Process, resource and success factors associated with chimeric antigen receptor T-cell therapy for multiple myeloma.

Background: Chimeric antigen receptor T-cell (CAR-T) therapy represents a new frontier in multiple myeloma. It is important to understand critical success factors (CSFs) that may optimize its use in this therapeutic area. Methods: We estimated the CAR-T process using time-driven activity-based costing. Information was obtained through interviews at four US oncology centers and with payer representatives, and through publicly available data. Results: The CAR-T process comprises 13 steps which take 177 days; it was estimated to include 46 professionals and ten care settings. CSFs included proactive collaboration, streamlined reimbursement and CAR-T administration in alternative settings when possible. Implementing CSFs may reduce episode time and costs by 14.4 and 13.2%, respectively. Conclusion: Our research provides a blueprint for improving efficiencies in CAR-T therapy, thereby increasing its sustainability for multiple myeloma.

Patients with multiple myeloma can now be treated with chimeric antigen receptor T-cell (CAR-T) therapy. We studied how CAR-T therapy is used for multiple myeloma. We also studied things that could help make this therapy easier for doctors to use. The CAR-T process takes 13 steps and 177 days. It begins with the choice to use the therapy and ends about 100 days after it is used. The process uses 46 different healthcare professionals and ten different locations. We found several possible changes that can improve this process. Of these changes, three stand out. First, improved teamwork between members of the care team can help them prepare for and resolve possible problems. Second, reducing insurance red tape will make it easier to provide CAR-T therapy to patients. Third, allowing use of CAR-T therapy in places other than hospitals can help more patients receive this therapy. If applied, these three things may lower the time needed to treat patients by 14.4% and may reduce costs by 13.2%.

Deployment of a Clinical Pathway to Improve Postcardiac Arrest Care: A Before-After Study.

OBJECTIVES: Postcardiac arrest care bundles following adult cardiac arrest are associated with improved survival to discharge. We aimed to evaluate whether a clinical pathway and computerized order entry were associated with improved pediatric postcardiac arrest care and discharge outcomes. DESIGN: Single-center retrospective before-after study. SETTING: Academic PICU. PATIENTS: Patients who suffered an in- or out-of-hospital cardiac arrest from January 2008 to December 2015 cared for in the PICU within 12 hours of sustained return of circulation. INTERVENTION: Deployment of a postcardiac arrest clinical pathway and computerized order entry system. MEASUREMENTS AND MAIN RESULTS: There were 380 patients included-163 in the pre-pathway period and 217 in the post-pathway period. Primary outcome was percent adherence to pathway clinical goals at 0-6 and 6-24 hours post-return of circulation and to diagnostics (continuous electroencephalogram monitoring, head CT for out-of-hospital cardiac arrests, echocardiogram). Secondary outcomes included survival to hospital discharge and survival with favorable neurologic outcome (Pediatric Cerebral Performance Category of 1-3 or no change from baseline). The pre-pathway and post-pathway groups differed in their baseline Pediatric Cerebral Performance Category scores and the following causes of arrest: airway obstruction, arrhythmias, and electrolyte abnormalities. Pathway adherence was not significantly different between the pre-pathway and post-pathway groups, with the exception of higher rates of continuous electroencephalogram monitoring (45% vs 64%; p < 0.001). There was no difference in survival to hospital discharge between the two groups (56% vs 67%; adjusted odds ratio, 1.68; 95% CI, 0.95-2.84; p = 0.05). Survival to discharge was higher in the post-pathway group for the in-hospital cardiac arrest cohort (55% vs 76%; adjusted odds ratio, 3.06; 95% CI, 1.44-6.51; p < 0.01). There was no difference in favorable neurologic outcome between all patients (adjusted odds ratio, 1.21; 95% CI, 0.72-2.04) or among survivors (adjusted odds ratio, 0.72; 95% CI, 0.27-1.43). CONCLUSIONS: After controlling for known potential confounders, the creation and deployment of a postcardiac arrest care pathway and computerized order entry set were not associated with improvement in pathway adherence or overall outcomes, but was associated with increased survival to hospital discharge for children with in-hospital cardiac arrests.

