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ABSTRACTGiven the colossal interest in creating ‘coaching cultures’, we update the 2014 literature review by Gormley and van Nieuwerburgh and extend this work by applying a Systematic Literature Review (SLR) methodology. In doing so, we detangle definitions and the conditions under which ‘coaching cultures’ can be developed. We also explore contemporary interventions, report on organisational level outcomes, and comment on how progress is measured and evaluated. In total, 1453 papers were identified using a systematic search, of which 42 met our initial screening criteria and nine were eligible for inclusion in our final review. Findings show that we remain with an unclear understanding of ‘coaching culture’; there is still no agreed definition and the building blocks (i.e., the foundational elements, interventions, outcomes, and measures) remain ambiguous. We recommend a framework for future research and practice and highlight a gap in our understanding of stakeholders’ behavioural and cultural patterns vis-à-vis the design and development of coaching culture programmes.

Background/AimsFor integrated care to truly become embedded in the UK health and social care system, there is need for a shared understanding of what integrated care looks like at the local level. This study aimed to identify the competencies and behaviours required for working across the full range of health and social care services in the Bedfordshire, Luton and Milton Keynes Integrated Care System.MethodsA multi-method approach was used to develop and refine the competency framework. An extensive evidence review of academic and practitioner literature was used to create the initial framework by synthesising previous frameworks. Four multi-agency focus groups were held to conduct utility testing and refine the framework. Quantitative testing was carried out using an 89-item online survey, including questions on the framework, a range of personal and work-related outcomes, and demographic characteristics. The survey was distributed to staff working across 13 different agencies within the integrated care system. Associations between variables were assessed using Spearman's Rho, using the Statistical Package for the Social Sciences.ResultsThe evidence review identified 21 relevant competency frameworks, originating from nine different countries, which were used to create the integrated care competency framework. A total of 91 staff members completed the survey, with results showing acceptable reliability and validity of the final framework (item total correlation >0.2; inter-item correlation ≤0.9). Differences were found between agencies and occupational groups in terms of their integrated care competencies. Those with shorter tenure described greater use of integrated care competencies. Those who demonstrated more integrated care competencies also saw their work as more meaningful and enjoyed greater levels of support from their peers.ConclusionsThis is the first UK framework of integrated care competencies to be subjected to empirical testing. Initial testing supports the validity and reliability of the framework, as well as showing the positive outcomes associated with integrated working. This framework could be developed and rolled out on a wider scale to support integrated care working.

Exercise and physical activity can improve bone strength and the risk of falls, which may offer benefits in the prevention and management of osteoporosis. However, uncertainty about the types of exercise that are safe and effective instigates lack of confidence in people with osteoporosis and health professionals. Existing guidelines leave some questions unresolved. This consensus statement aimed to determine the physical activity and exercise needed to optimise bone strength, reduce fall and fracture risk, improve posture and manage vertebral fracture symptoms, while minimising potential risks in people with osteoporosis. The scope of this statement was developed following stakeholder consultation. Meta-analyses were reviewed and where evidence was lacking, individual studies or expert opinion were used to develop recommendations. A multidisciplinary expert group reviewed evidence to make recommendations, by consensus when evidence was not available. Key recommendations are that people with osteoporosis should undertake (1) resistance and impact exercise to maximise bone strength; (2) activities to improve strength and balance to reduce falls; (3) spinal extension exercise to improve posture and potentially reduce risk of falls and vertebral fractures. For safety, we recommend avoiding postures involving a high degree of spinal flexion during exercise or daily life. People with vertebral fracture or multiple low trauma fractures should usually exercise only up to an impact equivalent to brisk walking. Those at risk of falls should start with targeted strength and balance training. Vertebral fracture symptoms may benefit from exercise to reduce pain, improve mobility and quality of life, ideally with specialist advice to encourage return to normal activities. Everyone with osteoporosis may benefit from guidance on adapting postures and movements. There is little evidence that physical activity is associated with significant harm, and the benefits, in general, outweigh the risks.

