Challenges and Lessons Learned in Autologous Chimeric Antigen Receptor T-Cell Therapy Development from a Statistical Perspective.

Chimeric antigen receptor (CAR) T-cell therapy is a human gene therapy product where T cells from a patient are genetically modified to enable them to recognize desired target antigen(s) more effectively. In recent years, promising antitumor activity has been seen with autologous CAR T cells. Since 2017, six CAR T-cell therapies for the treatment of hematological malignancies have been approved by the Food and Drug Administration (FDA). Despite the rapid progress of CAR T-cell therapies, considerable statistical challenges still exist for this category of products across all phases of clinical development that need to be addressed. These include (but not limited to) dose finding strategy, implementation of the estimand framework, use of real-world data in contextualizing single-arm CAR T trials, analysis of safety data and long-term follow-up studies. This paper is the first step in summarizing and addressing these statistical hurdles based on the development of the six approved CAR T-cell products.

Harvesting cereals at Tappeh Sang-e Chakhmaq and the introduction of farming in Northeastern Iran during the Neolithic.

Tappeh Sang-e Chakhmaq is the only Neolithic site in Northeastern Iran, characterised by aceramic and ceramic levels corresponding to an occupation of 1500 years from the eighth to the end of the sixth millennium BCE. The Western and Eastern Mounds represent the oldest and longest occupation among the sites identified East of the Zagros, providing a unique context to explore the origin and spread of farming outside the core area of the Eastern Fertile Crescent. We present data about the first harvesting activities in the Northeastern Iranian Central Plateau by applying usewear and microtexture analysis through confocal microscopy on sickle gloss blades. Our results indicate a community of pioneer farmers who settled down in the area carrying with them both domestic cereals as well as advanced techniques of cereal cultivation. We demonstrate that most of the tools were used for harvesting cereals in a fully ripened state collected near the ground, indicating a well-established cereal cultivation strategy. The use of straight shafts with parallel inserts in Tappeh Sang-e Chakhmaq, as known in some sites in the Zagros, suggests the dispersal of farming practices and technologies from the Eastern Fertile Crescent north-eastward across Iran. We observe an evolution in the degree of ripeness of harvested cereals along the first four levels of occupation of the Western Mound, where semi-ripe harvesting is relatively important, suggesting that domestic cereals to be harvested before full maturity were introduced into the village. From the topmost of the Western Mound and along the occupation of the Eastern Mound, ripe harvesting is dominant, showing a well-established cultivation strategy of fully mature cereal. This shift could indicate an in-situ evolution towards a better-established agricultural technology, including harvesting riper crops, that would have resulted in higher yields, as cereals were collected when the grain was fully formed.

A home-based, multidisciplinary liver optimisation programme for the first 28 days after an admission for acute-on-chronic liver failure (LivR well): a study protocol for a randomised controlled trial.

