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Background Non-visual hallucinations in Parkinson’s disease (PD) can be prevalent and distressing. Most existing research has however, focused on visual hallucinations as well as related risk factors. The current study thus conducted a systematic review to collate existing evidence on non-visual hallucinations in PD, focusing on their prevalence, phenomenology, and clinical-cognitive correlates. Methods Ninety-one relevant studies were included from a systematic search across PsycINFO APA, PubMed, and Web of Science, for peer-reviewed publications in the English language, from 1970 to the present. These comprised a mix of case (30 studies; n = 56) and group design (62 studies; n = 7346) studies, divided into three somewhat overlapping collections to address our three research foci. Results Prevalence estimates for hallucinations were: auditory 1.5–72.0%, olfactory 1.6–21.0%, somatic-tactile 0.4–22.5%, gustatory 1.0–15.0%, and sensed presence 0.9–73.3%. Phenomenological inquiries revealed descriptions of vivid, consuming events replete with elaborate detail, adversely affecting PD patients in different ways. Overt experiences of multisensory hallucinations were also highly variable (0.4–80%) but exceedingly common, reported by almost half of the 45 included prevalence studies. There was some evidence for modality-specific hallucination predictors, but this was largely tentative, pending robust replication. Conclusions Marked prevalence figures coupled with phenomenological descriptions implicating distress denote that non-visual and multisensory hallucinations in PD are of clinical significance. More direct research and clinical attention need to be devoted to the study and management of such hallucinatory experiences.

The plant-associated microbiome has been shown to vary considerably between species and across environmental gradients. The effects of genomic variation on the microbiome within single species are less clearly understood, with results often confounded by the larger effects of climatic and edaphic variation. In this study, our objective was to confirm that maize genomic variation effects the rhizosphere bacterial communities in the absence of confounding environmental variation. This was investigated by comparing different maize lines grown within controlled environments. Rhizosphere bacterial communities were profiled by metabarcoding the universal bacterial 16S rRNA v3-v4 region. Initially, plants from the inbred B73 line and the traditional Ancho landrace were grown for 12 weeks and compared. The experiment was then repeated with an additional four Mexican landraces (Apachito, Tehua, Serrano, and Harinoso) that were grown alongside additional B73 and Ancho plants. In both experiments, there were significant compositional differences in the rhizosphere bacteria associated with different genotypes. Additionally, we found that genetic distance (phylogenetic) correlated with bacterial community similarity (i.e., more closely related lines had more similar rhizosphere bacteria). We therefore confirm that heritable variation in maize landraces is associated with differences in the rhizosphere bacterial communities. Further studies are required to identify the mechanisms that translate variation in the genome to predictable variation in the root microbiome, which could potentially be exploited to optimize the root microbiome for particular functions as part of crop improvement strategies.

BACKGROUND Cyber-victimisation of people with long-term conditions is a disturbing phenomenon. Limited research was done to examine its impact, which was mostly done using quantitative methods and focused on children. Research focusing on the cyber-victimisation of adults with chronic conditions is scarce and lacks qualitative input from the ‘victims’ as experts in their own experiences. OBJECTIVE This study aims to understand the impact of cyber-victimisation on the self-management of chronic conditions among individuals living with long-term conditions in the UK. METHODS This paper reports the findings from the qualitative phase of a phenomenologically-informed mixed-method research. The biographical disruption concept was used to conceptualise the study. In-depth semi-structured interviews were conducted with 13 participants with chronic conditions who experienced cyber-victimisation. RESULTS Cyber-victimisation has imposed direct and indirect impacts on the self-management of chronic conditions. This impact was demonstrated in six overarching themes that emerged from this study: 1)Biomedical events included overall health deterioration of existing conditions, new diagnoses, and subjective physical complaints, 2) The impact on mental health included psychological consequences and developing psychiatric conditions following or during this traumatic experience, 3) The multi-level impact theme focused on the exacerbation of existing vulnerability and involved unplanned changes to victims’ health management priorities, 4) The impact of complexity reflected the struggle to get formal support and how this lead to further health complications, 5) Social network involvement signified the effects of social isolation, victim-blaming and experiencing deception, 6) Disability discrimination theme was focused on prejudice, issues in inclusion and the hostility in society. CONCLUSIONS People with long-term conditions experienced different forms of cyber-victimisation, all of these were disruptive, with complex impacts on health directly or indirectly. Awareness-raising campaigns, training to support channels, participatory and multidisciplinary research are indicated to initiate change.

