University Hospitals Plymouth NHS Trust

Chronic subdural haematoma (CSDH) is an encapsulated collection of blood and fluid on the surface of the brain. Historically considered a result of head trauma, recent evidence suggests there are more complex processes involved. Trauma may be absent or very minor and does not explain the progressive, chronic course of the condition. This review focuses on several key processes involved in CSDH development: angiogenesis, fibrinolysis and inflammation. The characteristic membrane surrounding the CSDH has been identified as a source of fluid exudation and haemorrhage. Angiogenic stimuli lead to the creation of fragile blood vessels within membrane walls, whilst fibrinolytic processes prevent clot formation resulting in continued haemorrhage. An abundance of inflammatory cells and markers have been identified within the membranes and subdural fluid and are likely to contribute to propagating an inflammatory response which stimulates ongoing membrane growth and fluid accumulation. Currently, the mainstay of treatment for CSDH is surgical drainage, which has associated risks of recurrence requiring repeat surgery. Understanding of the underlying pathophysiological processes has been applied to developing potential drug treatments. Ongoing research is needed to identify if these therapies are successful in controlling the inflammatory and angiogenic disease processes leading to control and resolution of CSDH.

Informed by a series of systematic reviews, scoping reviews and evidence updates from the International Liaison Committee on Resuscitation, the 2021 European Resuscitation Council Guidelines present the most up to date evidence-based guidelines for the practice of resuscitation across Europe. The guidelines cover the epidemiology of cardiac arrest; the role that systems play in saving lives, adult basic life support, adult advanced life support, resuscitation in special circumstances, post resuscitation care, first aid, neonatal life support, paediatric life support, ethics and education.

A general two‐stage theory of human inference is proposed. A distinction is drawn between heuristic processes which select items of task information as ‘relevant’, and analytic processes which operate on the selected items to generate inferences or judgements. These two stages are illustrated in a selective review of work on both deductive and statistical reasoning. Factors identified as contributing to heuristic selection include perceptual salience, linguistic suppositions and semantic associations. Analytic processes are considered to be context dependent: people reason from experience, not from inference rules. The paper includes discussion of the theory in comparison with other contemporary theories of human inference, and in relation to the current debate about human rationality.

PURPOSE: B cells. Single-agent epcoritamab previously demonstrated potent antitumor activity in dose escalation across B-cell non-Hodgkin lymphoma subtypes. PATIENTS AND METHODS: large B-cell lymphoma and at least two prior therapy lines (including anti-CD20 therapies) received subcutaneous epcoritamab in 28-day cycles (once weekly step-up doses in weeks 1-3 of cycle 1, then full doses once weekly through cycle 3, once every 2 weeks in cycles 4-9, and once every 4 weeks in cycle 10 and thereafter) until disease progression or unacceptable toxicity. The primary end point was overall response rate by the independent review committee. RESULTS: As of January 31, 2022, 157 patients were treated (median age, 64 years [range, 20-83]; median of three [range, 2-11] prior therapy lines; primary refractory disease: 61.1%; prior chimeric antigen receptor (CAR) T-cell exposure: 38.9%). At a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0 to 70.6) and the complete response rate was 38.9% (95% CI, 31.2 to 46.9). The median duration of response was 12.0 months (among complete responders: not reached). Overall and complete response rates were similar across key prespecified subgroups. The most common treatment-emergent adverse events were cytokine release syndrome (49.7%; grade 1 or 2: 47.1%; grade 3: 2.5%), pyrexia (23.6%), and fatigue (22.9%). Immune effector cell-associated neurotoxicity syndrome occurred in 6.4% of patients with one fatal event. CONCLUSION: Subcutaneous epcoritamab resulted in deep and durable responses and manageable safety in highly refractory patients with large B-cell lymphoma, including those with prior CAR T-cell exposure.

BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. METHODS: A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. RESULTS: Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). CONCLUSIONS: Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. CLINICALTRIALS. GOV NUMBER: NCT03056612. LAY SUMMARY: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk.

Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of tissue defects. As with other allografts, CTA can undergo immune-mediated rejection; therefore standardized criteria are required for characterizing and reporting severity and types of rejection. This article documents the conclusions of a symposium on CTA rejection held at the Ninth Banff Conference on Allograft Pathology in La-Coruňa, Spain, on 26 June 2007, and proposes a working classification, the Banff CTA-07, for the categorization of CTA rejection. This classification was derived from a consensus discussion session attended by the first authors of three published classification systems, pathologists and researchers from international centers where clinical CTA has been performed. It was open to all attendees to the Banff conference. To the extent possible, the format followed the established National Institutes of Health (NIH) guidelines on Consensus Development Programs. By consensus, the defining features to diagnose acute skin rejection include inflammatory cell infiltration with involvement of epidermis and/or adnexal structures, epithelial apoptosis, dyskeratosis and necrosis. Five grades of severity of rejection are defined. This classification refines proposed schemas, represents international consensus on this topic, and establishes a working collective classification system for CTA reporting of rejection in skin-containing CTAs. Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of tissue defects. As with other allografts, CTA can undergo immune-mediated rejection; therefore standardized criteria are required for characterizing and reporting severity and types of rejection. This article documents the conclusions of a symposium on CTA rejection held at the Ninth Banff Conference on Allograft Pathology in La-Coruňa, Spain, on 26 June 2007, and proposes a working classification, the Banff CTA-07, for the categorization of CTA rejection. This classification was derived from a consensus discussion session attended by the first authors of three published classification systems, pathologists and researchers from international centers where clinical CTA has been performed. It was open to all attendees to the Banff conference. To the extent possible, the format followed the established National Institutes of Health (NIH) guidelines on Consensus Development Programs. By consensus, the defining features to diagnose acute skin rejection include inflammatory cell infiltration with involvement of epidermis and/or adnexal structures, epithelial apoptosis, dyskeratosis and necrosis. Five grades of severity of rejection are defined. This classification refines proposed schemas, represents international consensus on this topic, and establishes a working collective classification system for CTA reporting of rejection in skin-containing CTAs. Composite tissue allotransplantation (CTA) is an emerging discipline for the treatment of functionally significant tissue or limb defects. In contrast to solid organ transplants, CTAs often include skin as well as tissues of diverse embryological origin. Most CTA recipients have experienced reversible episodes of acute rejection (1Lanzetta M Petruzzo P Dubernard JM et al.Second report (1998–2006) of the International Registry of Hand and Composite Tissue Transplantation.Transpl Immunol. 2007; 18: 1-6Crossref PubMed Scopus (119) Google Scholar) but to date, no universally accepted criteria for CTA rejection reporting has been established. Histopathology plays a key role in diagnosis of rejection, in understanding the physiopathology of rejection and in facilitating management. Currently, four classification systems have been published and as such, a universally accepted grading scheme for ranking pathological severity of rejection is needed. Standardization is necessary for reporting clinical results and to establish objective end points for clinical trials. Recognizing that a dispersed and unstandardized development of CTA would present a major barrier for progress and reporting, a collaborative relationship was established with investigators with experience in clinical CTA worldwide to initiate the groundwork for a universally accepted histological classification. In addition, as immunomodulatory regimens are minimized, CTA will experience a growth period in the near future. This article describes a consensus schema for the stardardization of clinical reporting for the advancement of the study of the histopathology in CTA-containing skin for dissemination to the health care practice and medical community. As a working classification, the schema will continue to be refined in subsequent meetings as more clinical and experimental data become available for skin and other tissues used in CTAs. Investigators in the field of CTA including representatives from multiple sites reporting a clinical CTA in the past decade were invited to a consensus discussion on CTA histopathology at the Ninth Banff Conference on Allograft Pathology. In keeping with established National Institutes of Health (NIH) guidelines on Consensus Development Programs (2NIH Consensus Development Program. http://consensus.nih.gov/ABOUTCDP.htm (accessed on March 15, 2007).Google Scholar), this conference included: (1Lanzetta M Petruzzo P Dubernard JM et al.Second report (1998–2006) of the International Registry of Hand and Composite Tissue Transplantation.Transpl Immunol. 2007; 18: 1-6Crossref PubMed Scopus (119) Google Scholar) a broad-based nonadvocacy, independent panel gathered to give balanced, objective and knowledgeable focus to the topic, (2NIH Consensus Development Program. http://consensus.nih.gov/ABOUTCDP.htm (accessed on March 15, 2007).Google Scholar) freedom from scientific or financial conflict of interest from the speakers, (3Bejarano PA Levi D Nassiri M et al.The pathology of full-thickness cadaver skin transplant for large abdominal defects.Am J Surg Pathol. 2004; 28: 670-675Crossref PubMed Scopus (41) Google Scholar) predetermined questions defining the scope and the direction of the conference, and (4Kanitakis J Petruzzo P Jullien D et al.Pathological score for the evaluation of allograft rejection in human hand (composite tissue) allotransplantation.Eur J Dermatol. 2005; 15: 235-238PubMed Google Scholar) a systematic literature review of the topic. The presenters included the three first authors of the four classification systems published and investigators who have actively followed CTA patients from a clinicopathological view and/or published reports on CTA rejection. A pathologist from the center where the fourth classification system was published was also invited, provided a presentation and participated in the discussions. Six out of six western international centers with reported experience in hand transplantation at the time of the call were invited and five centers were represented. Furthermore, two out of two centers with experience in other CTA’s-containing skin were represented (i.e. face and abdominal wall). All published scoring systems for CTA were reviewed (3Bejarano PA Levi D Nassiri M et al.The pathology of full-thickness cadaver skin transplant for large abdominal defects.Am J Surg Pathol. 2004; 28: 670-675Crossref PubMed Scopus (41) Google Scholar, 4Kanitakis J Petruzzo P Jullien D et al.Pathological score for the evaluation of allograft rejection in human hand (composite tissue) allotransplantation.Eur J Dermatol. 2005; 15: 235-238PubMed Google Scholar, 5Schneeberger S Kreczy A Brandacher G et al.Steroid and ATG-resistant rejection after double forearm transplantation responds to Campath 1-H.Am J Transplant. 2004; 4: 1372-1374Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 6Cendales L Kleiner D Proposed classification of human composite tissue allograft acute rejection.Am J Transplant. 2003; 3: S154Google Scholar, 7Cendales L Kirk A Moresi M Ruiz P Kleiner D Composite tissue allotransplantation: Classification of clinical acute skin rejection.Transplantation. 2006; 81: 418-422Crossref PubMed Scopus (53) Google Scholar). In addition, a senior investigator in CTA was invited to provide a historic perspective. Each presenter provided data followed by a discussion. Of the presenters, five were clinical pathologists, three were surgeons and one was a basic investigator. The session was open to the public and all attendees of the Banff Conference. A total of 20 attendees provided oral and/or written comments to the questions posed. To date, 41 patients receiving skin-containing CTA’s have been reported; 28 have received hands, three faces, one knee with a skin island and nine abdominal walls. Essentially, all patients have experienced episodes of rejection (1Lanzetta M Petruzzo P Dubernard JM et al.Second report (1998–2006) of the International Registry of Hand and Composite Tissue Transplantation.Transpl Immunol. 2007; 18: 1-6Crossref PubMed Scopus (119) Google Scholar,8The challenge of dermatopathological diagnosis of rejection of composite tissue allografts: A review J Cutan Pathol (submitted).Google Scholar,10Diefenbeck M Wagner F Kirschner M Nerlich A Muckley T Hofmann G Outcome of allogeneic vascularized knee transplants.Transpl Int. 2007; 20: 410-418Crossref PubMed Scopus (32) Google Scholar). Clinical manifestations of rejection have been characterized by cutaneous changes including mild pink discoloration, gradual erythema, macules progressing to red infiltrated lichenoid papules with or without limb edema and onychomadesis in advanced rejection (1Lanzetta M Petruzzo P Dubernard JM et al.Second report (1998–2006) of the International Registry of Hand and Composite Tissue Transplantation.Transpl Immunol. 2007; 18: 1-6Crossref PubMed Scopus (119) Google Scholar,11Kanitakis J Jullien De Petruzzo P et al.Clinicopathologic features of graft rejection of the first human hand allograft.Transplantation. 2003; 76: 688-693Crossref PubMed Scopus (169) Google Scholar). Histological findings disclose predominantly lymphocytic inflammatory-cell infiltrate of variable density, epithelial intracellular edema (spongiosis), lymphocyte exocytosis and keratinocyte apoptosis (1Lanzetta M Petruzzo P Dubernard JM et al.Second report (1998–2006) of the International Registry of Hand and Composite Tissue Transplantation.Transpl Immunol. 2007; 18: 1-6Crossref PubMed Scopus (119) Google Scholar,12Dubernard J Lengele B Morelon E et al.Outcomes 18 months after the first human partial face transplantation.New Engl J Med. 2007; 357: 2451-2460Crossref PubMed Scopus (309) Google Scholar). Macroscopic skin changes in a case reported after steroid resistant rejection showed blisters in the superficial layers with epidermal desquamation. Histology revealed dermal and epidermal lymphocytic infiltration with apoptotic and necrotic keratinocytes (13Schneeberger S Kreczy A Brandacher G et al.Steroid- and ATG-resistant rejection after double forearm transplantation responds to Campath-1H.Am J Transplant. 2004; 4: 1372-1384Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The four published systems on grading CTA skin rejection ranked the degree of rejection based on evaluation of morphologic features (3Bejarano PA Levi D Nassiri M et al.The pathology of full-thickness cadaver skin transplant for large abdominal defects.Am J Surg Pathol. 2004; 28: 670-675Crossref PubMed Scopus (41) Google Scholar, 4Kanitakis J Petruzzo P Jullien D et al.Pathological score for the evaluation of allograft rejection in human hand (composite tissue) allotransplantation.Eur J Dermatol. 2005; 15: 235-238PubMed Google Scholar, 5Schneeberger S Kreczy A Brandacher G et al.Steroid and ATG-resistant rejection after double forearm transplantation responds to Campath 1-H.Am J Transplant. 2004; 4: 1372-1374Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 6Cendales L Kleiner D Proposed classification of human composite tissue allograft acute rejection.Am J Transplant. 