LKB1 inhibition of NF-κB in B cells prevents T follicular helper cell differentiation and germinal center formation.

T-cell-dependent antigenic stimulation drives the differentiation of B cells into antibody-secreting plasma cells and memory B cells, but how B cells regulate this process is unclear. We show that LKB1 expression in B cells maintains B-cell quiescence and prevents the premature formation of germinal centers (GCs). Lkb1-deficient B cells (BKO) undergo spontaneous B-cell activation and secretion of multiple inflammatory cytokines, which leads to splenomegaly caused by an unexpected expansion of T cells. Within this cytokine response, increased IL-6 production results from heightened activation of NF-κB, which is suppressed by active LKB1. Secreted IL-6 drives T-cell activation and IL-21 production, promoting T follicular helper (TFH ) cell differentiation and expansion to support a ~100-fold increase in steady-state GC B cells. Blockade of IL-6 secretion by BKO B cells inhibits IL-21 expression, a known inducer of TFH -cell differentiation and expansion. Together, these data reveal cell intrinsic and surprising cell extrinsic roles for LKB1 in B cells that control TFH -cell differentiation and GC formation, and place LKB1 as a central regulator of T-cell-dependent humoral immunity.

Implicit Bias in Pediatric Academic Medicine.

OBJECTIVE: Despite known benefits of diversity, certain racial/ethnic groups remain underrepresented in academic pediatrics. Little research exists regarding unconscious racial attitudes among pediatric faculty responsible for decisions on workforce recruitment and retention in academia. This study sought to describe levels of unconscious racial bias and perceived barriers to minority recruitment and retention among academic pediatric faculty leaders. METHODS: Authors measured unconscious racial bias in a sample of pediatric faculty attending diversity workshops conducted at local and national meetings in 2015. A paper version of the validated Implicit Association Test (IAT) measured unconscious racial bias. Subjects also reported perceptions about minority recruitment and retention. RESULTS: Of 68 eligible subjects approached, 58 (85%) consented and completed the survey with IAT. Of participants, 83% had leadership roles and 93% were involved in recruitment. Participants had slight pro-white/anti-black bias on the IAT (M = 0.28, SD = 0.49). There were similar IAT scores among participants in leadership roles (M = 0.33, SD = 0.47) and involved in recruitment (M = 0.28, SD = 0.43). Results did not differ when comparing participants in local workshops to the national workshop (n = 36, M = 0.29, SD = 0.40 and n = 22, M = 0.27, SD = 0.49 respectively; p = 0.88). Perceived barriers to minority recruitment and retention included lack of minority mentors, poor recruitment efforts, and lack of qualified candidates. CONCLUSIONS: Unconscious pro-white/anti-black racial bias was identified in this sample of academic pediatric faculty and leaders. Further research is needed to examine how unconscious bias impacts decisions in academic pediatric workforce recruitment. Addressing unconscious bias and perceived barriers to minority recruitment and retention represent opportunities to improve diversity efforts.

Nursing Considerations for Cytokine Release Syndrome in Relapsed/Refractory Multiple Myeloma: Experience with Teclistamab from the MajesTEC-1 Study.