Background Carpal tunnel syndrome is the most common upper-extremity nerve compression syndrome. Over 500,000 carpal tunnel release (CTR) procedures are performed in the U.S. yearly. We estimated the cost-effectiveness of endoscopic CTR (ECTR) versus open CTR (OCTR) using data from published meta-analyses comparing outcomes for ECTR and OCTR. Methods We developed a Markov model to examine the cost-effectiveness of OCTR versus ECTR for patients undergoing unilateral CTR in an office setting under local anesthesia and in an operating-room (OR) setting under monitored anesthesia care. The main outcomes were costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). We modeled societal (modeled with a 50-year-old patient) and Medicare payer (modeled with a 65-year-old patient) perspectives, adopting a lifetime time horizon. We performed deterministic and probabilistic sensitivity analyses (PSAs). Results ECTR resulted in 0.00141 additional QALY compared with OCTR. From a societal perspective, assuming 8.21 fewer days of work missed after ECTR than after OCTR, ECTR cost less across all procedure settings. The results are sensitive to the number of days of work missed following surgery. From a payer perspective, ECTR in the OR (ECTROR) cost $1,872 more than OCTR in the office (OCTRoffice), for an ICER of approximately $1,332,000/QALY. The ECTROR cost $654 more than the OCTROR, for an ICER of $464,000/QALY. The ECTRoffice cost $107 more than the OCTRoffice, for an ICER of $76,000/QALY. From a payer perspective, for a willingness-to-pay threshold of $100,000/QALY, OCTRoffice was preferred over ECTROR in 77% of the PSA iterations. From a societal perspective, ECTROR was preferred over OCTRoffice in 61% of the PSA iterations. Conclusions From a societal perspective, ECTR is associated with lower costs as a result of an earlier return to work and leads to higher QALYs. Additional research on return to work is needed to confirm these findings on the basis of contemporary return-to-work practices. From a payer perspective, ECTR is more expensive and is cost-effective only if performed in an office setting under local anesthesia. Level of evidence Economic and Decision Analysis Level I. See Instructions for Authors for a complete description of levels of evidence.

Background: The Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors (CLARINET) trial showed prolonged progression-free survival in patients initially treated with lanreotide versus placebo. We evaluated the cost-effectiveness of upfront lanreotide versus active surveillance with lanreotide administered after progression in patients with metastatic enteropancreatic neuroendocrine tumors (NETs), both of which are treatment options recommended in NCCN Clinical Practice Guidelines in Oncology for Neuroendocrine and Adrenal Tumors. Methods: We developed a Markov model calibrated to the CLARINET trial and its extension. We based the active surveillance strategy on the CLARINET placebo arm. We calculated incremental cost-effectiveness ratios (ICERs) in dollars per quality-adjusted life-year (QALY). We modeled lanreotide’s cost at $7,638 per 120 mg (average sales price plus 6%), used published utilities (stable disease, 0.77; progressed disease, 0.61), adopted a healthcare sector perspective and lifetime time horizon, and discounted costs and benefits at 3% annually. We examined sensitivity to survival extrapolation and modeled octreotide long-acting release (LAR) ($6,183 per 30 mg). We conducted one-way, multiway, and probabilistic sensitivity analyses. Results: Upfront lanreotide led to 5.21 QALYs and a cost of $804,600. Active surveillance followed by lanreotide after progression led to 4.84 QALYs and a cost of $590,200, giving an ICER of $578,500/QALY gained. Reducing lanreotide’s price by 95% (to $370) or 85% (to $1,128) per 120 mg would allow upfront lanreotide to reach ICERs of $100,000/QALY or $150,000/QALY. Across a range of survival curve extrapolation scenarios, pricing lanreotide at $370 to $4,000 or $1,130 to $5,600 per 120 mg would reach ICERs of $100,000/QALY or $150,000/QALY, respectively. Our findings were robust to extensive sensitivity analyses. The ICER modeling octreotide LAR is $482,700/QALY gained. Conclusions: At its current price, lanreotide is not cost-effective as initial therapy for patients with metastatic enteropancreatic NETs and should be reserved for postprogression treatment. To be cost-effective as initial therapy, the price of lanreotide would need to be lowered by 48% to 95% or 27% to 86% to reach ICERs of $100,000/QALY or $150,00/QALY, respectively.