2003; 3: S154Google Scholar, 7Cendales L Kirk A Moresi M Ruiz P Kleiner D Composite tissue allotransplantation: Classification of clinical acute skin rejection.Transplantation. 2006; 81: 418-422Crossref PubMed Scopus (53) Google Scholar). All systems illustrated substantial agreement on the basic grade stratification for acute rejection. All agreed that perivascular lymphocytic infiltrates become progressively denser and involve more vessels as the severity of rejection increases. The inflammation then extends to involve dermal stroma, epidermis (including the basal cell layer) and adnexa at moderate to marked grades of rejection. Epidermal apoptosis/necrosis is a marker of severe rejection in all of the published systems where it was observed. The classification based on full thickness, vascularized, myocutaneous-free flaps for closure of abdominal defects (3Bejarano PA Levi D Nassiri M et al.The pathology of full-thickness cadaver skin transplant for large abdominal defects.Am J Surg Pathol. 2004; 28: 670-675Crossref PubMed Scopus (41) Google Scholar) stratified rejection based on the extent of vessels infiltrated, from <10%, to 11–50% in mild, and to more than 50% in moderate and severe rejection. Severe rejection of abdominal wall grafts showed dyskeratosis and spongiosis. The discussion initiated with the following predetermined questions chosen by the CTA session committee chair in conjunction with investigators in the field: (1) Specimen and Slide Preparation: which structures are required to constitute an adequate sample? How will the biopsy be taken to appropriately reflect the clinical involvement? How many samples are required? What are the stains besides hematoxylin and eosin (H&E) that should be applied? (2) Scope of disease-acute: What are the basic features to diagnose rejection? What other features should be recorded and how? What should be excluded from acute rejection? (3) Lesion scoring-acute: How will severity be graded? (4) Scope of disease-chronic: What are the defining features of chronic injury? (5) Scope of disease-humoral: What information should be collected to define this effector mechanism in CTA? The questions were provided to the participants in both oral and written formats. Oral and written comments were collected throughout the consensus discussion session. This article represents the recompilation of the discussions including all oral and written comments. Allografts that include skin are distinctive in that rejection can be recognized by visual inspection. To include this unique feature of CTA, the clinical involvement as assessed visually at the time of biopsy or rejection should be reported as no visible changes, <10%, 10–50% and >50% of the CTA. Features include but are not limited to rash, edema, erythema, vesiculation, desquamation, necrosis and/or ulceration. To diagnose and classify skin rejection, specimen adequacy is defined as at least one 4-mm punch biopsy taken from the most reddened and/or indurated but apparently viable area of involved skin. Only one biopsy is required for diagnosis, to avoid unnecessary scarring, especially with multiple episodes of rejection. The structures required to constitute an adequate sample are the epidermis and its adnexa, dermis, subcutaneous tissue and vessels. The recommendations for slide preparation are hematoxylin and eosin (H&E) and periodic acid Schiff (PAS) stains. Immunohistochemical stains are also recognized as potentially important and are thus recommended “as needed” based on H&E findings and/or for research purposes. These included but are not limited to CD3, CD4, CD8, CD19, CD20 and CD68, as well as HLA-DR, CMV and C4d. The use of trichrome stain is not considered mandatory at this time but could be performed if desired. The basic features to diagnose and classify rejection requiring specific comment in diagnostic reports are immune cell infiltration, and epidermal and/or adnexal involvement namely spongiosis, apoptosis, dyskeratosis and necrosis. The cellular infiltrate can be mixed (e.g. including neutrophils) and not limited to lymphocytes. The pattern of the infiltrate should be characterized as perivascular or interstitial, focal or diffuse and dermal and/or hypodermal. Early signs of rejection may include the presence of scattered dermal infiltrates. Interface inflammation/dermatitis is an important feature to identify, as this may relate to the severity of the rejection or may signal a nonrejection etiology. Infiltration of eosinophils should be recorded descriptively but is not included in the current classification. This will allow the study of its significance in the future. As in other pathologies in which ulceration or necrosis develops, vasculitis may be either primary or secondary to the ulceration. Indications of rejection-related vasculitis include: absence of a history of trauma; involvement of vessels distant from the ulcer; multi-focality of the necrotizing process within the affected vessel; and involvement of several vessels within the biopsy, particularly vessels of various sizes and depths within the dermis. The pathologic and clinical features of immune and nonimmune processes are potentially overlapping and will require further study. Because there is insufficient data to absolutely exclude nonimmune conditions from a particular CTA biopsy, a descriptive observation is currently the appropriate format for reporting findings. As with solid organ transplants, other inflammatory, infectious or neoplastic processes may coincide with acute rejection. The acute/active skin rejection scoring system was divided in five grades, based on intensity and localization of infiltrates. The rejection classification is shown in Table 1.Table 1The Banff 2007 working classification of skin-containing composite tissue allograft pathologyGrade 0. No or rare inflammatory infiltrates.Grade I. Mild. Mild perivascular infiltration. No involvement of the overlying epidermis.Grade II. Moderate. Moderate-to-severe perivascular inflammation with or without mild epidermal and/or adnexal involvement (limited to spongiosis and exocytosis). No epidermal dyskeratosis or apoptosis.Grade III. Severe. Dense inflammation and epidermal involvement with epithelial apoptosis, dyskeratosis and/or keratinolysis.Grade IV. Necrotizing acute rejection. Frank necrosis of epidermis or other skin structures. Open table in a new tab Currently, insufficient data are available to define specific changes of chronic rejection in a CTA. Chronic changes and injury to an allograft evolve time with immune and are to be in and by changes can also be by nonimmune and in both can and clinical features as of chronic injury in a CTA include of adnexa, skin and of and As with other solid it is that injury a histological a of A and was is not information to conclusions several of and clinical information should be gathered in to define in CTA. These include the presence of and its relationship with as well as the presence of and necrosis. A history including (e.g. and as well as the presence or absence of and and is to be performed The graft and rejection in CTAs has not been established. clinical of graft is not included at this It was recognized that skin changes in a CTA are not limited to injury challenge of dermatopathological diagnosis of rejection of composite tissue allografts: A review J Cutan Pathol (submitted).Google Scholar). to (e.g. or other or and Table of processes are the scope of this but should be in reporting CTA diagnosis in skin allograft or Open table in a new tab this international have initiated an international consensus that will progress reporting of results should research to CTA. of data clinical and pathologists and data for As a working classification, the schema will continue to evolve and as more scientific information available for skin and other tissues included in CTA. This new international classification the published systems, which a to grading rejection. systems to of severity by the of a new at In this classification, the first to is perivascular which is mild and In grade there is of the infiltrate by involvement of epidermis or adnexa but without dyskeratosis or epidermal features of cell grade necrosis. dermal edema and spongiosis are in a of including with and of injury in the is to be the with dermal to the epidermis spongiosis. the field of and processes have been in the with other of wall and epidermal is to be of many in the allograft and is the severity and extent of edema may in the of the further are in this was to the histopathology of cutaneous as a to injury in skin-containing CTA. In the National Institutes of Health Consensus Development Pathology for the diagnosis of chronic Kleiner D S et diagnosis of chronic National Institutes of Health consensus development on criteria for clinical in chronic II. Pathology working Transplant. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). The report the of changes from cutaneous including four chronic skin and The is characterized by a of which the and dermis. there is with of changes of the basal cell and lymphocytic infiltration and epidermal The report the changes in chronic to and the for the significance of perivascular lymphocytic inflammation or after It is that chronic skin changes in CTA of chronic cutaneous and in other types of from data will in the of chronic changes in CTA not for skin but for all tissues involved in a CTA. The of several pathological changes unique to limb transplantation to be These include changes with the which have been to be of chronic immune injury but could also be by more acute inflammatory of the the Banff CTA 2007 scoring system on the rejection-related changes, there are a of other immune and nonimmune processes that be recognized and in the diagnosis challenge of dermatopathological diagnosis of rejection of composite tissue allografts: A review J Cutan Pathol (submitted).Google Scholar). The Banff CTA 2007 grading scheme for acute rejection is to have clinical It is to solid organ CTAs will undergo chronic changes and a grading of severity of chronic rejection will evolve in this working classification. CTAs that skin are unique in that rejection-related changes can be observed. it has been shown that significant perivascular infiltration with a skin (13Schneeberger S Kreczy A Brandacher G et al.Steroid- and ATG-resistant rejection after double forearm transplantation responds to Campath-1H.Am J Transplant. 2004; 4: 1372-1384Abstract Full Text Full Text PDF PubMed Scopus (0) Google L Hand Full Text PDF PubMed Google Scholar, JM E G et hand report on first Full Text Full Text PDF PubMed Scopus Google Scholar). of from chronic infiltration and injury have been at in the absence of significant infiltrates Spain, June the of and the that inflammation could as chronic it is important to the of CTA rejection in objective The of skin changes can be used as a clinical of rejection; the and of and/or other as of rejection to be as the of histological to To this the clinical of graft involvement has been as a for clinical presentation and severity of rejection. The CTA is to that of other solid that of rejection will as the clinical experience including chronic and rejection. These will be at subsequent and characterized based on experience in the As an emerging many questions and there is for clinical and basic include the of the and the study of chronic injury and the of and the inflammatory in this This Banff classification is an international to the groundwork to the understanding of CTA It will the investigators and will to clinical The authors are to the of attendees of the CTA Consensus Conference at the Ninth Banff Conference on Allograft This study was in by the Programs of the National and the National of and and The participants of the Ninth Banff Conference the financial provided by the following of A and