A 41-year-old never-smoking female was diagnosed with epidermal growth factor receptor (EGFR)-mutated T2bN3M1b lung adenocarcinoma with axillary lymph nodes. She complained of blurred vision in the left eye (2/60) and was subsequently found to have a left choroidal metastasis. Treatment with tyrosine kinase inhibitor (TKI) erlotinib was started, and after 1 year of disease stability, she developed unsteadiness and worsening visual disturbance (1/60). Brain imaging showed 24 new brain metastases, which were treated with Gamma Knife stereotactic radiosurgery. An enlarging axillary lymph node was biopsied, which identified the T790M mutation, and she commenced the novel TKI osimertinib. Three weeks later, her choroidal lesion had regressed from 3.1 mm to 2.2 mm, and after 2 months of osimertinib, her visual acuity had improved to 6/9. At the last follow-up 8 months after initiation of osimertinib, her choroidal metastasis remains stable, and visual acuity has improved to 6/6. Evidence suggests that osimertinib’s efficacy in treating cerebral metastases is superior to that of chemotherapy and other EGFR-TKIs (gefitinib and erlotinib); however, the literature is sparse with regards to the use of osimertinib for the treatment of intraocular disease. In this case, the need for intense daily radiation treatment with its associated toxicities was negated, and as such we propose that osimertinib may be a promising treatment for choroidal metastasis secondary to EGFR-mutated lung adenocarcinoma.

This is a retrospective chart review of 20 patients treated with a consensus-driven treatment algorithm in multisystem inflammatory syndrome in children patients across a wide clinical spectrum. Their treatments and clinical status are described as well as their favorable return to functional baseline by 30 days post presentation.

Background Enhanced recovery after surgery (ERAS) protocols are widely utilized for elective colorectal surgery to improve outcomes and decrease costs, but few studies have evaluated the impact of ERAS protocols on cost with respect to anatomic site of resection. This study evaluated the impact of ERAS protocol on elective colon resections by site and longitudinal impact over time.Methods A single-center retrospective cohort study of 598 consecutive patients undergoing elective colorectal resection before and after implementation of ERAS protocol from 2013 to 2017 was performed. The primary outcomes were length of stay (LOS) and cost. Comparative and multivariate inferential statistics were used to assess additional outcomes.Results A total of 598 patients (100 pre-ERAS vs 498 post-ERAS) were evaluated with an overall median LOS of 4 days for right and left colectomies and 3 days for transverse colectomies. When comparing type of resection before and after ERAS protocol introduction, an increased LOS for left hemicolectomies from 3.09 to 4.03 days (P= .047) was noted, with all other comparisons failing to reach statistical significance. Over time, an initial decrease in LOS for MIS approach after protocol introduction was observed; however, this effect diminished in the ensuing years and had no significant effect overall. Total cost of care was significantly increased post-ERAS for all cohorts except transverse colectomies. No further statistically significant differences were found.Conclusion After an initial improvement in outcomes, continued utilization of ERAS protocols demonstrated no improvement in LOS compared to pre-ERAS data and increased cost overall for patients regardless of site of resection.

Introduction: The development of chronic groin pain after inguinal hernia repair is a complex problem with many potential factors contributing to its development. Surgical options for alleviation of symptoms are limited and only performed by a few centers dedicated to its treatment. Opportunities to apply the principles of a prehabilitation program, including Cognitive Behavioral Therapy (CBT), aim to improve the surgical outcomes for this condition. Methods and procedures: A multi-disciplinary hernia team has implemented a clinical quality improvement (CQI) effort in an attempt to better measure and improve outcomes for patients suffering with chronic groin pain after inguinal hernia repair. Between April 2011 and August 2018, 129 patients (157 groins) underwent surgical treatment for chronic groin pain after inguinal hernia repair. Data were collected to compare outcomes for those undergoing preoperative CBT and patients who did not have CBT prior to their operation. Results: Of 129 total patients, baseline demographics were similar in terms of gender, age, and BMI. In total, 27 patients (32 groins) underwent prehabilitation with CBT (20.93%). We found none of the patients who underwent preoperative CBT had new postoperative pain and all patient procedures were able to be performed on an outpatient basis. Overall, 15 (14.7%) patients had no improvement in symptoms after surgery from the non-CBT group, whereas there was improvement in chronic pain for all patients who underwent CBT. Conclusion: This attempt at process improvement demonstrated beneficial effects for patients who had CBT as part of a prehabilitation program prior to a surgical procedure to attempt to relieve groin pain after inguinal hernia repair. As with any CQI analysis, other factors may have contributed to these outcomes and these results may be different in another local environment.