Cladonia rangiferina is a lichen that produces usnic acid, a selectively toxic biomolecule, allowing the lichen to protect itself from predators and regulate populations of microorganisms, other fungi, and animals in its vicinity. Unfortunately, metal pollution associated with human industrial activity has hindered C. rangiferina’s metabolism, as indicated by its decreasing population in areas with high metal concentrations. It was unclear whether C. rangiferina’s ability to produce usnic acid was also hindered in polluted environments and whether the type of metal pollutant led to different effects. A short-term experimental study was used to isolate the effects of concentrated copper, nickel, and zinc ions on this metabolic pathway. It was found that nickel (+2) does not significantly affect usnic acid production, whereas even small concentrations of copper (+2) dramatically reduce it. Meanwhile, the concentration of zinc (+2) seems to be negatively correlated with usnic acid production in the short term. This means that priority regions for C. rangiferina population restoration projects include areas with critically high concentrations of copper and zinc, but not nickel. Further research is needed to a) explain how usnic acid synthesis changed rapidly under varying copper conditions compared to zinc and b) identify changes to this molecule’s synthesis under a combination of metal stresses. This study could clarify the metabolic pathway of usnic acid production and refine plans for artificial dispersal (a lichen conservation method).

BACKGROUND People living with chronic conditions and disabilities experience harassment both offline and on the web. Cybervictimization is an umbrella term for negative web-based experiences. It has distressing consequences on physical health, mental well-being, and social relationships. These experiences have mostly been documented among children and adolescents. However, the scope of such experiences is not well documented among adults with long-term conditions, and the potential impact has not been examined from a public health perspective. OBJECTIVE This study aimed to examine the scope of cybervictimization among adults living with long-term conditions in the United Kingdom and the perceived impact on self-management of chronic conditions. METHODS This paper reports the findings of the quantitative phase of a mixed methods study in the United Kingdom. This cross-sectional study targeted adults aged ≥18 years with long-term conditions. Using a web-based link, the survey was shared on the web via 55 victim support groups, health support organizations, and social media accounts of nongovernmental organizations and activists such as journalists and disability campaigners. People with long-term conditions were asked about their health conditions, comorbidities, self-management, negative web-based experiences, their impact on them, and support sought to mitigate the experiences. The perceived impact of cybervictimization was measured using a set of questions on a Likert scale, frequency tables, and the Stanford Self-Efficacy for Managing Chronic Diseases Scale. Demographic data and the impact on self-management were cross-tabulated to identify the demographic characteristics of the targeted individuals and potential conditions with complications and highlight directions for future research. RESULTS Data from 152 participants showed that almost 1 in every 2 adults with chronic conditions was cybervictimized (69/152, 45.4%). Most victims (53/69, 77%) had disabilities; the relationship between cybervictimization and disability was statistically significant (P=.03). The most common means of contacting the victims was Facebook (43/68, 63%), followed by personal email or SMS text messaging, each accounting for 40% (27/68). Some participants (9/68, 13%) were victimized in web-based health forums. Furthermore, 61% (33/54) of victims reported that experiencing cybervictimization had affected their health condition self-management plan. The highest impact was on lifestyle changes such as exercise, diet, avoiding triggers, and avoiding excessive smoking and alcohol consumption. This was followed by changes to medications and follow-ups with health care professionals. Most victims (38/55, 69%) perceived a worsened self-efficacy on the Self-Efficacy for Managing Chronic Diseases Scale. Formal support was generally rated as poor, with only 25% (13/53) of victims having disclosed this experience to their physicians. CONCLUSIONS Cybervictimization of people with chronic conditions is a public health issue with worrying consequences. This triggered considerable fear and negatively influenced the self-management of different health conditions. Further context- and condition-specific research is needed. Global collaborations to address inconsistencies in research are recommended.

