Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy.

The American Society for Transplantation and Cellular Therapy (ASTCT) published its first white paper on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) in 2015. It was identified at the time that periodic updates of indications would be required to stay abreast with state of the art and emerging indications and therapy. In recent years the field has not only seen an improvement in transplantation technology, thus widening the therapeutic scope of HCT, but additionally a whole new treatment strategy using modified immune effector cells, including chimeric antigen receptor T cells and engineered T-cell receptors, has emerged. The guidelines review committee of the ASTCT deemed it optimal to update the ASTCT recommendations for indications for HCT to include new data and to incorporate indications for immune effector cell therapy (IECT) where appropriate. The guidelines committee established a multiple stakeholder task force consisting of transplant experts, payer representatives, and a patient advocate to provide guidance on indications for HCT and IECT. This article presents the updated recommendations from the ASTCT on indications for HCT and IECT. Indications for HCT/IECT were categorized as (1) Standard of care, where indication is well defined and supported by evidence; (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but have been shown to be effective therapy; (3) Standard of care, rare indication, for rare diseases where demonstrated effectiveness exists but large clinical trials and observational studies are not feasible; (4) Developmental, for diseases where preclinical and/or early-phase clinical studies show HCT/IECT to be a promising treatment option; and (5) Not generally recommended, where available evidence does not support the routine use of HCT/IECT. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.

Guidelines for defining and implementing standard episode of care for hematopoietic stem cell transplantation within the context of clinical trials.

The Patient Protection and Affordable Care Act requires that health care insurers cover routine patient costs associated with participating in clinical trials for cancer and other life-threatening diseases. There is a need to better define routine costs within the context of hematopoietic stem cell transplantation (HSCT) clinical trials. This white paper presents guidance on behalf of the American Society for Blood and Marrow Transplantation for defining a standard HSCT episode and delineates components that may be considered as routine patient costs versus research costs. The guidelines will assist investigators, trial sponsors, and transplantation centers in planning for clinical trials that are conducted as a part of the HSCT episode and will inform payers who provide coverage for transplantation.

Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation.

Approximately 20,000 hematopoietic cell transplantation (HCT) procedures are performed in the United States annually. With advances in transplantation technology and supportive care practices, HCT has become safer, and patient survival continues to improve over time. Indications for HCT continue to evolve as research refines the role for HCT in established indications and identifies emerging indications where HCT may be beneficial. The American Society for Blood and Marrow Transplantation (ASBMT) established a multiple-stakeholder task force consisting of transplant experts, payer representatives, and a patient advocate to provide guidance on "routine" indications for HCT. This white paper presents the recommendations from the task force. Indications for HCT were categorized as follows: (1) Standard of care, where indication for HCT is well defined and supported by evidence; (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but HCT has been shown to be effective therapy; (3) Standard of care, rare indication, for rare diseases where HCT has demonstrated effectiveness but large clinical trials and observational studies are not feasible; (4) Developmental, for diseases where preclinical and/or early phase clinical studies show HCT to be a promising treatment option; and (5) Not generally recommended, where available evidence does not support the routine use of HCT. The ASBMT will periodically review these guidelines and will update them as new evidence becomes available.

Standardization of terminology for episodes of hematopoietic stem cell patient transplant care.

The nomenclature describing hematopoietic stem cell transplantation has evolved, adding precision and definition in research and regulation. The lack of coordination and standardization in terminology has left some gaps in the definition of episodes of clinical care. These voids have caused particular problems in contracting for payment and billing for services rendered. The purpose of this report is to propose definitions for cell products, cell infusions, and transplantation episodes.

Seasonal activity of spotted lanternfly (Hemiptera: Fulgoridae), in Southeast Pennsylvania.

The spotted lanternfly, Lycorma delicatula (White, 1845), is an invasive species in the United States. This pest causes damage to vineyards and has the potential to negatively affect other crops and industries. Information describing the seasonal timing of life stages can improve its management. In 2019 and 2020, spotted lanternfly seasonal activity was followed weekly from spring egg hatch to the first hard freeze. Weighted mean timing of activity for each nymphal instar, early adults, late adults, total adults, and egg mass deposition are presented for 2019 and 2020 on Acer rubrum and 2020 on Ailanthus altissima. Logistic equations describing the percentage completion of each activity period on these hosts were fitted using a start date of 1 January to calculate accumulated degree days (ADD). For the adult and egg mass deposition periods, we additionally used a biofix of the date adults were first observed to calculate ADD. ADD from 1 January adequately estimated the timing of nymphal instars but ADD from observation of the first adult better estimated the timing of adult activity and egg mass deposition. Late adult activity and egg mass deposition periods appeared to be influenced by another environmental cue, such as day length. Maps of season-long ADD show that spotted lanternflies are unlikely to reach adulthood in colder regions of the northeast United States, and therefore may not establish there. We also report a strong seasonal trend in sex ratio on A. rubrum, where the population shifted from over 80% male to over 80% female in October.