Postoperative pain managed with opioids has contributed to the opioid crisis through over-prescribing practices. We assessed opioid-prescribing habits and their use by patients undergoing surgery for cutaneous malignancies. An Institutional Review Board–approved retrospective analysis was conducted for patients who underwent skin cancer resection between January 2018 and June 2018. Data were collected from the electronic medical record, and opioid-related data were collected from patient interviews and state registries. There were 120 study participants (42 females and 78 males) with a median age of 67 years (range, 21–94 years). All received preincision local anesthetic: 64 had liposomal bupivacaine (LB) (53%) and 56 had non-LB bupivacaine (47%). Most participants (n = 88) used 0 opioids (73%), including 43 LB-anesthetic (67%) and 45 non–LB-anesthetic (80%). No significance was seen between those with a diagnosis of chronic pain, narcotic tolerance, an area of resection, and nodal sampling groups in opioid use. Four patients (3%) requested a refill. Of 105 prescriptions written for opioids, 99 had leftover opioids for an over-prescribing rate of 94 per cent. This study suggests pain after skin cancer surgery is manageable with very limited opioid requirements. Our results support prescribing no more than five opioid tablets for postoperative pain control in patients undergoing resection for skin malignancies.

Skin substitutes have shown success in complex wound reconstruction. We evaluate the use of a human acellular dermal matrix (ADM) as a viable alternative to autologous skin grafting for defects secondary to skin cancer excision. An institutional review board–approved, retrospective review of ADM-reconstructed defects secondary to skin cancer excision between 2012 and 2018 was conducted. ADM was indicated in patients with preclusive factors for general anesthesia, protracted procedure time, reluctance for additional donor site wound, and personal choice. We reviewed defect characteristics, healing time, postoperative outcomes, and patient demographics. The 228 participants (151 males, 77 females) had a median age of 72 years (range, 29–95 years), with melanoma diagnosed in 113 (49.6%), squamous cell carcinoma in 61 (26.8%), and basal cell carcinoma in 28 (12.2%) patients. The median interval to complete epidermal coverage was 42 days, with graft failure evident in six patients (2.6%). ADM is a viable, low-morbid alternative for reconstruction of defects secondary to skin cancer excision, with no donor site morbidity. With exception to complete healing time, outcomes are similar to those of autologous grafting.

There is growing interest in the role of psychological flexibility as a potential resilience factor in workplace settings for protecting employees against the risk of job burnout. This field study contributes to the literature by investigating the utility of delivering brief ACT-informed training to the entire regional workforce of an innovation and manufacturing organization. A total of 504 employees attended the training, 281 of whom completed study measures prior to the training and three months later. Across the 3-month timeframe, participants reported a statistically small and significant increase in work-related psychological flexibility. Increased psychological flexibility was associated with improved stress resilience, reduced exhaustion, and increased personal accomplishment. No change was observed on the depersonalization component of burnout or task performance. Moderation analyses revealed that residual change associations between work-related psychological flexibility and both exhaustion and resilience were stronger among participants with higher baseline exhaustion. By contrast, work-related psychological flexibility trended toward a stronger residual change relationship with personal accomplishment among participants with lower baseline exhaustion. We interpret these findings from the perspective of resource-based theories of workplace functioning, and highlight the potential of cultivating psychological flexibility as part of organization-wide personnel development initiatives.

Persistent human papillomavirus (HPV) infection is necessary but insufficient for viral oncogenesis. Additional contributing co-factors, such as immune evasion and viral integration have been implicated in HPV-induced cancer progression. It is widely accepted that HPV + keratinocytes require co-culture with fibroblasts to maintain viral DNA as episomes. How fibroblasts regulate viral episome maintenance is a critical knowledge gap. Here we present comprehensive RNA sequencing and proteomic analysis demonstrating that coculture with fibroblasts is supportive of the viral life cycle, and is confirmatory of previous observations. Novel observations suggest that errors in “cross-talk” between fibroblasts and infected keratinocytes may regulate HPV integration and drive oncogenic progression. Our co-culture models offer new insights into HPV-related transformation mechanisms.

End-of-life care refers to the care of patients with progressive, incurable conditions and considered to be in the last year of life. Approximately 75% of end-of-life patients will die from non-malignant conditions. There are significant challenges, both in the identification of patients with chronic disease who are nearing the end of life and in the provision of high-quality palliative care in this group. This article explores the role of GPs in the management of end-of-life care in the most common non-malignant conditions, including management of symptoms and advance care planning.