The plant-associated microbiome has been shown to vary considerably between species and across environmental gradients. The effects of genomic variation on the microbiome within single species are less clearly understood, with results often confounded by the larger effects of climatic and edaphic variation.In this study, the effect of genomic variation on the rhizosphere bacterial communities of maize was investigated by comparing different genotypes grown within controlled environments. Rhizosphere bacterial communities were profiled by metabarcoding the universal bacterial 16S rRNA v3-v4 region. Initially, plants from the inbred B73 line and the Ancho - More 10 landrace were grown for 12- weeks and compared. The experiment was then repeated with an additional four Mexican landraces (Apachito - Chih 172, Tehua - Chis 204, Serrano - Pueb 180 and Hairnoso de Ocho) that were grown alongside additional B73 and Ancho – More 10 genotypes.In both experiments there were significant genotypic differences in the rhizosphere bacteria. Additionally, the bacterial communities were significantly correlated with genomic distance between genotypes, with the more closely related landraces being more similar in rhizosphere bacterial communities.Despite limited sampling numbers, here we confirm that genomic variation in maize landraces is associated with differences in the rhizosphere bacterial communities. Further studies that go beyond correlations to identify the mechanisms that determine the genotypic variation of the rhizosphere microbiome are required.

While metabarcoding of plant DNA from their environment is an exciting method that can supplement inventorying of live plant species, the accuracy and specificity has yet to be fully assessed over complex continuous landscapes. In this work, we evaluate plant community profiles produced via metabarcoding of soil by comparing them to a morphological survey. We assessed plant communities by metabarcoding of soil DNA in 130 sites along ecological gradients (nutrients, succession, moisture) in Denmark using chloroplast trnL region (10–143 bp) primer set and compared the resulting communities to communities produced with a longer nuclear ITS2 region (~216 bp) and a morphological survey. We found that the community variation observed within the morphological survey was well represented by molecular surveys, with significant correlation with both community composition and richness using both primer sets. While the majority of the ITS2 sequences could be assigned to species (over 80%), we had less success with the trnL sequences (70%), which was only possible after restricting the reference database to local species. We conclude that the community profiles produced by metabarcoding can be highly effective in performing large-scale macroecological studies. However, the discovery rates and taxonomic assignments produced via metabarcoding remained inferior to morphological surveys, but manual curation of databases improves the specificity of assignments made by the trnL primers, and improves the accuracy of the assignments made with the ITS2 primers. Finally, we suggest that a greater percentage of named diversity would be recovered by increasing soil sampling with the use of additional universal primer sets.

Background. Whole pancreas transplantation (Tx) is a successful treatment for type 1 diabetes resulting in independence from antidiabetic therapies. Transplant-related factors contributing to pancreatic islet failure are largely unknown; both recurring insulitis and pancreatitis have been implicated. The aim was to determine if cellular changes in islets and exocrine tissue are evident early in Tx, which could contribute to eventual graft failure using well-preserved tissue of grafts explanted from largely normoglycemic recipients. Methods. Histological specimens of explants (n = 31), Tx duration 1 day–8 years (median 29 d), cold ischemia time 7.2–17.3 hours (median 11.1 h), donor age 13–54 years (median 38 y) were examined; sections were labeled for inflammation, islet amyloidosis, and tissue fibrosis, and morphometry performed on immunolabeled insulin and glucagon positive islet cells. Data were related to clinical details of donor, recipient, and features of Tx. Results. Islet inflammation consistent with recurrent insulitis was not seen in any sample. Insulin-labeled islet cell proportion decreased with donor age (P Conclusions. Explant histological changes after short-term Tx are similar to those seen in type 2 diabetes and occur in the absence of immunologic rejection without causing hyperglycemia. This suggests that factors associated with Tx affect islet stability; persistent deterioration of islet integrity and exocrine tissue fibrosis could impact on sustainability of islet function.