PURPOSE: While there are studies under way to characterize the direct effects of the COVID-19 pandemic on the care of patients with cancer, there have been few quantitative reports of the impact that efforts to control the pandemic have had on the normal course of cancer diagnosis and treatment encounters. METHODS: We used the TriNetX platform to analyze 20 health care institutions that have relevant, up-to-date encounter data. Using this COVID and Cancer Research Network (CCRN), we compared cancer cohorts identified by querying encounter data pre-COVID (January 2019-April 2019) and current (January 2020-April 2020). Cohorts were generated for all patients with neoplasms (malignant, benign, in situ, and of unspecified behavior), with new incidence neoplasms (first encounter), with exclusively malignant neoplasms, and with new incidence malignant neoplasms. Data from a UK institution were similarly analyzed. Additional analyses were performed on patients with selected cancers, as well as on those having had cancer screening. RESULTS: Clear trends were identified that suggest a significant decline in all current cohorts explored, with April 2020 displaying the largest decrease in the number of patients with cancer having encounters. Of the cancer types analyzed, lung, colorectal, and hematologic cancer cohorts exhibited smaller decreases in size in April 2020 versus 2019 (-39.1%, -39.9%, -39.1%, respectively) compared with cohort size decreases for breast cancer, prostate cancer, and melanoma (-47.7%, -49.1%, -51.8%, respectively). In addition, cancer screenings declined drastically, with breast cancer screenings dropping by -89.2% and colorectal cancer screenings by -84.5%. CONCLUSION: Trends seen in the CCRN clearly suggest a significant decrease in all cancer-related patient encounters as a result of the pandemic. The steep decreases in cancer screening and patients with a new incidence of cancer suggest the possibility of a future increase in patients with later-stage cancer being seen initially as well as an increased demand for cancer screening procedures as delayed tests are rescheduled.