Spatio-Temporal Model for Predicting Spring Hatch of the Spotted Lanternfly (Hemiptera: Fulgoridae).

The effect of temperature on the rate of spotted lanternfly, Lycorma delicatula (White) (Hemiptera: Fulgoridae), egg development was investigated for a population in Pennsylvania. Mean developmental duration (days ± SE) for egg hatch was evaluated at five constant temperatures of 19.9, 24.2, 25.1, 26.7, and 30°C using egg masses laid during the fall of 2018 and collected in 2019 from Berks Co., Pennsylvania. Base temperature thresholds for egg development were estimated using intercept and slope parameters by fitting a linear relationship between average temperature and developmental rate for the Pennsylvania study, two Korean studies, and the combined data sets. The base threshold estimates were then used to calculate seasonal accumulated degree-days (ADD) and construct logistic equations for predicting cumulative proportion of hatch in the spring. The fitted logistic prediction equations were then graphed against the egg hatch observations from field sites in Pennsylvania (2017) and Virginia (2019). When base temperature estimates from the three studies and combined studies were used to calculate ADD, the logistic models predicted similar timing for seasonal egg hatch. Because the slopes and intercepts for these four data sets were not statistically different, a base temperature threshold of 10.4°C derived from the combined model is a good estimate for computing ADD to predict spotted lanternfly spring emergence across a spatio-temporal scale. The combined model was linked with open source weather database and mapping programs to provide spatiotemporal prediction maps to aid pest surveillance and management efforts for spotted lanternfly.

Effect of information availability on assessment and designation of species at risk.

Information required to evaluate the extent to which species are at risk of extinction is usually limited and characterized as highly uncertain. In this context, we define information availability as the presence or absence of information used to determine the value of an ecological variable. We examined which of three hypothetical approaches best matched how levels of risk are assigned to species: (1) precautionary approach in which analysts designate levels of risk regardless of the amount of information available, (2) worst-case approach in which analysts assign the maximum level of risk possible from the criteria, and (3) insurance approach in which analysts assign poorly known species to a high-risk category when little information is available. We used the quantitative assessment criteria of the Committee on the Status of Endangered Wildlife in Canada (COSEWIC) as a case study. We created a binary (0/1) matrix of all 2.4192 × 10(7) logical combinations of available information for the 14 ecological variables included in the quantitative criteria. We processed each combination of information availability represented in the matrix with a computer algorithm designed to emulate COSEWIC decision-making rules. Low information availability was associated with a relatively high frequency of not being able to assign a candidate taxon to a risk category, which does not follow the precautionary principle. Information availability and the level of risk assigned to species were directly related, which is associated with the worst-case approach, and counter to the insurance approach. Our results suggest that information availability can have a major effect on the level of risk assigned to a species. We recommend a conscious determination of whether such effects are desired, and we recommend the development of methods to explicitly characterize and incorporate information availability and other sources of uncertainty in decision-making processes.

Antibodies against fetal brain in sera of mothers with autistic children.

Serum antibodies in 100 mothers of children with autistic disorder (MCAD) were compared to 100 age-matched mothers with unaffected children (MUC) using as antigenic substrates human and rodent fetal and adult brain tissues, GFAP, and MBP. MCAD had significantly more individuals with Western immunoblot bands at 36 kDa in human fetal and rodent embryonic brain tissue. The density of bands was greater in fetal brain at 61 kDa. MCAD plus developmental regression had greater reactivity against human fetal brain at 36 and 39 kDa. Data support a possible complex association between genetic/metabolic/environmental factors and the placental transfer of maternal antibodies in autism.

Hepatic fat and adenosine triphosphate measurement in overweight and obese adults using 1H and 31P magnetic resonance spectroscopy.