OBJECTIVES: Cytokine release syndrome (CRS) is a systemic inflammatory response that is commonly observed as a class effect of T-cell-redirecting therapies. This article provides important practical guidance for nurses relating to the diagnosis, monitoring, and management of CRS in patients receiving teclistamab, based on experience from the MajesTEC-1 clinical trial and real-life nursing practice. METHODS: MajesTEC-1 is a phase 1/2 study of teclistamab in heavily pretreated patients with relapsed/refractory multiple myeloma. To mitigate the risk of high-grade CRS, patients were carefully monitored for early signs and symptoms of CRS (including fever, which must have fully resolved before teclistamab administration). RESULTS: A survey of nurses from several of the study sites provided additional real-life insights into nursing best practices for managing CRS from four academic institutions in three countries. CONCLUSIONS: In MajesTEC-1, 72% of patients treated with teclistamab experienced CRS, the majority of which was low grade. All cases resolved and none led to treatment discontinuation. Real-life supportive measures for CRS are generally aligned with those outlined in the study. IMPLICATIONS FOR NURSING PRACTICE: Because nurses are on the frontline of patient care, they play a crucial role in promptly recognizing the signs and symptoms of CRS and responding with timely and appropriate supportive treatment. This review provides important practical guidance for nurses on diagnosis, monitoring, and management of CRS in patients receiving teclistamab, based on experience from the MajesTEC-1 trial and real-life nursing practice.

Panel Interview of ONcology practices with Emergent Experience of teclistamab in the Real world: the TecPIONEER Study.

OBJECTIVE: To understand clinicians' current teclistamab step-up dosing (SUD) model and how they envision future administration models, as well as perceived barriers and facilitators to these models in day-to-day clinical practice. METHODS: Interviews of clinicians with RW experience administering teclistamab, with a subsequent roundtable discussion to discuss interview findings. Topics of interest included managing adverse events (AE), and handling logistics of SUD and transition of care (ToC). RESULTS: 20 clinicians representing 19 practices participated. Of 14 practices administering inpatient teclistamab SUD, 12 (86%) utilized a single admission. A day 1-3-5 dosing schedule with a 7-day length of stay was planned in 10/14 (71%). The remaining 5 practices employed outpatient or hybrid SUD. SUD models depended on cellular therapy experience, patient volume, and monitoring capabilities. Clinicians desired to administer SUD outpatient for convenience and reduced healthcare resource use. 11% of practices reported using tocilizumab for cytokine release syndrome (CRS) prophylaxis, whilst it was uniformly used to treat grade 2+ CRS. Corticosteroids were the preferred treatment for neurotoxicity. Infection prophylaxis with intravenous immunoglobulin was reported by 89% of practices. Patient- and institution-level factors affected decision-making of transitioning patients back to referring sites after SUD. CONCLUSION: The results consolidated practice-based experiences and indicated diverse RW SUD models and patient management strategies in practices with familiarity with teclistamab AE management and ToC protocols. Inpatient SUD is common, with expectations that approaches will evolve toward outpatient or community-based administration. Further research is needed to investigate outcomes of different care models and AE management strategies.

Multiple myeloma is a blood cancer that forms in plasma cells. Teclistamab is a new treatment for patients with multiple myeloma who have received prior treatment but for whom their multiple myeloma has come back or stopped responding to treatment multiple times. Because teclistamab works differently than other existing multiple myeloma treatments, there is a need to understand how oncologists who have experience with teclistamab are managing their patients in order to inform best practices for use by more healthcare providers. We interviewed oncologists that treat patients with multiple myeloma to understand their experiences with teclistamab, including how they manage initial dosing (step-up dosing) processes, treat adverse events, and transition patients to outpatient or external clinics for continued care. Most practices were administering step-up dosing of teclistamab in an inpatient setting soon after teclistamab became a treatment option, with a high level of desire to move the initial dosing to an outpatient setting in the near future. Those that were already administering step-up dosing in an outpatient setting had models unique to their practice. Oncologists described numerous processes for monitoring and managing adverse events of the treatment, including treating patients with preventative medications and regularly monitoring vital signs throughout step-up dosing. Oncologists expected that their teclistamab administration processes will likely evolve over time as they gain more familiarity with the treatment, and will need to consider patient-level factors to administer step-up dosing in an outpatient setting.

Host-derived adiponectin is tumor-suppressive and a novel therapeutic target for multiple myeloma and the associated bone disease.