Purpose:Detection of copy-number variation (CNV) is important for investigating many genetic disorders. Testing a large clinical cohort by array comparative genomic hybridization provides a deep perspective on the spectrum of pathogenic CNV. In this context, we describe a bioinformatics approach to extract CNV information from whole-exome sequencing and demonstrate its utility in clinical testing.Methods:Exon-focused arrays and whole-genome chromosomal microarray analysis were used to test 14,228 and 14,000 individuals, respectively. Based on these results, we developed an algorithm to detect deletions/duplications in whole-exome sequencing data and a novel whole-exome array.Results:In the exon array cohort, we observed a positive detection rate of 2.4% (25 duplications, 318 deletions), of which 39% involved one or two exons. Chromosomal microarray analysis identified 3,345 CNVs affecting single genes (18%). We demonstrate that our whole-exome sequencing algorithm resolves CNVs of three or more exons.Conclusion:These results demonstrate the clinical utility of single-exon resolution in CNV assays. Our whole-exome sequencing algorithm approaches this resolution but is complemented by a whole-exome array to unambiguously identify intragenic CNVs and single-exon changes. These data illustrate the next advancements in CNV analysis through whole-exome sequencing and whole-exome array.Genet Med 17 8, 623–629.

Purpose:Mendelian disorders are most commonly caused by mutations identifiable by DNA sequencing. Exonic deletions and duplications can go undetected by sequencing, and their frequency in most Mendelian disorders is unknown.Methods:We designed an array comparative genomic hybridization (CGH) test with probes in exonic regions of 589 genes. Targeted testing was performed for 219 genes in 3,018 patients. We demonstrate for the first time the utility of exon-level array CGH in a large clinical cohort by testing for 136 autosomal dominant, 53 autosomal recessive, and 30 X-linked disorders.Results:Overall, 98 deletions and two duplications were identified in 53 genes, corresponding to a detection rate of 3.3%. Approximately 40% of positive findings were deletions of only one or two exons. A high frequency of deletions was observed for several autosomal dominant disorders, with a detection rate of 2.9%. For autosomal recessive disorders, array CGH was usually performed after a single mutation was identified by sequencing. Among 138 individuals tested for recessive disorders, 10.1% had intragenic deletions. For X-linked disorders, 3.5% of 313 patients carried a deletion or duplication.Conclusion:Our results demonstrate that exon-level array CGH provides a robust option for intragenic copy number analysis and should routinely supplement sequence analysis for Mendelian disorders.Genet Med 2012:14(6):594–603

Mendelian disorders are most commonly caused by mutations identifiable by DNA sequencing. Exonic deletions and duplications can go undetected by sequencing, and their frequency in most Mendelian disorders is unknown.

Methods for the rapid identification of defined cell growth conditions are lacking. This deficiency is a major barrier to the investigation and application of human embryonic stem (ES) cells. To address this problem, we developed a method for generating arrays of self-assembled monolayers (SAMs) in which each element constitutes a defined surface. By screening surface arrays, we identified peptidic surfaces that support ES cell growth and self-renewal. The ability of the active surface array elements to support ES cell growth depends on their composition: both the density of the peptide presented and its sequence are critical. These findings support a role for specific surface–cell interactions. Moreover, the data from the surface arrays are portable. They can be used to design an effective 3D synthetic scaffold that supports the growth of undifferentiated human ES cells. Our results demonstrate that synthetic substrates for promoting and probing human ES cell self-renewal can be discovered through SAM surface arrays.

The human/sheep xenograft model has proven valuable in assessing the in vivo hematopoietic activity of stem cells from a variety of fetal and postnatal human sources. CD34+/lineage-or CD34+/CD38-cells isolated from human embryonic stem cells (hESCs) differentiated on S17 feeder layer were transplanted by intraperitoneal injections into fetal sheep. Chimerism in primary transplants was established with polymerase chain reaction (PCR) and flow cytometry of bone marrow and peripheral blood samples. Whole bone marrow cells harvested from a primary recipient were transplanted into a secondary recipient. Chimerism was established as described before. This animal was stimulated with human GM-CSF, and an increase in human hematopoietic activity was noted by flow cytometry. Bone marrow aspirations cultured in methylcellulose generated colonies identified by PCR to be of human origin. We therefore conclude that hESCs are capable of generating hematopoietic cells that engraft primary recipients. These cells also fulfill the criteria for long-term engrafting hematopoietic stem cells as demonstrated by engraftment and differentiation in the secondary recipient.