AIMS: To determine the effect of exercise training on clinical events and health-related quality of life (HRQoL) of patients with systolic heart failure. METHODS AND RESULTS: We searched electronic databases including Medline, EMBASE, and Cochrane Library up to January 2008 to identify randomized controlled trials (RCTs) comparing exercise training and usual care with a minimum follow-up of 6 months. Nineteen RCTs were included with a total of 3647 patients, the majority of whom were male, low-to-medium risk, and New York Heart Association class II-III with a left ventricular ejection fraction of <40%. There was no significant difference between exercise and control in short-term (<or=12 months) or longer-term all-cause mortality or overall hospital admissions. Heart failure-related hospitalizations were lower [relative risk: 0.72, 95% confidence interval (CI): 0.52-0.99] and HRQoL improved (standardized mean difference: -0.63, 95% CI: -0.80 to -0.37) with exercise therapy. Any effect of cardiac exercise training on total mortality and HRQoL was independent of degree of left ventricular dysfunction, type of cardiac rehabilitation, dose of exercise intervention, length of follow-up, trial quality, and trial publication date. CONCLUSION: Compared with usual care, in selected heart failure patients, exercise training reduces heart failure-related hospitalizations and results in clinically important improvements in HRQoL. High-quality RCT and cost-effectiveness evidence is needed for the effect of exercise training in community-based settings and in more severe heart failure patients, elderly people, and women.