BACKGROUND/AIMS: Magnetic resonance spectroscopy (MRS) measures hepatic fat and adenosine triphosphate (ATP), but magnetic resonance studies are challenging in obese subjects. We aimed to evaluate the inter- and intrarater reliability and stability of hepatic fat and ATP measurements in a cohort of overweight and obese adults. METHODS: We measured hepatic fat and ATP using proton MRS ((1)H MRS) and phosphorus MRS ((31)P MRS) at baseline in adults enrolled in the Action for Health in Diabetes (Look AHEAD) clinical trial at one site. Using logistic regression, we determined factors associated with successful MRS data acquisition. We calculated the intra- and inter-rater reliability for hepatic fat and ATP based on 20 scans analysed twice by two readers. We also calculated the stability of these measures three times on five healthy volunteers. RESULTS: Of 244 participants recruited into our ancillary study, 185 agreed to MRS. We obtained usable hepatic fat data from 151 (82%) and ATP data from 105 (58%). Obesity was the strongest predictor of failed data acquisition; every unit increase in the body mass index reduced the likelihood of successful fat data by 11% and ATP data by 14%. The inter- and intrarater reliability were excellent for fat (intraclass correlation coefficient=0.99), but substantially more variable for ATP. Fat measures appeared relatively stable, but this was less true for ATP. CONCLUSIONS: Obesity can hinder (1)H and (31)P MRS data acquisition and subsequent analysis. This impact was greater for hepatic ATP than hepatic fat.

TOMMORROW neuropsychological battery: German language validation and normative study.

INTRODUCTION: Assessment of preclinical Alzheimer's disease (AD) requires reliable and validated methods to detect subtle cognitive changes. The battery of standardized cognitive assessments that is used for diagnostic criteria for mild cognitive impairment due to AD in the TOMMORROW study have only been fully validated in English-speaking countries. We conducted a validation and normative study of the German language version of the TOMMORROW neuropsychological test battery, which tests episodic memory, language, visuospatial ability, executive function, and attention. METHODS: German-speaking cognitively healthy controls (NCs) and subjects with AD were recruited from a memory clinic at a Swiss medical center. Construct validity, test-retest, and alternate form reliability were assessed in NCs. Criterion and discriminant validities of the cognitive measures were tested using logistic regression and discriminant analysis. Cross-cultural equivalency of performance of the German language tests was compared with English language tests. RESULTS: A total of 198 NCs and 25 subjects with AD (aged 65-88 years) were analyzed. All German language tests discriminated NCs from persons with AD. Episodic memory tests had the highest potential to discriminate with almost twice the predictive power of any other domain. Test-retest reliability of the test battery was adequate, and alternate form reliability for episodic memory tests was supported. For most tests, age was a significant predictor of group effect sizes; therefore, normative data were stratified by age. Validity and reliability results were similar to those in the published US cognitive testing literature. DISCUSSION: This study establishes the reliability and validity of the German language TOMMORROW test battery, which performed similarly to the English language tests. Some variations in test performance underscore the importance of regional normative values. The German language battery and normative data will improve the precision of measuring cognition and diagnosing incident mild cognitive impairment due to AD in clinical settings in German-speaking countries.

Using Reiki to decrease memory and behavior problems in mild cognitive impairment and mild Alzheimer's disease.

OBJECTIVES: This empirical study explored the efficacy of using Reiki treatment to improve memory and behavior deficiencies in patients with mild cognitive impairment or mild Alzheimer's disease. Reiki is an ancient hands-on healing technique reputedly developed in Tibet 2500 years ago. DESIGN: This study was a quasi-experimental study comparing pre- and post-test scores of the Annotated Mini-Mental State Examination (AMMSE) and Revised Memory and Behavior Problems Checklist (RMBPC) after four weekly treatments of Reiki to a control group. SETTINGS/LOCATION: The participants were treated at a facility provided by the Pleasant Point Health Center on the Passamaquoddy Indian Reservation. SUBJECTS: The sample included 24 participants scoring between 20 and 24 on the AMMSE. Demographic characteristics of the sample included an age range from 60 to 80, with 67% female, 46% American Indian, and the remainder white. INTERVENTIONS: Twelve participants were exposed to 4 weeks of weekly treatments of Reiki from two Reiki Master-level practitioners; 12 participants served as controls and received no treatment. OUTCOME MEASURES: The two groups were compared on pre- and post-treatment scores on the AMMSE and the Revised Memory and Behavior Problems Checklist (RMBPC). RESULTS: Results indicated statistically significant increases in mental functioning (as demonstrated by improved scores of the AMMSE) and memory and behavior problems (as measured by the RMBPC) after Reiki treatment. This research adds to a very sparse database from empirical studies on Reiki results. CONCLUSION: The results indicate that Reiki treatments show promise for improving certain behavior and memory problems in patients with mild cognitive impairment or mild Alzheimer's disease. Caregivers can administer Reiki at little or no cost, resulting in significant societal value by potentially reducing the needs for medication and hospitalization.