The human/sheep xenograft model has proven valuable in assessing the in vivo hematopoietic activity of stem cells from a variety of fetal and postnatal human sources. CD34+/lineage- or CD34+/CD38- cells isolated from human embryonic stem cells (hESCs) differentiated on S17 feeder layer were transplanted by intraperitoneal injections into fetal sheep. Chimerism in primary transplants was established with polymerase chain reaction (PCR) and flow cytometry of bone marrow and peripheral blood samples. Whole bone marrow cells harvested from a primary recipient were transplanted into a secondary recipient. Chimerism was established as described before. This animal was stimulated with human GM-CSF, and an increase in human hematopoietic activity was noted by flow cytometry. Bone marrow aspirations cultured in methylcellulose generated colonies identified by PCR to be of human origin. We therefore conclude that hESCs are capable of generating hematopoietic cells that engraft primary recipients. These cells also fulfill the criteria for long-term engrafting hematopoietic stem cells as demonstrated by engraftment and differentiation in the secondary recipient.

mproving the efficacy and availability of therapies for HIV is arguably the greatest medical problem of the 21st century. HIV-1 and cancer often occur together, and cancer remains a common cause of morbidity and mortality in the 60 million individuals infected with the retrovirus. In particular, there is a marked increase in risk of Kaposi's sarcoma and non-Hodgkin's lymphoma with HIV-1 infection. Other cancers are also significantly more common in the context of immunosuppression. Data demonstrate that the principles behind the management of AIDS-associated cancers include treatment of both HIV infection and the cancer itself. Therapy for AIDS-defining tumors involves antiretroviral therapy to suppress HIV viremia and to maintain CD4 cell counts, followed by chemotherapy. Cytotoxic treatment is complicated, however, by underlying immunoparesis, and options are often limited. Despite these difficulties, outcomes are improving, and an increased appreciation of the biological mechanisms underlying viral tumorigenesis will hopefully delineate new treatments.

We have used rhesus monkey embryonic stem (ES) cells to study endothelial cell development. Rhesus ES cells (R366.4 cell line) exposed to medium containing vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF), and epidermal growth factor (EGF) assumed a relatively uniform endothelial cell morphology and could be propagated and expanded with a consistent phenotype and normal karyotype. When placed in Matrigel, these rhesus ES cell–derived endothelial cells (RESDECs) formed capillary-like structures characteristic of endothelial cells. Immunohistochemical and flow cytometric analysis of RESDECs showed that they take up acetylated low-density lipoprotein (LDL), express CD146, von Willebrand factor, and the integrin αvβ3, and bind the lectin ulex europaeus agglutinin-1. These cells also express the VEGF receptor Flk-1 and secrete VEGF. When introduced in a Matrigel plug implanted subcutaneously in mice, RESDECs formed intact vessels and recruited new endothelial cell growth. In vivo function was demonstrated by coinjection of RESDECs with murine tumor cells subcutaneously into immunocompromised adult mice. RESDECs injected alone did not form measurable tumors. Tumor cells grew more rapidly and had increased vascularization when coinjected with the RESDECs. Immunohistochemical staining demonstrated that the RESDECs participated in forming the tumor neovasculature. RESDECs provide a novel means to examine the mechanisms of endothelial cell development, and may open up new therapeutic strategies.

We have used rhesus monkey embryonic stem (ES) cells to study endothelial cell development. Rhesus ES cells (R366.4 cell line) exposed to medium containing vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF), and epidermal growth factor (EGF) assumed a relatively uniform endothelial cell morphology and could be propagated and expanded with a consistent phenotype and normal karyotype. When placed in Matrigel, these rhesus ES cell–derived endothelial cells (RESDECs) formed capillary-like structures characteristic of endothelial cells. Immunohistochemical and flow cytometric analysis of RESDECs showed that they take up acetylated low-density lipoprotein (LDL), express CD146, von Willebrand factor, and the integrin αvβ3, and bind the lectin ulex europaeus agglutinin-1. These cells also express the VEGF receptor Flk-1 and secrete VEGF. When introduced in a Matrigel plug implanted subcutaneously in mice, RESDECs formed intact vessels and recruited new endothelial cell growth. In vivo function was demonstrated by coinjection of RESDECs with murine tumor cells subcutaneously into immunocompromised adult mice. RESDECs injected alone did not form measurable tumors. Tumor cells grew more rapidly and had increased vascularization when coinjected with the RESDECs. Immunohistochemical staining demonstrated that the RESDECs participated in forming the tumor neovasculature. RESDECs provide a novel means to examine the mechanisms of endothelial cell development, and may open up new therapeutic strategies.

