strengthen the efficacy of this promising practice.

Hydrophilic protein associated with desiccation tolerance exhibits broad protein stabilization function.

The ability of certain plants, invertebrates, and microorganisms to survive almost complete loss of water has long been recognized, but the molecular mechanisms of this phenomenon remain to be defined. One phylogenetically widespread adaptation is the presence of abundant, highly hydrophilic proteins in desiccation-tolerant organisms. The best characterized of these polypeptides are the late embryogenesis abundant (LEA) proteins, first described in plant seeds >20 years ago but recently identified in invertebrates and bacteria. The function of these largely unstructured proteins has been unclear, but we now show that a group 3 LEA protein from the desiccation-tolerant nematode Aphelenchus avenae is able to prevent aggregation of a wide range of other proteins both in vitro and in vivo. The presence of water is essential for maintenance of the structure of many proteins, and therefore desiccation stress induces unfolding and aggregation. The nematode LEA protein is able to abrogate desiccation-induced aggregation of the water-soluble proteomes from nematodes and mammalian cells and affords protection during both dehydration and rehydration. Furthermore, when coexpressed in a human cell line, the LEA protein reduces the propensity of polyglutamine and polyalanine expansion proteins associated with neurodegenerative diseases to form aggregates, demonstrating in vivo function of an LEA protein as an antiaggregant. Finally, human cells expressing LEA protein exhibit increased survival of dehydration imposed by osmotic upshift, consistent with a broad protein stabilization function of LEA proteins under conditions of water stress.

Elucidation of the Streptomyces coelicolor pathway to 4-methoxy-2,2'-bipyrrole-5-carboxaldehyde, an intermediate in prodiginine biosynthesis.

The biosynthetic pathway to 4-methoxy-2,2'-bipyrrole-5-carboxaldehyde (MBC), a key intermediate in the biosynthesis of prodiginine antibiotics in Streptomyces coelicolor, has been elucidated using a combination of gene replacements and feeding experiments with chemically synthesised MBC and a synthetic analogue of a pathway intermediate.

A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders.

BACKGROUND: This pilot study examined the effectiveness of memantine hydrochloride in improving cognitive functioning and behavioral symptoms in children with pervasive developmental disorders (PDDs). METHOD: Subjects aged 3-12 years inclusive were enrolled in this 8-week, open-label study. Expressive and receptive language, nonverbal IQ, and nonverbal memory measures were administered at baseline and after 8 weeks of treatment with 0.4 mg/kg of memantine hydrochloride. Throughout the study, the Aberrant Behavior Checklist (ABC) was sent in weekly by parents as a measure of behavioral change. RESULTS: Twelve of 14 subjects completed the study. Significant improvement from baseline was noted on the memory test (Children's Memory Scale Dot Learning Subtest). There were no significant differences from baseline on measures of expressive or receptive language or nonverbal IQ. There were significant improvements on a number of ABC subscales, including hyperactivity, lethargy, and irritability. There were no overall significant statistical differences from baseline on the Clinical Global Improvement-Severity (CGI-S) scale. On the Clinical Global Improvement-Improvement (CGI-I), 4 of 14 subjects showed minimal improvement, and none was deemed "much-improved" or "very much improved." CONCLUSIONS: This small, prospective, open-label study suggests that memantine may be useful in the treatment of memory functioning and some behavioral symptoms in PDDs. The investigators did not see the same degree of change as endorsed by caretakers. Controlled studies are needed to substantiate and clarify these preliminary findings.

LEA proteins prevent protein aggregation due to water stress.

LEA (late embryogenesis abundant) proteins in both plants and animals are associated with tolerance to water stress resulting from desiccation and cold shock. However, although various functions of LEA proteins have been proposed, their precise role has not been defined. Recent bioinformatics studies suggest that LEA proteins might behave as molecular chaperones, and the current study was undertaken to test this hypothesis. Recombinant forms of AavLEA1, a group 3 LEA protein from the anhydrobiotic nematode Aphelenchus avenae, and Em, a group 1 LEA protein from wheat, have been subjected to functional analysis. Heat-stress experiments with citrate synthase, which is susceptible to aggregation at high temperatures, suggest that LEA proteins do not behave as classical molecular chaperones, but they do exhibit a protective, synergistic effect in the presence of the so-called chemical chaperone, trehalose. In contrast, both LEA proteins can independently protect citrate synthase from aggregation due to desiccation and freezing, in keeping with a role in water-stress tolerance; similar results were obtained with lactate dehydrogenase. This is the first evidence of anti-aggregation activity of LEA proteins due to water stress. Again, a synergistic effect of LEA and trehalose was observed, which is significant given that non-reducing disaccharides are known to accumulate during dehydration in plants and nematodes. A model is proposed whereby LEA proteins might act as a novel form of molecular chaperone, or 'molecular shield', to help prevent the formation of damaging protein aggregates during water stress.

Principles and Biomechanical Considerations of Tendon Transfers.

Whether performed as a primary procedure or used to augment and support osseous reconstruction, tendon transfers are a key skill for the foot and ankle surgeon. Understanding the biomechanics preoperative and postoperatively is essential in performing appropriate procedures and in supporting patients through the rehabilitation process. Often the complexity of tendon transfer surgery is lost because it is deemed a soft tissue procedure and in theory should be less complex than osseous procedures. However, the dynamic nature of musculature and tendons require a deeper understanding of surgical and biomechanical concepts.

An open-label trial of escitalopram in pervasive developmental disorders.