Disability hate crime is under-reported in the UK with perceived lim-ited support given to the victims. The use of online communication resulted in cyber-disability hate cases, recognised by the Police with the addition of an ‘online-flag’ in the documentation. However, the cases remain under-reported, with potential individual, societal and organisational barriers to reporting espe-cially during a pandemic. This paper aims to contextualise the reporting of cyber-disability hate cases, identify potential barriers, and provide recommendations to improve support to victims by the Police.The retrospective examination was car-ried out on disability-related cyber incidentsdocumented by a police force in the UK for 19 months. Among 3,349 cyber-crimes, 23 cases were included. The anal-ysis covereddescriptive statistics and qualitative document analysis (QDA). Only 0.7% of cyber incidentsor 6.7% of cyber-hate incidentswere disability re-lated. The age of victims ranged between 15 and61 years, with a mean of 25.8 years. Most of the victims (78%) were from White ethnic background, and the majority were females (61.5%). Three overarching themes emerged from the qualitative dataas influencers of reporting or documentation, these were: psy-chological impact, fear for safety, and the type of disability.Cyber-offences re-sulted in a serious impact on wellbeing, however, cases that included people with visible disabilitieswere more documented. Further awareness-raising targeting the police and public is needed to understand the impact of cyber-offences and recognise the different types of disabilities, which might encourage both report-ing and documentation

This report describes the clinical signs, diagnostic findings and treatment of a female spayed Domestic Shorthair with exocrine pancreatic insufficiency (EPI) who presented in shock due to severe gastrointestinal haemorrhage secondary to coagulopathy caused by vitamin K-dependent clotting factor deficiency. Diagnostics revealed a prolonged prothrombin time, activated partial thromboplastin time, low trypsin-like immunoreactvity and gross evidence of pancreatic atrophy. Gastrointestinal haemorrhage resolved quickly with transfusion of fresh frozen plasma and vitamin K supplementation. Following treatment with oral pancreatic enzyme supplementation, the cat was found to have resolution of gastrointestinal signs, improved body condition and normalisation of clotting times. Fat-soluble vitamin levels were below the expected range and improved following treatment. This is the second report of coagulopathy in a cat with EPI and the first to describe fat-soluble vitamin deficiency that improved with pancreatic enzyme supplementation.

PURPOSE Two anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapies are approved for diffuse large B-cell lymphoma, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel; each costs $373,000. We evaluated their cost effectiveness. METHODS We used a decision analytic Markov model informed by recent multicenter, single-arm trials to evaluate axi-cel and tisagenlecleucel in multiply relapsed/refractory, adult, diffuse large B-cell lymphoma from a US health payer perspective over a lifetime horizon. Under a range of plausible long-term effectiveness assumptions, each therapy was compared with salvage chemoimmunotherapy regimens and stem-cell transplantation. Main outcomes were undiscounted life years, discounted lifetime costs, discounted quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (3% annual discount rate). Sensitivity analyses explored uncertainty. RESULTS In an optimistic scenario, assuming a 40% 5-year progression-free survival (PFS), axi-cel increased life expectancy by 8.2 years at $129,000/QALY gained (95% uncertainty interval, $90,000 to $219,000). At a 30% 5-year PFS, improvements in life expectancy were more modest (6.4 years) and expensive ($159,000/QALY gained [95% uncertainty interval, $105,000 to $284,000]). In an optimistic scenario, assuming a 35% 5-year PFS, tisagenlecleucel increased life expectancy by 4.6 years at $168,000/QALY gained (95% uncertainty interval, $105,000 to $414,000/QALY). At a 25% 5-year PFS, improvements in life expectancy were smaller (3.4 years) and more expensive ($223,000/QALY gained [95% uncertainty interval, $123,000 to $1,170,000/QALY]). Administering CAR-T to all indicated patients would increase US health care costs by approximately $10 billion over 5 years. Price reductions to $250,000 and $200,000, respectively, or payment only for initial complete response (at current prices) would allow axi-cel and tisagenlecleucel to cost less than $150,000/QALY, even at 25% PFS. CONCLUSION At 2018 prices, it is possible that both CAR-T therapies meet a less than $150,000/QALY threshold. This depends on long-term outcomes compared with chemoimmunotherapy and stem-cell transplantation, which are uncertain. Widespread adoption would substantially increase non-Hodgkin lymphoma health care costs. Price reductions or payment for initial response would improve cost effectiveness, even with modest long-term outcomes.