BACKGROUND: Acute-on-chronic liver failure (ACLF) represents a rising global healthcare burden, characterised by increasing prevalence among patients with decompensated cirrhosis who have a 28-day transplantation-free mortality of 33.9%. Due to disease complexity and a high prevalence of socio-economic disadvantage, there are deficits in quality of care and adherence to guideline-based treatment in this cohort. Compared to other chronic conditions such as heart failure, those with liver disease have reduced access to integrated ambulatory care services. The LivR Well programme is a multidisciplinary intervention aimed at improving 28-day mortality and reducing 30-day readmission through a home-based, liver optimisation programme implemented in the first 28 days after an admission with either ACLF or hepatic decompensation. Outcomes from our feasibility study suggest that the intervention is safe and acceptable to patients and carers. METHODS: We will recruit adult patients with chronic liver disease from the emergency departments, in-patient admissions, and an ambulatory liver clinic of a multi-site quaternary health service in Melbourne, Australia. A total of 120 patients meeting EF-Clif criteria will be recruited to the ACLF arm, and 320 patients to the hepatic decompensation arm. Participants in each cohort will be randomised to the intervention arm, a 28-day multidisciplinary programme or to standard ambulatory care in a 1:1 ratio. The intervention arm includes access to nursing, pharmacy, physiotherapy, dietetics, social work, and neuropsychiatry clinicians. For the ACLF cohort, the primary outcome is 28-day mortality. For the hepatic decompensation cohort, the primary outcome is 30-day re-admission. Secondary outcomes assess changes in liver disease severity and quality of life. An interim analysis will be performed at 50% recruitment to consider early cessation of the trial if the intervention is superior to the control, as suggested in our feasibility study. A cost-effectiveness analysis will be performed. Patients will be followed up for 12 weeks from randomisation. Three exploratory subgroup analyses will be conducted by (a) source of referral, (b) unplanned hospitalisation, and (c) concurrent COVID-19. The trial has been registered with the Australian New Zealand Clinical Trials Registry. DISCUSSION: This study implements a multidisciplinary intervention for ACLF patients with proven benefits in other chronic diseases with the addition of novel digital health tools to enable remote patient monitoring during the COVID-19 pandemic. Our feasibility study demonstrates safety and acceptability and suggests clinical improvement in a small sample size. An RCT is required to generate robust outcomes in this frail, high healthcare resource utilisation cohort with high readmission and mortality risk. Interventions such as LivR Well are urgently required but also need to be evaluated to ensure feasibility, replicability, and scalability across different healthcare systems. The implications of this trial include the generalisability of the programme for implementation across regional and urban centres. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621001703897 . Registered on 13 December 2021. WHO Trial Registration Data Set. See Appendix 1.

Opaganib in Coronavirus Disease 2019 Pneumonia: Results of a Randomized, Placebo-Controlled Phase 2a Trial.

Background: Opaganib, an oral sphingosine kinase-2 inhibitor with antiviral and anti-inflammatory properties, was shown to inhibit severe acute respiratory syndrome coronavirus 2 replication in vitro. We thus considered that opaganib could be beneficial for moderate to severe coronavirus disease 2019 (COVID-19) pneumonia. The objective of the study was to evaluate the safety of opaganib and its effect on supplemental oxygen requirements and time to hospital discharge in COVID-19 pneumonia hospitalized patients requiring supplemental oxygen. Methods: This Phase 2a, randomized, double-blind, placebo-controlled study was conducted between July and December 2020 in 8 sites in the United States. Forty-two enrolled patients received opaganib (n = 23) or placebo (n = 19) added to standard of care for up to 14 days and were followed up for 28 days after their last dose of opaganib/placebo. Results: There were no safety concerns arising in this study. The incidence of ≥Grade 3 treatment-emergent adverse events was 17.4% and 33.3% in the opaganib and placebo groups, respectively. Three deaths occurred in each group. A numerical advantage for opaganib over placebo was observed in in this nonpowered study reflected by total supplemental oxygen requirement from baseline to Day 14, the requirement for supplemental oxygen for at least 24 hours by Day 14, and hospital discharge. Conclusions: In this proof-of-concept study, hypoxic, hospitalized patients receiving oral opaganib had a similar safety profile to placebo-treated patients, with preliminary evidence of benefit for opaganib as measured by supplementary oxygen requirement and earlier hospital discharge. These findings support further evaluation of opaganib in this population.

The Rise of the Expert Patient in Cancer: From Backseat Passenger to Co-navigator.

PURPOSE: Patients who have cancer have leveraged the Internet to gain a better understanding of their disease and connect across geographic boundaries with others facing the same challenges. Online cancer communities have developed into resources that highlight new research and evolving care pathways. Combined with increasing health literacy and social media, they have enabled some patients to become experts in their cancer. This combination of empowerment and expertise describes the new "e-patients." METHODS: We reviewed the literature to identify key areas where expert e-patients have directly participated in advancing cancer medicine, as well as opportunities available to those who wish to become more involved in research advocacy. RESULTS: E-patients are widely acknowledged as key stakeholders in oncology by clinicians, researchers, cancer centers, government agencies, and nonprofits. Their input is vital for informing cancer care delivery, developing and launching research initiatives, creating care guidelines and pathways, and formulating policy. CONCLUSION: Expert e-patients play an expanded role in their own care and in larger conversations regarding practice, research, and policy. Clinicians can engage e-patients as partners in cancer care as we work together towards improving health care access and outcomes for people with cancer.