Bariatric surgery is recognized as the most clinically and cost-effective treatment for people with severe and complex obesity. Many people presenting for surgery have pre-existing low vitamin and mineral concentrations. The incidence of these may increase after bariatric surgery as all procedures potentially cause clinically significant micronutrient deficiencies. Therefore, preparation for surgery and long-term nutritional monitoring and follow-up are essential components of bariatric surgical care. These guidelines update the 2014 British Obesity and Metabolic Surgery Society nutritional guidelines. Since the 2014 guidelines, the working group has been expanded to include healthcare professionals working in specialist and non-specialist care as well as patient representatives. In addition, in these updated guidelines, the current evidence has been systematically reviewed for adults and adolescents undergoing the following procedures: adjustable gastric band, sleeve gastrectomy, Roux-en-Y gastric bypass and biliopancreatic diversion/duodenal switch. Using methods based on Scottish Intercollegiate Guidelines Network methodology, the levels of evidence and recommendations have been graded. These guidelines are comprehensive, encompassing preoperative and postoperative biochemical monitoring, vitamin and mineral supplementation and correction of nutrition deficiencies before, and following bariatric surgery, and make recommendations for safe clinical practice in the U.K. setting.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

### Spontaneous pneumothorax #### Acute management for spontaneous pneumothorax ##### Recommendations ##### Good practice points #### Optimal management after the resolution of a first episode of pneumothorax ##### Good practice points #### Optimal management for spontaneous pneumothorax and ongoing air leak ##### Good practice point

BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes. METHODS: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. RESULTS: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality. CONCLUSIONS: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis. LAY SUMMARY: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.

Pain is a key unmet need and a major aspect of non-motor symptoms of Parkinson's disease (PD). No specific validated scales exist to identify and grade the various types of pain in PD. We report an international, cross-sectional, open, multicenter, one-point-in-time evaluation with retest study of the first PD-specific pain scale, the King's PD Pain Scale. Its seven domains include 14 items, each item scored by severity (0-3) multiplied by frequency (0-4), resulting in a subscore of 0 to 12, with a total possible score range from 0 to 168. One hundred seventy-eight PD patients with otherwise unexplained pain (age [mean ± SD], 64.38 ± 11.38 y [range, 29-85]; 62.92% male; duration of disease, 5.40 ± 4.93 y) and 83 nonspousal non-PD controls, matched by age (64.25 ± 11.10 y) and sex (61.45% males) were studied. No missing data were noted, and floor effect was observed in all domains. The difference between mean and median King's PD Pain Scale total score was less than 10% of the maximum observed value. Skewness was marginally high (1.48 for patients). Factor analysis showed four factors in the King's PD Pain Scale, explaining 57% of the variance (Kaiser-Mayer-Olkin, 0.73; sphericity test). Cronbach's alpha was 0.78, item-total correlation mean value 0.40, and item homogeneity 0.22. Correlation coefficients of the King's PD Pain Scale domains and total score with other pain measures were high. Correlation with the Scale for Outcomes in PD-Motor, Non-Motor Symptoms Scale total score, and quality of life measures was high. The King's PD Pain Scale seems to be a reliable and valid scale for grade rating of various types of pain in PD.