Artificial pancreas (AP) device development for ambulatory subjects with type 1 diabetes, has focused on using continuous subcutaneous (SC) insulin infusion (CSII) and glucose measurement. The substantial insulin absorption time-lag associated with CSII makes successful automatic glucose regulation extremely difficult. This work considers using an alternative approach, namely continuous intra-peritoneum (IP) insulin infusion (CIPII) which simplifies the control problem by reducing the insulin absorption time-lag. This could lead to improved glucose regulation and as a consequence improve subject safety with a corresponding reduction in time spent in both hypo- and hyper-glycaemic zones. An in silico performance comparison, between a CSII-based AP, that uses Model Predictive Control, and a CIPII-based AP, that uses Proportional, Integral and Derivative Control is carried out where the virtual subject has a heavy daily meal intake. AP performance both with and without a mealtime prandial bolus is examined as well as the robust performance of a single tuned controller, based on an average subject, on a cohort of simulated type 1 diabetes mellitus subjects.

Background Complex regional pain syndrome (CRPS) occurs in 2 to 8% of patients that receive open or endoscopic carpal tunnel release (CTR). Because CRPS is difficult to treat after onset, identifying risk factors can inform prevention. We determined the incidence of CRPS following open and endoscopic CTR using a national claims database. We also examined whether psychosocial conditions were associated with CRPS after CTR. Methods We accessed insurance claims using diagnostic and procedural codes. We calculated the incidence of CRPS following open carpal tunnel release and endoscopic carpal tunnel release within 1 year. The response variable was the presence of CRPS after CTR. Explanatory variables included procedure type, age, gender, and preoperative diagnosis of anxiety or depression. Results The number of open CTRs (85% of total) outweighs the number of endoscopic procedures. In younger patients, the percentage of endoscopic CTRs is increasing. Rates of CRPS are nearly identical between surgery types for both privately insured (0.3%) and Medicare patients (0.1%). Middle aged (range: 40–64 years) and female patients had significantly higher rates of CRPS than did the general population. Preoperative psychosocial conditions did not correlate with the presence of CRPS in surgical patients. Clinical Relevance The decision between endoscopic and open CTR should not be made out of concern for development of CRPS postsurgery, as rates are low and similar for both procedures. Rates of CRPS found in this study are much lower than rates found in previous studies, indicating inconsistency in diagnosis and reporting or generalizability of prior work. Preoperative psychosocial disorders and CRPS are unrelated.

Transition metal dichalcogenides (TMDCs) are a family of materials whose crystalline structure consists of a layer of transition metal atoms sandwiched between 2 layers of chalcogenide atoms. Some of these materials can be grown in 2D hexagonal phase and show tunability of their electrical and magnetic properties based on layer thickness. One aspect of these materials that has received little attention is their magnetic properties. Hence, we have investigated magnetic properties of CoSe and NiSe (both 2D semiconductors), and their heterostructure. The reason for choosing these intrinsically ferromagnetic transition metal atoms based TMCs was to examine how reduction from the bulk to 2D films would influence the magnetic activity of these samples. In order to produce large area films, we have employed atomic layer deposition (ALD) for growth of uniform, few layer-thick films. First the composition and crystal structure of these films are characterized, and then their magnetic properties analyzed. We have found that thin films of both these materials show mostly paramagnetic behavior.