Short-term intraperitoneal catheters: An ambulatory care intervention for refractory ascites secondary to cirrhosis during COVID-19.

BACKGROUND AND AIM: Patients with refractory ascites have frequent hospital admissions, which pose exposure risks in the context of the COVID-19 pandemic. The aim of this study was to investigate the safety and efficacy of a novel 12-week, multidisciplinary ambulatory care program allowing frequent low-volume ascitic drainage through a tunneled, intraperitoneal catheter (IPC). METHODS: Adult patients with cirrhosis complicated by refractory ascites were recruited through a liver clinic in a tertiary health service in Melbourne, Australia from April to December 2020. All patients were enrolled in a 12-week multidisciplinary program including medical, nursing, dietetics, and pharmacy support. A Rocket Medical IPC was inserted on day 1 with 1-2 L of ascitic fluid drained over 1-3 sessions per week either at the patients' homes or at the hospital day ward. Patients' demographics, death, complications, and self-reported outcomes were recorded. RESULTS: Twelve patients were enrolled with a median of 65-day (interquartile range [IQR]: 16.5-93) IPC duration between April and December 2020 across two periods of COVID-related lockdown in Melbourne, Australia. There were no IPC-related deaths. Early removal was necessitated in three patients due to leakage, nonadherence, and bacteremia. On day 30, the median self-reported health score increased from 50 (IQR: 50-70) to 78 (IQR: 50-85), attributable to a reduction in symptom burden. CONCLUSION: A multidisciplinary IPC program including the use of short-term IPC was safe and associated with a self-reported improvement in perceptions of health. In the context of the COVID-19 pandemic, the program aimed to reduce patient and clinician exposure, which is maintaining engagement and management of decompensated cirrhosis.

Successful Islet Outcomes Using Australia-Wide Donors: A National Centre Experience.

Cold ischemia and hence travel time can adversely affect outcomes of islet isolation. The aim of this study was to compare the isolation and transplant outcomes of donor pancreata according to the distance from islet isolation facility. Principally, those within a 50 km radius of the centre were compared with those from regional areas within the state and those from interstate donors within Australia. Organ donors were categorised according to distance from National Pancreas Transplant Unit Westmead (NPTU). Donor characteristics were analysed statistically against islet isolation outcomes. These were age, BMI, cause and mechanism of death, days in ICU, gender, inotrope and steroid use, cold ischemia time (CIT) and retrieval surgical team. Between March 2007 and December 2020, 297 islet isolations were performed at our centre. A total of 149 donor pancreata were local area, and 148 non-local regions. Mean distance from the isolation facility was 780.05 km. Mean pancreas CIT was 401.07 ± 137.71 min and was significantly different between local and non-local groups (297.2 vs. 487.5 min, p < 0.01). Mean age of donors was 45.22 years, mean BMI was 28.82, sex ratio was 48:52 F:M and mean time in ICU was 3.07 days. There was no significant difference between local and non-local for these characteristics. The mean CIT resulting in islet transplantation was 297.1 ± 91.5 min and longest CIT resulting in transplantation was 676 min. There was no significant difference in islet isolation outcomes between local and non-local donors for characteristics other than CIT. There was also no significant effect of distance from the isolation facility on positive islet transplant outcomes (C-peptide > 0.2 at 1 month post-transplant). Conclusions: Distance from the isolation centre did not impact on isolation or transplant outcomes supporting the ongoing nationwide use of shipping pancreata for islet isolation and transplantation.

Australian experience with total pancreatectomy with islet autotransplantation to treat chronic pancreatitis.