BACKGROUND: The use of transvaginal mesh and biological graft material in prolapse surgery is controversial and has led to a number of enquiries into their safety and efficacy. Existing trials of these augmentations are individually too small to be conclusive. We aimed to compare the outcomes of prolapse repair involving either synthetic mesh inlays or biological grafts against standard repair in women. METHODS: We did two pragmatic, parallel-group, multicentre, randomised controlled trials for our study (PROSPECT [PROlapse Surgery: Pragmatic Evaluation and randomised Controlled Trials]) in 35 centres (a mix of secondary and tertiary referral hospitals) in the UK. We recruited women undergoing primary transvaginal anterior or posterior compartment prolapse surgery by 65 gynaecological surgeons in these centres. We randomly assigned participants by a remote web-based randomisation system to one of the two trials: comparing standard (native tissue) repair alone with standard repair augmented with either synthetic mesh (the mesh trial) or biological graft (the graft trial). We assigned women (1:1:1 or 1:1) within three strata: assigned to one of the three treatment options, comparison of standard repair with mesh, and comparison of standard repair with graft. Participants, ward staff, and outcome assessors were masked to randomisation where possible; masking was obviously not possible for the surgeon. Follow-up was for 2 years after the surgery; the primary outcomes, measured at 1 year and 2 years, were participant-reported prolapse symptoms (i.e. the Pelvic Organ Prolapse Symptom Score [POP-SS]) and condition-specific (ie, prolapse-related) quality-of-life scores, analysed in the modified intention-to-treat population. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN60695184. FINDINGS: Between Jan 8, 2010, and Aug 30, 2013, we randomly allocated 1352 women to treatment, of whom 1348 were included in the analysis. 865 women were included in the mesh trial (430 to standard repair alone, 435 to mesh augmentation) and 735 were included in the graft trial (367 to standard repair alone, 368 to graft augmentation). Because the analyses were carried out separately for each trial (mesh trial and graft trial) some women in the standard repair arm assigned to all treatment options were included in the standard repair group of both trials. 23 of these women did not receive any surgery (15 in the mesh trial, 13 in the graft trial; five were included in both trials) and were included in the baseline analyses only. Mean POP-SS at 1 year did not differ substantially between comparisons (standard 5·4 [SD 5·5] vs mesh 5·5 [5·1], mean difference 0·00, 95% CI -0·70 to 0·71; p=0·99; standard 5·5 [SD 5·6] vs graft 5·6 [5·6]; mean difference -0·15, -0·93 to 0·63; p=0·71). Mean prolapse-related quality-of-life scores also did not differ between groups at 1 year (standard 2·0 [SD 2·7] vs mesh 2·2 [2·7], mean difference 0·13, 95% CI -0·25 to 0·51; p=0·50; standard 2·2 [SD 2·8] vs graft 2·4 [2·9]; mean difference 0·13, -0·30 to 0·56; p=0·54). Mean POP-SS at 2 years were: standard 4·9 (SD 5·1) versus mesh 5·3 (5·1), mean difference 0·32, 95% CI -0·39 to 1·03; p=0·37; standard 4·9 (SD 5·1) versus graft 5·5 (5·7); mean difference 0·32, -0·48 to 1·12; p=0·43. Prolapse-related quality-of-life scores at 2 years were: standard 1·9 (SD 2·5) versus mesh 2·2 (2·6), mean difference 0·15, 95% CI -0·23 to 0·54; p=0·44; standard 2·0 (2·5) versus graft 2·2 (2·8); mean difference 0·10, -0·33 to 0·52; p=0·66. Serious adverse events such as infection, urinary retention, or dyspareunia or other pain, excluding mesh complications, occurred with similar frequency in the groups over 1 year (mesh trial: 31/430 [7%] with standard repair vs 34/435 [8%] with mesh, risk ratio [RR] 1·08, 95% CI 0·68 to 1·72; p=0·73; graft trial: 23/367 [6%] with standard repair vs 36/368 [10%] with graft, RR 1·57, 0·95 to 2·59; p=0·08). The cumulative number of women with a mesh complication over 2 years in women actually exposed to synthetic mesh was 51 (12%) of 434. INTERPRETATION: Augmentation of a vaginal repair with mesh or graft material did not improve women's outcomes in terms of effectiveness, quality of life, adverse effects, or any other outcome in the short term, but more than one in ten women had a mesh complication. Therefore, follow-up is vital to identify any longer-term potential benefits and serious adverse effects of mesh or graft reinforcement in vaginal prolapse surgery. FUNDING: UK National Institute of Health Research.