OBJECTIVE: To assess the effect of escitalopram in the treatment of pervasive developmental disorders (PDDs). METHOD: This 10-week study had a forced titration, open-label design. Twenty-eight subjects (mean age 125.1 +/- 33.5 months) with a PDD received escitalopram at a dose that increased weekly to a maximum dose of 20 mg as tolerated. The Aberrant Behavior Checklist-Community Version (ABC-CV) and the Clinical Global Impression scale (CGI) were used to assess outcome. RESULTS: There was significant improvement in ABC-CV Irritability Subscale Scores (baseline mean 20.5 +/- 5.9 to final mean 10.9 +/- 7.2; p < or = .001) and in the other ABC-CV Subscales. Improvement on Clinical Global Improvement Scale severity rating was also significant (baseline mean 5.2 +/- 1.0 to final mean 4.6 +/- 1.2; p < or = .001). Twenty-five percent of the subjects responded at a dose less than 10 mg and did not tolerate the 10-mg dose, and an additional 36% responded at a dose greater than or equal to 10 mg. Final dose was unrelated to weight and only weakly correlated with age. CONCLUSIONS: This open-label study found escitalopram to be useful in treating some difficulties common in PDDs. A wide variability in dose was found that could not be accounted for by weight and only partially by age. The study provides information useful for the design of double-blind, placebo-controlled studies of escitalopram in PDDs.

Pregnant smokers who quit, pregnant smokers who don't: does history of problem behavior make a difference?

More than half of women who smoke in the USA continue to do so while pregnant. While socioeconomic and demographic factors that distinguish pregnancy quitters from persistent smokers have been identified, less is known about behavioral factors that are associated with persistent smoking. Because smoking during pregnancy is not only an individual, but also a maternal behavior, it may have different behavioral correlates than women's smoking has in general. We propose a conceptual framework in which smoking during pregnancy is viewed as a maternal problem behavior. We explore this conceptualization by examining whether persistent smoking during pregnancy is associated with a pattern of psychosocial risk- and health-compromising behaviors in multiple domains, with pilot data from a small clinic-based sample. Data are presented for 96 predominantly Caucasian, working-class pregnant women recruited from prenatal clinics in the USA. Smoking during pregnancy was measured repeatedly by self-report and biochemical assay. Participants were non-smokers (37%), pregnancy quitters (17%), and persistent smokers (46%). These groups were compared in terms of their history of problem behavior in three domains: interpersonal difficulties, problems in adaptive functioning and problematic health behaviors. With few exceptions, smokers were more likely to have problematic relationships, poorer adaptive functioning and to engage in problematic health behaviors, than both pregnancy quitters and non-smokers. This pattern of problem behavior may interfere with the effectiveness of standard public health prenatal cessation interventions for a sub-group of women. Examining pregnancy smoking as part of a broader matrix of problem behavior may help to identify pregnant women most at risk for persistent smoking and inform the development of targeted interventions.

Perioperative oxygen toxicity.

This article challenges the use of hyperoxia in the perioperative period. It describes the biochemical and physiologic basis for both the direct and indirect adverse effects of oxygen. The reasons for using hyperoxia in the perioperative period are critically evaluated, and the evidence and guidelines for oxygen use in common acute medical conditions are reviewed.

A pharmacogenetic study of escitalopram in autism spectrum disorders.

OBJECTIVE: To determine the effect of serotonin transporter polymorphism promoter region (5-HTTPLR) genotypic variation (low, intermediate, and high expression groups) on response to escitalopram treatment of children and adolescents with autism spectrum disorders (ASDs). METHOD: The study used a forced titration, open label design, with genotype blind until study completion. Participants were children and adolescents aged 4-17 years of age with a confirmed ASD (autistic disorder, Asperger's disorder, or pervasive developmental disorder, not otherwise specified). RESULTS: There was an interaction between genotype group and time on the Aberrant Behavior Checklist (ABC) Irritability Subscale (primary outcome variable) (linear maximum marginal likelihood estimation=-4.84, Z=-2.89, SE=1.67, P=0.004). Examination of baseline to last visit revealed that a genotype grouping based on a previous study of platelet 5-HT uptake revealed less response in the genotype group that had S/S genotype for 5-HTTLPR and did not have a diplotype in intron 1 previously shown to be associated with increased platelet 5-HT uptake. CONCLUSION: This genotype-blind, prospective pharmacogenetic study found the group of subjects with associated with the lowest platelet 5-HT uptake from previous study had the smallest reduction in ABC-Irritability scores after open label treatment with escitalopram. Replication is necessary to confirm these findings.

Association of surgical care practices with length of stay and use of clinical protocols after elective bowel resection: results of a national survey.

BACKGROUND: Although management techniques have been proposed to accelerate gastrointestinal recovery after elective bowel resection (BR), most data are derived from single-institution experience. This study assessed the current state of perioperative care for elective BRs and the effect of pathway components on length of stay. METHODS: A web-based survey was conducted among surgeons regarding their last elective BR. RESULTS: Among 207 general and 200 colorectal surgeons, 30% practice in hospitals with a perioperative surgical care pathway intended to accelerate gastrointestinal recovery. Pathway components included early ambulation, early diet progression, early nasogastric tube removal/avoidance, and opioid-sparing pain control. Care practices associated with decreased length of stay included laparoscopic technique, early mobilization, early liquids, and antiemetic use to prevent symptoms associated with prolonged postoperative ileus. CONCLUSIONS: Few hospitals have pathways but most surgeons likely would implement nationally endorsed guidelines. These data, along with other studies, may lead to well-accepted BR care pathways.