BACKGROUND: This study aimed to describe the clinical outcomes of total pancreatectomy with islet autotransplantation (TP-IAT) in Australia. METHODS: Individuals selected for TP-IAT surgery according to the Minnesota Criteria (Appendix) without evidence of diabetes were evaluated including time to transplantation from pancreatectomy, islet numbers infused and post-transplantation HbA1c, C-peptide, total daily insulin and analgesic requirement. RESULTS: Sixteen individuals underwent TP-IAT from Australia and New Zealand between 2010 and 2020. Two recipients are deceased. The median islet equivalents/kg infused was 4244 (interquartile range (IQR) 2290-7300). The median C-peptide 1 month post-TP-IAT was 384 (IQR 210-579) pmol/L and at median 29.5 (IQR 14.5-46.5) months from transplant was 395 (IQR 139-862) pmol/L. Insulin independence was achieved in eight of 15 (53.3%) surviving recipients. A higher islet equivalents transplanted was most strongly associated with the likelihood of insulin independence (P < 0.05). Of the 15 surviving recipients, 14 demonstrated substantial reduction in analgesic requirement. CONCLUSION: The TP-IAT programme in Australia has been a successful new therapy for the management of individuals with chronic pancreatitis including hereditary forms refractory to medical treatment to improve pain management with 50% insulin independence rates.

Cardiac Autonomic Neuropathy Is Not Reversed by Euglycemia Following Islet Transplantation.

BACKGROUND: Cardiac autonomic neuropathy (CAN) is a significant cause of morbidity and mortality for people with type 1 (T1D) and type 2 (T2D) diabetes. Heart rate variability (HRV) has been shown to be a marker of CAN with 24-hour Holter monitoring being a robust modality to assess HRV. METHODS: To investigate the impact of hypoglycemia on CAN and its potential reversibility with islet transplantation, we compared HRV assessment by 24-hour Holter monitor on a total of 109 subjects from 5 cohorts: (1) T1D with recurrent severe hypoglycemia and on waiting list for islet transplant, (2) T1D following islet cell transplantation (ICT), (3) T2D without hypoglycemia, (4) individuals with prediabetes, and (5) controls without diabetes. SD of the normal-normal interval, square root of the mean squared differences of successive normal-normal intervals (rMSSD) and total spectral power were analyzed. RESULTS: There was no significant difference in HRV parameters between T1D subjects and T1D post ICT suggesting CAN is not reversible at a median of 4 years postislet transplant. There was a significant difference in controls and T1D in rMSSD and between controls and T2D in total power. The differential effect on rMSSD in T1D and T2D suggests potential greater impact of hypoglycemia on rMSSD. CONCLUSIONS: Achieving euglycemia after ICT may not reverse CAN once established with no significant difference in HRV parameters at a median of 4 years postislet transplant. Differential effects of T1D as compared with T2D on CAN were identified.

From Hospital to the Community: Redesigning the Human Immunodeficiency Virus (HIV) Clinical Service Model to Respond to an Outbreak of HIV Among People Who Inject Drugs.

An outbreak of human immunodeficiency virus (HIV) among people who inject drugs in Glasgow, Scotland started in 2014. We describe 156 cases over 5 years and evaluate the impact of clinical interventions using virological and phylogenetic analysis. We established (1) HIV services within homeless health facilities, including outreach nurses, and (2) antiretroviral therapy (ART) via community pharmacies. Implementation of the new model reduced time to ART initiation from 264 to 23 days and increased community viral load suppression rates to 86%. Phylogenetic analysis demonstrated that 2019 diagnoses were concentrated within a single network. Traditional HIV care models require adaptation for this highly complex population.

From enhanced collaborations to space advancements: technologies to bring libraries (and librarians) full circle and into the future.

Since the Journal of the Medical Library Association (JMLA) Virtual Projects section was first announced in 2012, the virtual projects featured in the JMLA have expanded or improved library spaces, services, collaborations, connections, and future directions. Virtual projects selected by the JMLA Virtual Projects Section Advisory Committee have been both practical and responsive to library and patron needs and illustrate ways that librarians are leading their communities and services in new directions. Virtual projects highlighted in this year's section demonstrate innovative adaptations of technology into the modern medical library that strengthen collaborative commitments and clinical and research partnerships. They also illustrate how technologies support the idea of "library as place" by providing spaces for users to explore new technologies, as well as tools for space and service planning. This year's virtual projects fully embrace changes in learning, research patterns, technologies, and the role of the health sciences librarian and the library.