Human embryonic stem (ES) cells provide a unique model and an important resource to analyze early hematopoietic development. Other systems to study mammalian hematopoiesis include mouse ES cells, dissection of timed mouse embryos, or use of human postnatal hematopoietic tissue typically isolated from bone marrow or umbilical cord blood. All these models have particular strengths and weaknesses. The extensive studies on murine hematopoiesis provide a basis for work on the human developmental system. Since there are likely some important species differences, use of human ES cells now provides an optimal means to evaluate basic cellular and molecular mechanisms that regulate the beginning stages of human blood development, prior to derivation of hematopoietic stem cells (HSCs). Eventually, research on human ES cells may provide an alternative source of HSCs and other blood products for hematopoietic cell transplantation or other cellular therapies.

Many studies of angiogenesis inducers and inhibitors rely on in vitroor in vivomodels as indicators of efficacy. However, as valuable as these models are, there are limitations to each one of these. This overview describes some of the principal methods now in use and discusses the advantages and some of the limitations of these methods. It is suggested that multiple assays, involving both in vitroand in vivoassays, are at present the best way to minimize the problems inherent in any specific assay.

Phospholipid asymmetry in the red blood cell (RBC) lipid bilayer is well maintained during the life of the cell, with phosphatidylserine (PS) virtually exclusively located in the inner monolayer. Loss of phospholipid asymmetry, and consequently exposure of PS, is thought to play an important role in red cell pathology. The anemia in the human thalassemias is caused by a combination of ineffective erythropoiesis (intramedullary hemolysis) and a decreased survival of adult RBCs in the peripheral blood. This premature destruction of the thalassemic RBC could in part be due to a loss of phospholipid asymmetry, because cells that expose PS are recognized and removed by macrophages. In addition, PS exposure can play a role in the hypercoagulable state reported to exist in severe β-thalassemia intermedia. We describe PS exposure in RBCs of 56 comparably anemic patients with different genetic backgrounds of the α- or β-thalassemia phenotype. The use of fluorescently labeled annexin V allowed us to determine loss of phospholipid asymmetry in individual cells. Our data indicate that in a number of thalassemic patients, subpopulations of red cells circulate that expose PS on their outer surface. The number of such cells can vary dramatically from patient to patient, from as low as that found in normal controls (less than 0.2%) up to 20%. Analysis by fluorescent microscopy of β-thalassemic RBCs indicates that PS on the outer leaflet is distributed either over the entire membrane or localized in areas possibly related to regions rich in membrane-bound α-globin chains. We hypothesize that these membrane sites in which iron carrying globin chains accumulate and cause oxidative damage, could be important in the loss of membrane lipid organization. In conclusion, we report the presence of PS-exposing subpopulations of thalassemic RBC that are most likely physiologically important, because they could provide a surface for enhancing hemostasis as recently reported, and because such exposure may mediate the rapid removal of these RBCs from the circulation, thereby contributing to the anemia.

Phospholipid asymmetry in the red blood cell (RBC) lipid bilayer is well maintained during the life of the cell, with phosphatidylserine (PS) virtually exclusively located in the inner monolayer. Loss of phospholipid asymmetry, and consequently exposure of PS, is thought to play an important role in red cell pathology. The anemia in the human thalassemias is caused by a combination of ineffective erythropoiesis (intramedullary hemolysis) and a decreased survival of adult RBCs in the peripheral blood. This premature destruction of the thalassemic RBC could in part be due to a loss of phospholipid asymmetry, because cells that expose PS are recognized and removed by macrophages. In addition, PS exposure can play a role in the hypercoagulable state reported to exist in severe β-thalassemia intermedia. We describe PS exposure in RBCs of 56 comparably anemic patients with different genetic backgrounds of the α- or β-thalassemia phenotype. The use of fluorescently labeled annexin V allowed us to determine loss of phospholipid asymmetry in individual cells. Our data indicate that in a number of thalassemic patients, subpopulations of red cells circulate that expose PS on their outer surface. The number of such cells can vary dramatically from patient to patient, from as low as that found in normal controls (less than 0.2%) up to 20%. Analysis by fluorescent microscopy of β-thalassemic RBCs indicates that PS on the outer leaflet is distributed either over the entire membrane or localized in areas possibly related to regions rich in membrane-bound α-globin chains. We hypothesize that these membrane sites in which iron carrying globin chains accumulate and cause oxidative damage, could be important in the loss of membrane lipid organization. In conclusion, we report the presence of PS-exposing subpopulations of thalassemic RBC that are most likely physiologically important, because they could provide a surface for enhancing hemostasis as recently reported, and because such exposure may mediate the rapid removal of these RBCs from the circulation, thereby contributing to the anemia.