The contributions of the host microenvironment to the pathogenesis of multiple myeloma, including progression from the non-malignant disorder monoclonal gammopathy of undetermined significance, are poorly understood. In the present study, microarray analysis of a murine model requiring a unique host microenvironment for myeloma development identified decreased host-derived adiponectin compared with normal mice. In support, clinical analysis revealed decreased serum adiponectin concentrations in monoclonal gammopathy of undetermined significance patients who subsequently progressed to myeloma. We investigated the role of adiponectin in myeloma pathogenesis and as a treatment approach, using both mice deficient in adiponectin and pharmacologic enhancement of circulating adiponectin. Increased tumor burden and bone disease were observed in myeloma-bearing adiponectin-deficient mice, and adiponectin was found to induce myeloma cell apoptosis. The apolipoprotein peptide mimetic L-4F was used for pharmacologic enhancement of adiponectin. L-4F reduced tumor burden, increased survival of myeloma-bearing mice, and prevented myeloma bone disease. Collectively, our studies have identified a novel mechanism whereby decreased host-derived adiponectin promotes myeloma tumor growth and osteolysis. Furthermore, we have established the potential therapeutic benefit of increasing adiponectin for the treatment of myeloma and the associated bone disease.

Chimeric Antigen Receptor T-Cell Therapies: Barriers and Solutions to Access.

Chimeric antigen receptor T-cell (CAR-T) therapies are relatively new treatments for patients with heavily pretreated hematologic malignancies. Although these innovative therapies can offer substantial benefit to patients with limited alternative treatment options, patient-access barriers exist. Conventional clinical trials are time-consuming and may be limited by strict patient eligibility criteria, resources, and availability of enrollment slots. Because of the complexity of the CAR-T administration process, treatment delivery can be associated with additional burden for the patient, including requiring patients to reside close to treatment centers and remain with a caregiver after infusion. Manufacturing of CAR-T cells is completed in specialized facilities and depends on the availability of reagents, manufacturing workforce, and timely transportation. CAR-T therapy is costly, and many US health plans restrict coverage of cell and gene therapies. Several of the existing challenges because of these barriers have been exacerbated during the COVID-19 pandemic. This review discusses these barriers and proposes some potential solutions to improving patient access, including innovation in clinical trial design and manufacturing, location of treatment delivery, and key stakeholder opinions regarding treatment and reimbursement. We propose a call to action for key stakeholder groups to address these barriers to CAR-T therapy to expand treatment access for patients. Future collaboration between key stakeholders, including payers, regulatory agencies, and industry/academia, will be critical to continue to address these barriers and enhance patient access to these therapies.

A Blueprint for Increasing Ethnic and Racial Diversity in U.S. Residency Training Programs.

PROBLEM: People who identify as African Americans, Latinos, or from indigenous backgrounds, are dramatically underrepresented in the U.S. physician workforce. It is critical for academic health centers to recognize racial and ethnic diversity at the residency level and implement changes to enhance diversity among trainees. APPROACH: The Office of Graduate Medical Education (GME) at the University of Pennsylvania Health System (UPHS) developed a multipronged approach to enhance diversity and inclusion (D&I) among residency trainees. The approach included the development of an underrepresented in medicine (UIM) professional network; UIM-focused visiting clerkship programs; holistic review implementation by selection committees; and targeted outreach to UIM candidates, overseen by an associate designated institutional official for UIM Affairs. The authors reported demographic data on residency applicants invited for interviews and matching for all programs at UPHS from 2014-2015 (baseline) to 2020-2021. They also reported data on maximum ranking number programs reached to fill their positions and the average United States Medical License Examination (USMLE) Step 1 scores of matched candidates. Finally, they discussed the implications for leaders who wish to enhance D&I at academic health centers. OUTCOMES: During the baseline year (2014-2015), UIMs represented 12.1% of interviewees and 8.7% of all matched candidates into UPHS residency programs. Over the successive 6 years after incremental implementation of the approach, UIM representation steadily increased. In 2020-2021, UIMs represented 23.2% of interviewees and 26.4% of matched candidates. Programs' maximum rank number to fill and USMLE Step 1 scores of matched candidates remained relatively unchanged. NEXT STEPS: The UPHS Office of GME incorporated a purposeful approach to enhance the D&I of its residents. Across 6 years of implementation, UIM representation among resident matches tripled while quantitative program and candidate metrics remained unchanged. Similar efforts should be given further consideration for implementation and evaluation nationwide.