Organizing Online Health Content: Developing Hashtag Collections for Healthier Internet-Based People and Communities.

Twitter use has increased among patients with cancer, advocates, and oncology professionals. Hashtags, a form of metadata, can be used to share content, organize health information, and create virtual communities of interest. Cancer-specific hashtags modeled on a breast cancer community, #bcsm, led to the development of a structured set of hashtags called the cancer tag ontology. In this article, we review how these hashtags have worked with the aim of describing our experience from 2011 to 2017. We discuss useful guidelines for the development and maintenance of health-oriented communities on Twitter, including possible challenges to community sustainability and opportunities for future improvement and research.

Standardisation of flow cytometry for whole blood immunophenotyping of islet transplant and transplant clinical trial recipients.

Understanding the immunological phenotype of transplant recipients is important to improve outcomes and develop new therapies. Immunophenotyping of whole peripheral blood (WPB) by flow cytometry is a rapid method to obtain large amounts of data relating to the outcomes of different transplant treatments with limited patient impact. Healthy individuals and patients with type 1 diabetes (T1D) enrolled in islet transplantation were recruited and WPB was collected. 46 fluorochrome-conjugated mouse-anti-human antibodies were used (43 of 46 antibodies were titrated). BD cytometer setup and tracking beads were used to characterize and adjust for cytometer performance. Antibody cocktails were pre-mixed <60 minutes before staining. Multicolour panels were designed based on fluorochrome brightness, antigen density, co-expression, and fluorochrome spillover into non-primary detectors in each panel on a 5 laser flow cytometer. WPB sample staining used 50-300 µl WPB for each panel and was performed within 2 hours of blood sample collection. Samples were acquired on a BD-LSRFortessa. The operating procedures, including specimen collection, antibody cocktails, staining protocol, flow-cytometer setup and data analysis, were standardized. The staining index of 43 antibodies and the spillover spreading matrix for each panel was calculated. The final concentrations for the 46 antibodies used was determined for staining of WPB samples. Absolute cell-count and 7 leukocyte profiling panels consisting of subsets and/or status of granulocytes, monocytes, dendritic, B, NK, and T cells including regulatory T cells (Tregs) and NKT were designed and established on a 5 laser BD-LSR Fortessa. 13 T1D patients, including 4 islet transplant recipients and 8 healthy controls, were evaluated. The ability to reproducibly measure immune subsets and immune-profiles of islet transplant patients up to 18 months post transplantation has been established as a tool to measure immune cell reconstitution after transplantation.

Australia and New Zealand Islet and Pancreas Transplant Registry Annual Report 2018-Islet Donations, Islet Isolations, and Islet Transplants.

BACKGROUND: This is an excerpt from chapter 4 of the annual registry report from the Australia and New Zealand islet and pancreas transplant registry. The full report is available at http://anziptr.org/reports/. METHODS: We report data for all allogeneic islet isolation and transplant activity from 2002 to end 2017. Solid organ pancreas transplantation activity is reported separately. New Zealand does not have an islet transplant program. Data analysis was performed using Stata software version 14 (StataCorp, College Station, TX). RESULTS: From 2002 to 2017, a total of 104 allogeneic islet transplants were performed in 62 recipients. CONCLUSIONS: The number of islet transplants performed in Australia was slightly lower in 2017 but continues to increase over time.

Understanding recent trends in childhood obesity in the United States.