Purpose The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel was recently approved to treat relapsed or refractory pediatric acute lymphoblastic leukemia. With a one-time infusion cost of $475,000, tisagenlecleucel is currently the most expensive oncologic therapy. We aimed to determine whether tisagenlecleucel is cost effective compared with currently available treatments. Methods Markov modeling was used to evaluate tisagenlecleucel in pediatric relapsed or refractory acute lymphoblastic leukemia from a US health payer perspective over a lifetime horizon. The model was informed by recent multicenter, single-arm clinical trials. Tisagenlecleucel (under a range of plausible long-term effectiveness) was compared with blinatumomab, clofarabine combination therapy (clofarabine, etoposide, and cyclophosphamide), and clofarabine monotherapy. Scenario and probabilistic sensitivity analyses were used to explore uncertainty. Main outcomes were life-years, discounted lifetime costs, discounted quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (3% discount rate). Results With an assumption of a 40% 5-year relapse-free survival rate, tisagenlecleucel increased life expectancies by 12.1 years and cost $61,000/QALY gained. However, at a 20% 5-year relapse-free survival rate, life-expectancies were more modest (3.8 years) and expensive ($151,000/QALY gained). At a 0% 5-year relapse-free survival rate and with use as a bridge to transplant, tisagenlecleucel increased life expectancies by 5.7 years and cost $184,000/QALY gained. Reduction of the price of tisagenlecleucel to $200,000 or $350,000 would allow it to meet a $100,000/QALY or $150,000/QALY willingness-to-pay threshold in all scenarios. Conclusion The long-term effectiveness of tisagenlecleucel is a critical but uncertain determinant of its cost effectiveness. At its current price, tisagenlecleucel represents reasonable value if it can keep a substantial fraction of patients in remission without transplantation; however, if all patients ultimately require a transplantation to remain in remission, it will not be cost effective at generally accepted thresholds. Price reductions would favorably influence cost effectiveness even if long-term clinical outcomes are modest.

Ibrutinib is a novel oral therapy that has shown significant efficacy as initial treatment of chronic lymphocytic leukemia (CLL). It is a high-cost continuous therapy differing from other regimens that are given for much shorter courses. Our objective was to evaluate the cost-effectiveness of ibrutinib for first-line treatment of CLL in patients older than age 65 years without a 17p deletion. We developed a semi-Markov model to analyze the cost-effectiveness of ibrutinib vs a comparator therapy from a US Medicare perspective. No direct comparison between ibrutinib and the best available treatment alternative, obinutuzumab plus chlorambucil (chemoimmunotherapy), exists. Therefore, we compared ibrutinib to a theoretical treatment alternative, which was modeled to confer the effectiveness of an inferior treatment (chlorambucil alone) and the costs and adverse events of chemoimmunotherapy, which would provide ibrutinib with the best chance of being cost-effective. Even so, the incremental cost-effectiveness ratio of ibrutinib vs the modeled comparator was $189 000 per quality-adjusted life-year (QALY) gained. To reach a willingness-to-pay threshold (WTP) of $150 000 per QALY, the monthly cost of ibrutinib would have to be at most $6800, $1700 less than the modeled cost of $8500 per month (a reduction of $20 400 per year). When the comparator efficacy is increased to more closely match that seen in trials evaluating chemoimmunotherapy, ibrutinib costs more than $262 000 per QALY gained, and the monthly cost of ibrutinib would need to be lowered to less than $5000 per month to be cost-effective. Ibrutinib is not cost-effective as initial therapy at a WTP threshold of $150 000 per QALY gained.