Diabetes medication use and blood lactate level among participants with type 2 diabetes: the atherosclerosis risk in communities carotid MRI study.

BACKGROUND: The objective of this study is to compare lactate levels between users and non-users of diabetes medications under the hypothesis that the level of lactate is a marker of oxidative capacity. METHODS: The cross-sectional data of 493 participants aged 61-84 with type 2 diabetes who participated in the Atherosclerosis Risk in Communities Carotid MRI study were analyzed using survey weighted linear regression. RESULTS: Median plasma lactate level was 8.58 (95% CI: 8.23, 8.87) mg/dl. Comparing users of diabetic medications with non-users, thiazolidinedione use was significantly associated with lower lactate level (7.57 (6.95-8.25) mg/dL vs. 8.78 (8.43-9.14) mg/dL), metformin use with a slightly higher lactate level (9.02 (8.51-9.58) mg/dL vs. 8.36 (7.96-8.77) mg/dL), and sulfonylurea and insulin use were not associated with lactate level. After adjustment for demographic and lifestyle factors, the plasma lactate level for thiazolidinedione users was 15.78% lower than that for non-users (p<0.001). Considering use of each medication separately and in combination did not change the results. CONCLUSION: In conclusion, thiazolidinedione use was associated with lower plasma lactate level compared to non-use and metformin use was only marginally associated with a slightly higher lactate level. These results are consistent with the previously demonstrated effects of diabetes medications on oxidative metabolism. Further investigation of the role that diabetes medications play in improvement of oxidative metabolism is warranted.

On the electronic structure of nitro-substituted bipyridines and their platinum complexes.

We report the preparation and electrochemical studies of a systematic series of mono- and di-nitro-substituted 2,2'-bipyridine (bipy) compounds [x-NO(2)-bipy (x = 3,4) and x,x'-(NO(2))(2)-bipy (x,x' = 3, 4, 5)] and their complexes with platinum(II), [Pt(x-NO(2)-bipy)Cl(2)] and [Pt(x,x'-(NO(2))(2)-bipy)Cl(2)]. The effect of the number and substitution pattern of the nitro groups on the low-lying acceptor molecular orbitals (involved in charge transfer transitions) is probed by in situ UV/Vis/NIR and EPR spectroelectrochemical methods, supported by DFT calculations. The LUMOs of x-NO(2)-bipy (x = 3-5) are largely localised on the NO(2)-pyridyl moiety; this is also true of their {PtCl(2)} complexes but with a small but significant shift of electron density from the nitro groups. The LUMOs of x,x'-(NO(2))(2)-bipy with x = 3 and 5 are delocalised over both NO(2)-pyridyl rings, but for 4,4'-(NO(2))(2)-bipy is localised on a single NO(2)-pyridyl ring. In all cases the LUMO of the [Pt(x,x'-(NO(2))(2)-bipy)Cl(2)] complexes is delocalised over both nitro-pyridyl rings. For all complexes, the 4(4') derivatives allows greatest overlap with metal valence orbitals in the LUMO.

A stochastic simulator of a blood product donation environment with demand spikes and supply shocks.

The availability of an adequate blood supply is a critical public health need. An influenza epidemic or another crisis affecting population mobility could create a critical donor shortage, which could profoundly impact blood availability. We developed a simulation model for the blood supply environment in the United States to assess the likely impact on blood availability of factors such as an epidemic. We developed a simulator of a multi-state model with transitions among states. Weekly numbers of blood units donated and needed were generated by negative binomial stochastic processes. The simulator allows exploration of the blood system under certain conditions of supply and demand rates, and can be used for planning purposes to prepare for sudden changes in the public's health. The simulator incorporates three donor groups (first-time, sporadic, and regular), immigration and emigration, deferral period, and adjustment factors for recruitment. We illustrate possible uses of the simulator by specifying input values for an 8-week flu epidemic, resulting in a moderate supply shock and demand spike (for example, from postponed elective surgeries), and different recruitment strategies. The input values are based in part on data from a regional blood center of the American Red Cross during 1996-2005. Our results from these scenarios suggest that the key to alleviating deficit effects of a system shock may be appropriate timing and duration of recruitment efforts, in turn depending critically on anticipating shocks and rapidly implementing recruitment efforts.

Association of blood lactate with type 2 diabetes: the Atherosclerosis Risk in Communities Carotid MRI Study.

BACKGROUND: Accumulating evidence implicates insufficient oxidative capacity in the development of type 2 diabetes. This notion has not been well tested in large, population-based studies. METHODS: To test this hypothesis, we assessed the cross-sectional association of plasma lactate, an indicator of the gap between oxidative capacity and energy expenditure, with type 2 diabetes in 1709 older adults not taking metformin, who were participants in the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study. RESULTS: The prevalence of type 2 diabetes rose across lactate quartiles (11, 14, 20 and 30%; P for trend <0.0001). Following adjustment for demographic factors, physical activity, body mass index and waist circumference, the relative odds of type 2 diabetes across lactate quartiles were 0.98 [95% confidence interval (CI) 0.59-1.64], 1.64 (95% CI 1.03-2.64) and 2.23 (95% CI 1.38-3.59), respectively. Furthermore, lactate was associated with higher fasting glucose among non-diabetic adults. CONCLUSIONS: Plasma lactate was strongly associated with type 2 diabetes in older adults. Plasma lactate deserves greater attention in studies of oxidative capacity and diabetes risk.

Association of lactate with blood pressure before and after rapid weight loss.

BACKGROUND: The mechanism linking obesity with its downstream complications is poorly understood. Accumulating evidence suggests that insufficient oxidative capacity plays a central role in the development of insulin resistance and, perhaps, hypertension. METHODS: To investigate this hypothesis, we measured lactate, a marker of the gap between energy expenditure and oxidative capacity, in 40 obese subjects with the metabolic syndrome (Ob-MS), 40 obese subjects without the metabolic syndrome (Ob), and 20 lean controls (LCs). The 40 Ob-MS participants were then entered into a 12-20 week very low-calorie diet (VLCD) intervention. The change in lactate and a number of other metabolic factors including blood pressure were subsequently assessed. RESULTS: At baseline, median lactate levels were significantly higher in both the Ob (36.4 mg/dl) and Ob-MS (34.7 mg/dl) groups when compared to LCs (17.4 mg/dl; P < 0.001). After the VLCD intervention, Ob-MS subjects lost 14.7 kg on average, corresponding to a 5.0 kg/m(2) decrease in body mass index (BMI). Lactate levels fell from 41.3 to 28.7 mg/dl, a 31% reduction (P = 0.006). Even after adjustment for BMI change, change in lactate was strongly associated with change in diastolic blood pressure (DBP) (P = 0.007) and mean arterial pressure (P = 0.014), but not with systolic blood pressure (SBP) (P = 0.20) or other obesity-related traits. CONCLUSIONS: Baseline and longitudinal associations between lactate and DBP suggest that insufficient oxidative capacity may play a role in obesity-related hypertension.

Regional and temporal variation in American Red Cross blood donations, 1995 to 2005.

BACKGROUND: Maintaining a stable blood supply is a critical goal of the American Red Cross Blood Services. Extensive Red Cross data provided the opportunity to assess both long-term and short-term trends in the variation of weekly blood donations. STUDY DESIGN AND METHODS: Overall trends and week-to-week variation in donation rates were assessed in volunteer, whole-blood donations from 1995 to 2005 among three Red Cross donor regions: the Connecticut region, the Greater Chesapeake and Potomac (Maryland) region, and the Southern California region, adjusting for population change, calendar time, age, sex, and donor region. RESULTS: Weekly donation rates varied widely by region, ranging from 3.5 donations per 10,000 persons in Southern California to 10.2 donations per 10,000 in Connecticut. Week-to-week variation in donation rates within each region was also quite high. Typical swings in weekly donation rates ranged from 38 percent in Connecticut to 56 percent in Southern California. Week-to-week variation was also 103 percent higher (95% confidence interval [CI], 87%-120%) among 18- to 24-year-old donors, compared to 25- to 44-year-olds, ranging from 32 to 49 percent. By comparison, week-to-week variation among adults 25 and older was more stable, ranging from 16 to 21 percent. CONCLUSION: This study suggests that there is a great deal of variation in donation rates, particularly among the youngest donors. Improving recruitment and retention among these donors will be critical to maintaining an adequate blood supply as the donor population ages.