The prevalence of childhood obesity in the United States has more than tripled over the last four decades from 5 percent in 1978 to 18.5 percent in 2016. There is evidence for a break in trend in recent years: after growing from 0.4 to 0.7 percentage point per year between 1978 and 2004, the rate of increase has slowed to 0.1 percentage point per year from 2004 to 2016. To better understand these trends, in this paper we analyze a range of datasets that collect information on childhood obesity. We analyze the data overall, across the age distribution, across birth cohorts, and for subgroups of interest. We find steady increases in cohort-level obesity prevalence through approximately age 10, with levels unchanged thereafter, suggesting a need for additional interventions at early ages. We find that the prevalence of obesity has diverged by race and gender in recent years, especially among children entering kindergarten. Compared with 5-year-olds in 1997, 5-year-olds in 2010 were 2 percentage points more likely to be obese overall. Black and Hispanic 5-year-olds were 5 and 3 percentage points more likely to be obese, respectively, while whites had a 1 percentage point increase in obesity. However, overall and among all subgroups the rate of growth in obesity from kindergarten through 3rd grade has declined in recent years. Together, these findings can inform a future research literature that aims to target obesity interventions where they will be most impactful.

Past and future global transformation of terrestrial ecosystems under climate change.

Impacts of global climate change on terrestrial ecosystems are imperfectly constrained by ecosystem models and direct observations. Pervasive ecosystem transformations occurred in response to warming and associated climatic changes during the last glacial-to-interglacial transition, which was comparable in magnitude to warming projected for the next century under high-emission scenarios. We reviewed 594 published paleoecological records to examine compositional and structural changes in terrestrial vegetation since the last glacial period and to project the magnitudes of ecosystem transformations under alternative future emission scenarios. Our results indicate that terrestrial ecosystems are highly sensitive to temperature change and suggest that, without major reductions in greenhouse gas emissions to the atmosphere, terrestrial ecosystems worldwide are at risk of major transformation, with accompanying disruption of ecosystem services and impacts on biodiversity.

Systematic reviews and tech mining: A methodological comparison with case study.

When the Medical Library Association identified questions critical for the future of the profession, it assigned groups to use systematic reviews to find the answers to these questions. Group 6, whose question was on emerging technologies, recognized early on that the systematic review process would not work well for this question, which looks forward to predict future trends, whereas the systematic review process looks back in time. We searched for new methodologies that were more appropriate to our question, developing a process that combined systematic review, text mining, and visualization techniques. We then discovered tech mining, which is very similar to the process we had created. In this paper, we describe our research design and compare tech mining and systematic review methodologies. There are similarities and differences in each process: Both use a defined research question, deliberate database selection, careful and iterative search strategy development, broad data collection, and thoughtful data analysis. However, the focus of the research differs significantly, with systematic reviews looking to the past and tech mining mainly to the future. Our comparison demonstrates that each process can be enhanced from a purposeful consideration of the procedures of the other. Tech mining would benefit from the inclusion of a librarian on their research team and a greater attention to standards and collaboration in the research project. Systematic reviews would gain from the use of tech mining tools to enrich their data analysis and corporate management communication techniques to promote the adoption of their findings.

Evaluating the capacity of California's publicly funded universities to provide medication abortion.

OBJECTIVE: To explore capacity of University of California (UC) and California State University (CSU) student health centers (SHCs) to provide medication abortion (MA) and SHC staff perspectives on providing MA. STUDY DESIGN: SHC staff completed an online survey; we conducted site visits and conference calls with a subset of SHCs. The survey focused on barriers to abortion, resources needed for MA, and potential benefits and challenges. RESULTS: 11 UCs (100%) and 20 CSUs (87%) completed surveys. All facilities provided basic primary care, including sexual and reproductive health services and some contraceptive services, but not abortion. All sites had adequate staffing and physical plant, but most would require training, access to ultrasound when needed, 24-hour hotlines (CSUs), and back-up care to provide MA. CONCLUSION: It would be feasible to provide MA at SHCs, but investment is needed to support staff training, equipment, 24-hour hotlines, back-up care, and minimal security upgrades, in order to implement MA services. IMPLICATIONS: If SB320 is passed, provision of MA services at student health centers could improve access to early abortion for students in California. This model may be scaled up at other universities around the country.