Hospital outcomes for children with severe sepsis in the USA by race or ethnicity and insurance status: a population-based, retrospective cohort study.

BACKGROUND: Disparities in outcomes of adult sepsis are well described by insurance status and race and ethnicity. There is a paucity of data looking at disparities in sepsis outcomes in children. We aimed to determine whether hospital outcomes in childhood severe sepsis were influenced by race or ethnicity and insurance status, a proxy for socioeconomic position. METHODS: This population-based, retrospective cohort study used data from the 2016 database release from the Healthcare Cost and Utilization Project Kids' Inpatient Database (KID). The 2016 KID included 3 117 413 discharges, accounting for 80% of national paediatric discharges from 4200 US hospitals across 47 states. Using multilevel logistic regression, clustered by hospital, we tested the association between race or ethnicity and insurance status and hospital mortality, adjusting for individual-level and hospital-level characteristics, in children with severe sepsis. The secondary outcome of length of hospital stay was examined through multilevel time to event (hospital discharge) regression, with death as a competing risk. FINDINGS: 12 297 children (aged 0-21 years) with severe sepsis with or without shock were admitted to 1253 hospitals in the 2016 KID dataset. 1265 (10·3%) of 12 297 patients did not have race or ethnicity data recorded, 15 (0·1%) were missing data on insurance, and 1324 (10·8%) were transferred out of hospital, resulting in a final cohort of 9816 children. Black children had higher odds of death than did White children (adjusted odds ratio [OR] 1·19, 95 % CI 1·02-1·38; p=0·028), driven by higher Black mortality in the south (1·30, 1·04-1·62; p=0·019) and west (1·58, 1·05-2·38; p=0·027) of the USA. We found evidence of longer hospital stays for Hispanic children (adjusted hazard ratio 0·94, 95% CI 0·88-1·00; p=0·049) and Black children (0·88, 0·82-0·94; p=0·0002), particularly Black neonates (0·53, 95% CI 0·36-0·77; p=0·0011). We observed no difference in survival between publicly and privately insured children; however, other insurance status (self-pay, no charge, and other) was associated with increased mortality (adjusted OR 1·30, 95% CI 1·04-1·61; p=0·021). INTERPRETATION: In this large, representative analysis of paediatric severe sepsis in the USA, we found evidence of outcome disparities by race or ethnicity and insurance status. Our findings suggest that there might be differential sepsis recognition, approaches to treatment, access to health-care services, and provider bias that contribute to poorer sepsis outcomes for racial and ethnic minority patients and those of lower socioeconomic position. Studies are warranted to investigate the mechanisms of poorer sepsis outcomes in Black and Hispanic children. FUNDING: None.

Racial, ethnic, and socioeconomic disparities in paediatric critical care in the USA.

In an era of tremendous medical advancements, it is important to characterise and address inequities in the provision of health care and in outcomes. There is a large body of evidence describing such disparities by race or ethnicity and socioeconomic position in critically ill adults; however, this important issue has received less attention in children and adolescents (aged ≤21 years). This Review presents a summary of the available evidence on disparities in outcomes in paediatric critical illness in the USA as a result of racism and socioeconomic privilege. The majority of evidence of racial and socioeconomic disparities in paediatric critical care originates from the USA and is retrospective, with only one prospective intervention-based study. Although there is mixed evidence of disparities by race or ethnicity and socioeconomic position in general paediatric intensive care unit admissions and outcomes in the USA, there are striking trends within some disease processes. Notably, there is evidence of disparities in management and outcomes for out-of-hospital cardiac arrest, asthma, severe trauma, sepsis, and oncology, and in families' perceptions of care. Furthermore, there is clear evidence that critical care research is limited by under-enrolment of participants from minority race or ethnicity groups. We advocate for rigorous research standards and increases in the recruitment and enrolment of a diverse range of participants in paediatric critical care research to better understand the disparities observed, including the effects of racism and poverty. A clearer understanding of when, where, and how such disparities affect patients will better enable the development of effective strategies to inform practice, interventions, and policy.