OBJECTIVE: Monogenic diabetes is rare but is an important diagnosis in pediatric diabetes clinics. These patients are often not identified as this relies on the recognition of key clinical features by an alert clinician. Biomarkers (islet autoantibodies and C-peptide) can assist in the exclusion of patients with type 1 diabetes and allow systematic testing that does not rely on clinical recognition. Our study aimed to establish the prevalence of monogenic diabetes in U.K. pediatric clinics using a systematic approach of biomarker screening and targeted genetic testing. RESEARCH DESIGN AND METHODS: We studied 808 patients (79.5% of the eligible population) <20 years of age with diabetes who were attending six pediatric clinics in South West England and Tayside, Scotland. Endogenous insulin production was measured using the urinary C-peptide creatinine ratio (UCPCR). C-peptide-positive patients (UCPCR ≥0.2 nmol/mmol) underwent islet autoantibody (GAD and IA2) testing, with patients who were autoantibody negative undergoing genetic testing for all 29 identified causes of monogenic diabetes. RESULTS: A total of 2.5% of patients (20 of 808 patients) (95% CI 1.6-3.9%) had monogenic diabetes (8 GCK, 5 HNF1A, 4 HNF4A, 1 HNF1B, 1 ABCC8, 1 INSR). The majority (17 of 20 patients) were managed without insulin treatment. A similar proportion of the population had type 2 diabetes (3.3%, 27 of 808 patients). CONCLUSIONS: This large systematic study confirms a prevalence of 2.5% of patients with monogenic diabetes who were <20 years of age in six U.K. clinics. This figure suggests that ∼50% of the estimated 875 U.K. pediatric patients with monogenic diabetes have still not received a genetic diagnosis. This biomarker screening pathway is a practical approach that can be used to identify pediatric patients who are most appropriate for genetic testing.

These guidelines update the previous EANM 2009 guidelines on the diagnosis of pulmonary embolism (PE). Relevant new aspects are related to (a) quantification of PE and other ventilation/perfusion defects; (b) follow-up of patients with PE; (c) chronic PE; and (d) description of additional pulmonary physiological changes leading to diagnoses of left ventricular heart failure (HF), chronic obstructive pulmonary disease (COPD) and pneumonia. The diagnosis of PE should be reported when a mismatch of one segment or two subsegments is found. For ventilation, Technegas or krypton gas is preferred over diethylene triamine pentaacetic acid (DTPA) in patients with COPD. Tomographic imaging with V/PSPECT has higher sensitivity and specificity for PE compared with planar imaging. Absence of contraindications makes V/PSPECT an essential method for the diagnosis of PE. When V/PSPECT is combined with a low-dose CT, the specificity of the test can be further improved, especially in patients with other lung diseases. Pitfalls in V/PSPECT interpretation are discussed. In conclusion, V/PSPECT is strongly recommended as it accurately establishes the diagnosis of PE even in the presence of diseases like COPD, HF and pneumonia and has no contraindications.

Religious concerns may be an important reason why patients decline listing for a renal transplant. These issues may be equally, or even more, important when live donation is discussed. There is good reason to believe that religious concerns play a significant role much more often than clinicians and transplant teams believe. The issue is certainly further compounded by the fact that a few, if any, patients come forward with their religious concerns, not least because issue of transplantation is new to them anyway and because they meet with transplant teams whom they do not know. Health professionals, on the other hand, may wish to avoid this sensitive issue altogether or may lack knowledge on religious issues pertaining to transplantation. Some may be entirely unaware. We encountered a case in clinic that revealed our remarkable lack of knowledge in this regard. Here, we aim to provide an overview on how the different religions view transplantation and organ donation, with an emphasis on practical points for health care professionals who are involved in transplant listing, organ donation and retrieval, and transplantation itself. Knowledge of these facts may provide a background to deal with these issues professionally and appropriately and to increase transplant numbers.

UNLABELLED: Chinese translation BACKGROUND: Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person's lifetime risk for cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and persons with genetic variants near interleukin-28B (IL-28B), the genetic basis is not well-understood. OBJECTIVE: To evaluate the host genetic basis for spontaneous resolution of HCV infection. DESIGN: 2-stage, genome-wide association study. SETTING: 13 international multicenter study sites. PATIENTS: 919 persons with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 persons with serum HCV antibodies and HCV RNA (persistence). MEASUREMENTS: Frequencies of 792 721 single nucleotide polymorphisms (SNPs). RESULTS: Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL-28B and included rs12979860 (overall per-allele OR, 0.45; P = 2.17 × 10-30) and 10 additional SNPs spanning 55 000 base pairs. On chromosome 6, allele frequency differences localized near genes for HLA class II and included rs4273729 (overall per-allele OR, 0.59; P = 1.71 × 10-16) near DQB1*03:01 and an additional 116 SNPs spanning 1 090 000 base pairs. The associations in chromosomes 19 and 6 were independent and additive and explain an estimated 14.9% (95% CI, 8.5% to 22.6%) and 15.8% (CI, 4.4% to 31.0%) of the variation in HCV resolution in persons of European and African ancestry, respectively. Replication of the chromosome 6 SNP, rs4272729, in an additional 745 persons confirmed the findings (P = 0.015). LIMITATION: Epigenetic effects were not studied. CONCLUSION: IL-28B and HLA class II are independently associated with spontaneous resolution of HCV infection, and SNPs marking IL-28B and DQB1*03:01 may explain approximately 15% of spontaneous resolution of HCV infection.

Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP.