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One Size Does Not Fit All

The CD45 antigen (common leukocyte antigen) is expressed on the surface of virtually all hematopoietic cells, except mature red cells and platelets. In addition, CD45 expression has been detected in 85% to 90% of AML and ALL, and the antigen does not internalize after antibody binding. In a phase 1 study, patients with advanced acute leukemia or MDS were treated with escalating doses of 131I-labeled CD45 antibody, in combination with high-dose cyclophosphamide and TBI conditioning, followed by autologous or allogeneic HCT.91 This antibody was eventually explored in combination with high-dose targeted busulfan and cyclophosphamide conditioning,92 and, more recently, in combination with fludarabine and 2-Gy TBI in elderly patients with advanced AML or MDS93 with promising results, especially in patients with relapsed or refractory leukemias who would not have been eligible for high-dose conditioning. Conjugation of anti-CD45 antibody with alternative radioisotopes including 90Y is currently explored in clinical trials.

One Size Does Not Fit All

Antibodies targeting T lymphocytes, such as ATG and alemtuzumab, are commonly incorporated into high-dose and RIC regimens to decrease the incidence of graft rejection and to prevent GVHD. In general, ATG does not exert its immunomodulatory effects exclusively through in vivo host and donor T-lymphocyte depletion. Other mechanisms contribute, such as the modulation of cell surface molecules mediating interactions of lymphocytes and the endothelium, the modulation and depletion of antigen-presenting cells, and the induction of regulatory T lymphocytes.94,95 Consequently, the efficacy of ATG in preventing graft rejection and GVHD is affected by several factors including the dose administered, its source and formulation (rabbit vs horse; thymoglobulin, ATG-Fresenius vs Atgam), the timing of administration, the degree of HLA disparity between host and donor, the graft source (marrow vs granulocyte colony-stimulating factor-mobilized peripheral blood stem cells [PBSCs]), and the intensity of the conditioning regimen used, all of which complicates any attempt to compare the various single institution phase 2 studies currently being conducted.

We appreciate the concerns raised by Teachey and colleagues1 (Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'. Nat. Rev. Clin. Oncol. ) regarding the information presented in our Review2, including the fact that the timing and severity of toxicities might vary depending on the chimeric antigen receptor (CAR) construct used, type of cancer, disease subtype, tumour burden, age of the patient, and comorbidities. Indeed, we had acknowledged many of these considerations in our Review2. However, a number of differences in the management of CAR T cell-related toxicities that are mentioned by Teachey and colleagues1 need to be clarified.

Most importantly, the recommendations that we proposed in our Review2 are for the adult population only. This distinction is crucial because, as discussed by Teachey et al.1, the profile of toxicities and their management can be very different between children and adults. We had made this point clearly in our article and, again, emphasize that our recommendations are restricted to adult patients. We commend the authors for their extensive experience in administering CAR T cell therapy to paediatric patients, and believe similar guidelines for the management of children would be very valuable.

Artificial intelligence is so diverse in its range that no simple one-size-fits-all assessment approach can be adequately applied to it. AI systems have a wide variety of functionality, capabilities, and outputs. They are also created using different tools, data modalities, and resources, which adds to the diversity of their assessment. Thus, a collection of approaches and processes is needed to cover a wide range of AI products, tools, services, and resources.

There is no simple one-size-fits-all assessment approach that can be adequately applied to the diverse range of AI. AI systems have a wide variety of functionalities, capabilities, and outputs. They are also created using different tools, data types, and resources, adding to assessment diversity. A collection of approaches and processes are needed to cover a wide range of AI products, tools, services, and resources. Additionally, because the number and frequency of AI creation will greatly increase, resources need to include techniques and tools for scaling assessment, handling the variety and quantity of AI systems. With new AI innovations, assessment needs may change. This research will provide a foundation for assessment that can be adapted to future needs. It will also provide a better understanding of the current U.S. needs and capabilities for AI assessment, and support decisions on AI policy, resourcing, research, and national security.

One size does not fit all in innovation. Different innovation problems require different approaches. There is no method that is always good. In a 2008 article in the Harvard Business Review, Gary Pisano and I demonstrated that crowdsourcing is not always the best approach to collaboration. What is the best approach depends on several factors, including the distribution of talent among scientists and the cost of testing a proposed solution.

3. The board of directors plays a central role in governance quality. Nevertheless, a gap exists between what outsiders think a board does and what they actually do. Furthermore, outside observers, including shareholders, have very limited insight into the factors that would help them understand the quality of oversight that their board provides. How can our understanding of board quality improve without betraying the confidential information that a board discusses?