In Search of Workforce Diversity? A Program's Successful Approach.

SUMMARY: The persistence of health care disparities along racial and ethnic lines highlights the complex and multifactorial nature of this national concern. The paucity of physicians ethnically underrepresented in medicine to treat an ever-growing heterogeneous population inherently contributes to these ongoing disparities. The authors proposed an approach to improve the representation of physicians underrepresented in medicine in their plastic surgery residency program. With a renewed commitment to ethnic diversity and inclusion, a multifaceted recruitment and retention approach was implemented at the University of Pennsylvania plastic and reconstructive surgery residency program from 2015 to 2020 (5 academic years). A retrospective review of the demographics of the program's residents was then assessed over the past 9 academic years for comparison (2011 to 2020). The representation of underrepresented-in-medicine residents within the plastic and reconstructive surgery residency program steadily increased with the implementation of this multifaceted approach, reaching an unprecedented high. Currently, 29 percent of all residents are underrepresented in medicine and 29 percent are female, some of whom are also underrepresented in medicine. Although the female representation is on par with the national average, the underrepresented-in-medicine representation is far greater than the national average. As a result of this multifaceted approach, the representation of African American and Latino plastic surgery residents at the University of Pennsylvania now far exceeds current national averages. Unfortunately, the representation of Native American and Alaskan Natives is still lacking, despite the program's broadened recruitment efforts. The success of this experience describes a successful strategy that institutions can implement to enhance underrepresented-in-medicine representation among its plastic surgery trainees.

B-cell maturation antigen expression across hematologic cancers: a systematic literature review.

B-cell maturation antigen (BCMA) plays a critical role in regulating B-cell proliferation and survival. There is evidence for BCMA expression in various hematologic malignancies, suggesting that BCMA may play an important role as a biomarker or therapeutic target in these diseases. Given advances in understanding the role of BCMA in B-cell development and the promise of BCMA as a therapeutic target, a systematic review is needed to rigorously assess the evidence for BCMA expression and identify areas of consensus and future research. The objective of this review was to summarize the evidence on BCMA protein and mRNA expression across hematologic malignancies. Using a PubMed database search up to 28 August 2019, a systematic literature review of publications reporting BCMA expression in patients with hematologic malignancies was conducted. Data from published congress abstracts presented at the American Society of Clinical Oncology and the American Society of Hematology were also searched. Studies that assessed BCMA expression (protein or mRNA) in patients of any age with hematologic malignancies were included. A total of 21 studies met inclusion criteria and were included in the review. BCMA was expressed in several hematologic malignancies, including multiple myeloma (MM), chronic lymphocytic leukemia, acute B-lymphoblastic leukemia, non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma. BCMA was expressed at uniformly high levels across all 13 MM studies and at low to moderate levels in acute myeloid leukemia and acute lymphoblastic leukemia. These results suggest that BCMA is a relevant target in MM as well as in a subset of B-cell leukemia. BCMA expression in Hodgkin lymphoma and NHL varied across studies, and further research is needed to determine the utility of BCMA as an antibody target and biomarker in these diseases. Differences in sample type, timing of sample collection, and laboratory technique used may have affected the reporting of BCMA levels.

How to Train Your T Cells: Overcoming Immune Dysfunction in Multiple Myeloma.

The progression of multiple myeloma, a hematologic malignancy characterized by unregulated plasma cell growth, is associated with increasing innate and adaptive immune system dysfunction, notably in the T-cell repertoire. Although treatment advances in multiple myeloma have led to deeper and more durable clinical responses, the disease remains incurable for most patients. Therapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and activating the host immune system have recently shown promise in multiple myeloma, particularly in the relapsed and/or refractory disease setting. As the efficacy of T-cell-dependent immuno-oncology therapy is likely affected by the health of the endogenous T-cell repertoire, these therapies may also provide benefit in alternate treatment settings (e.g., precursor disease; after stem cell transplantation). This review describes T-cell-associated changes during the evolution of multiple myeloma and provides an overview of T-cell-dependent immuno-oncology approaches under investigation. Vaccine and checkpoint inhibitor interventions are being explored across the multiple myeloma disease continuum; treatment modalities that redirect patient T cells to elicit an anti-multiple myeloma response, namely, chimeric antigen receptor (CAR) T cells and bispecific antibodies [including BiTE (bispecific T-cell engager) molecules], have been primarily evaluated to date in the relapsed and/or refractory disease setting. CAR T cells and bispecific antibodies/antibody constructs directed against B-cell maturation antigen have generated excitement, with clinical data demonstrating deep responses. An increased understanding of the complex interplay between the immune system and multiple myeloma throughout the disease course will aid in maximizing the potential for T-cell-dependent immuno-oncology strategies in multiple myeloma.

Myeloma cells exhibit an increase in proteasome activity and an enhanced response to proteasome inhibition in the bone marrow microenvironment in vivo.

The proteasome inhibitor bortezomib has a striking clinical benefit in patients with multiple myeloma. It is unknown whether the bone marrow microenvironment directly contributes to the dramatic response of myeloma cells to proteasome inhibition in vivo. We have used the well-characterized 5TGM1 murine model of myeloma to investigate myeloma growth within bone and response to the proteasome inhibitor bortezomib in vivo. Myeloma cells freshly isolated from the bone marrow of myeloma-bearing mice were found to have an increase in proteasome activity and an enhanced response to in vitro proteasome inhibition, as compared with pre-inoculation myeloma cells. Treatment of myeloma-bearing mice with bortezomib resulted in a greater reduction in tumor burden when the myeloma cells were located within the bone marrow when compared with extra-osseous sites. Our results demonstrate that myeloma cells exhibit an increase in proteasome activity and an enhanced response to bortezomib treatment when located within the bone marrow microenvironment in vivo.

Measuring intra-abdominal pressure outside the ICU: validation of a simple bedside method.

Intra-abdominal pressure measurement is essential to the diagnosis of patients with intraabdominal hypertension or abdominal compartment syndrome. The most common method for measuring intra-abdominal pressure (IAP) is the intravesicular or "bladder" technique, which requires electronic monitoring technology not available on the typical surgical ward. Herein we describe and validate a simple, rapid screening method for bedside IAP measurement using the patient's indwelling urinary catheter and a readily available intravenous tubing extension. Validation of this technique across the clinically important IAP diagnostic spectrum demonstrated acceptable bias (1.6 mm Hg; 95% confidence interval 1.4-1.8) with limits of agreement of 0.36 to 2.8. This demonstrates good agreement between the two IAP methods and validates the bedside technique as a simple, cost-effective, and reproducible method for screening IAP measurements outside of the critical care setting.

Subcutaneous linea alba fasciotomy: a less morbid treatment for abdominal compartment syndrome.

Abdominal compartment syndrome is a cause of significant morbidity and mortality among surgical patients. It has traditionally been treated by abdominal decompression with the associated risks of chronic incisional hernia and enteroatmospheric fistula. Subcutaneous linea alba fasciotomy has recently been described as a new surgical technique for the treatment of abdominal compartment syndrome secondary to acute pancreatitis. This technique reduces intraabdominal pressure and restores organ function while maintaining the skin and peritoneum intact for visceral protection. We describe the application of subcutaneous linea alba fasciotomy as a safe and effective alternative for the surgical management of abdominal compartment syndrome in a traumatically injured patient refractory to comprehensive medical interventions.

Adult immunisation: A key element of public health programs: Synopsis of Asia Pacific Adult Immunisation Meeting, Tokyo, 1-2 December 2016.