Stock Purchase or MergerIn a stock purchase or merger, identifying the target IP (Level 1) may be slightly less important, as the stock deal does not require an actual assignment of the IP. However, analyzing whether the company owns or has the right to use (license) the IP is just as important. If some technologies are owned by third parties, even group companies of the seller, it can be difficult or impossible to convince these individuals to assign or license any missing IP after the main transaction has closed.

Recruitment started with four seeds in Port Moresby, four in Lae, and five in Mt. Hagen. Twelve additional seeds were added in Port Moresby, 15 in Lae, and 4 in Mt. Hagen to facilitate recruitment. Seeds were purposely selected to create diversity with respect to: age, sexual/gender identity, place of residence, region of origin, marital status, receipt of a unique object for size estimation, and affiliation with a non-governmental or community-based organization.

Our findings are limited by the cross-sectional nature of our study and the low sample size in Mt. Hagen which we believe is due to the particularly heteronormative culture of this highlands city. Given that the lack of legal protections for MSM and TGW (which do not exist in PNG) are associated with higher HIV prevalence in a global meta-analysis and that HIV prevalence in the general population is highest in Mt. Hagen, we suspect that our finding of 1.8% prevalence among survey participants is an underestimate [23]. As interview data were self-reported in face-to-face interviews, there may be some response bias. The use of audio-computer assisted self-interviews rather than face-to-face interviews may have helped decrease this bias [24].

Our survey was able to reach MSM and TGW that were not engaged in HIV services, revealing that MSM and TGW will access HIV services provided in a safe, affirming environment, providing further evidence to guide service providers and policy makers. As the first HIV biobehavioral survey in PNG among MSM and TGW, this study reveals the substantial vulnerabilities and HIV risks of these populations in PNG and their limited access to and uptake of routine HIV services. Without action, HIV prevalence stands to increase among MSM and TGW in PNG. Addressing the HIV epidemic in PNG will require continued and expanded engagement with MSM and TGW across the country, respecting and responding to their different needs and vulnerabilities, and moving beyond a once size fits all approach to these population in PNG.

Our major finding was that despite equal severity of illness upon presentation, mortality in obese and overweight patients was significantly lower than in patients with a BMI of less than 25 kg/m2 (Figure 1). Compared with those with a BMI of less than 25 kg/m2, obese and overweight patients had less frequent lung and fungal infections as the site and organism causing septic shock. We also found that obese and overweight patients were treated differently, in what appeared to be a 'one size fits all' non-weight-adjusted dosing, so that obese and overweight patients received less fluids and vasopressors per kilogram (norepinephrine and vasopressin) than patients with a BMI of less than 25 kg/m2. Unlike previous reports of obesity augmenting the inflammatory response [6, 7, 13], we found that the IL-6 inflammatory response was muted in overweight and obese patients compared with those with a BMI of less than 25 kg/m2 in early septic shock. This surprising result is novel and consistent with current and previous reports of improved survival outcomes in obese patients [8, 9].

Unlike in most medical therapies which rely upon weight-based dosing, we hypothesized that the empirical manner (1 L of fluid at a time mentality) in which fluid and vasopressor therapy are recommended for sepsis [22, 24] would cause obese and overweight patients to receive relatively less weight-adjusted fluids and vasopressors than normal-BMI patients. Alternatively, the treating physicians may have recognized that blood volume is not linearly related to weight [29, 30] and, therefore, may have followed the current Surviving Sepsis Campaign guidelines that suggest that fluid administration be based on ideal body weight, which did not differ between the three groups in this study (Table 4). Indeed, obese and overweight patients received less body weight-adjusted fluids, norepinephrine, and vasopressin in early septic shock compared with the patients with a BMI of less than 25 kg/m2. As excessive fluid and vasopressor resuscitation is associated with increased mortality [21, 22], it may be that using doses more typically used for smaller individuals was, ironically, protective. To directly assess whether this was the case, we measured vasopressin levels in patients randomly assigned to receive this drug in the protocolized non-body weight-adjusted dose used in the VASST. We found that, compared with those with a BMI of less than 25 kg/m2, obese and overweight patients had a trend toward lower serum vasopressin concentrations after 24 hours of vasopressin infusion. The net accumulated fluid balance differs by only 1 L between patients of normal weight and obese patients. It could be argued that this small difference is unlikely to account for the observed outcome differences. However, indexed to body mass, this amounts to a difference of 80 mL/kg, a remarkable difference that conceivably could be related to outcomes. In addition, although there was a statistically significant difference in CVP values between the three patient groups, which was possibly due to differences in chest wall compliance in the obese compared with the normal-BMI patients, the clinical significance of this small difference is uncertain. 041b061a72

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