OBJECTIVES: To (i) improve scientific knowledge and understanding of the importance of adult vaccination within a public health framework; (ii) share an understanding of the principles of good practice that have improved adult vaccination uptake rates; (iii) appreciate the diverse nature of country-specific barriers; and (iv) reach consensus on principles of a call to action to increase adult vaccination uptake rates. METHODS: Non-governmental organisations, the International Federation on Ageing and Friends of International Federation on Ageing Japan, convened the Asia Pacific Adult Immunisation Meeting, herein referred to as the 'Asia Pacific Meeting'. RESULTS: Delegates identified fundamental barriers to adult vaccination similar to those reported at previous meetings in Latin America and Europe and formed a road map to respond to key barriers in countries represented at the Asia Pacific Meeting. CONCLUSION: Older people are uniquely vulnerable to vaccine-preventable diseases and therefore need to be the target of a series of actions intended to improve uptake rates in this subpopulation.

Pharmacologic and genetic manipulation of MMP-2 and -9 affects retinal neovascularization in rodent models of OIR.

PURPOSE: The efficacy of three matrix metalloproteinase (MMP) inhibitors with various selectivities (Ro-31-9790, AG3340, and DPC-A37668) was investigated in a rat model of retinopathy of prematurity, to examine the roles of MMP-2 and -9 in retinal neovascularization. The susceptibilities of MMP-2(-/-) and -9(-/-) mice to preretinal neovascularization were investigated in a mouse model of oxygen-induced retinopathy. METHODS: Sprague-Dawley newborn rats were exposed to alternating episodes of 50% and 10% oxygen (variable oxygen exposure) to induce retinal neovascularization. Three MMP inhibitors with various selectivity profiles were administered to variable oxygen-exposed rats via local or systemic routes. Antineovascular efficacy was determined in drug-treated versus vehicle-treated rat pups by computerized imaging of adenosine diphosphatase (ADPase)-stained retinal flatmounts. Wild-type C57BL/6J and isogenic MMP-2(-/-) and -9(-/-) mice were exposed to 75% oxygen followed by normoxia. The mice were killed immediately before or after the normoxic exposure, and eyes were either harvested for retinal dissection and flatmounting or were paraffin embedded and sectioned. Retinal vascular area and retinal neovascularization were assessed by adenosine diphosphatase staining of retinal flatmounts and by counting preretinal nuclei of hematoxylin and eosin-stained retinal sections, respectively. RESULTS: Ro-31-9790, AG3340, and DPC-A37668 had no effect on normal development of the rat retinal vasculature, regardless of dose or route of administration. Intravitreal injection of Ro-31-9790 (broad-spectrum) immediately after variable-oxygen exposure and 2 days after exposure resulted in 78% and 82% inhibition of retinal neovascularization, respectively. AG3340 (MMP-2- and -9-selective inhibitor) and DPC-A37668 (MMP-2-selective inhibitor) resulted in 65% and 52% inhibition, respectively, when administered by intravitreal injection immediately after variable-oxygen exposure. Intraperitoneal injection of 5, 15, and 50 mg/mL AG3340 or DPC-A37668 for 6 days after variable oxygen exposure resulted in 22% to 39% and 0% to 31% inhibition of neovascularization, respectively. AG3340 and DPC-A37668 administered by oral gavage at doses of 3, 10, or 30 mg/mL provided up to 42% and 86% inhibition of neovascularization, respectively. The average vascular areas of retinas from MMP-2(-/-) or -9(-/-) mice at postnatal day 12 were not significantly different from the wild-type control. There was a 75% (P < 0.001) and 44% (P < 0.01) reduction in preretinal neovascularization in oxygen-exposed MMP-2(-/-) and -9(-/-) mice at postnatal day 19, respectively, compared with wild-type control mice. CONCLUSIONS: The results of this study suggest that MMP-2 plays a predominant role in retinal angiogenesis in both the mouse and rat models of oxygen-induced retinopathy. Furthermore, MMP-2 inhibition may be a viable therapeutic approach for ocular diseases characterized by retinal neovascularization.