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In Notaufnahmen werden regelmäßig PatientInnen am Lebensende versorgt. Neben PatientInnen, die im Rahmen der notfallmedizinischen Akutversorgung einer plötzlichen Erkrankung oder eines Traumas trotz Rettungsversuche des Behandlungsteams versterben, betrifft dies auch PatientInnen in der Finalphase chronischer Erkrankungen oder im hohen Alter. Um diesen PatientInnen gerecht zu werden, sollten NotfallmedizinerInnen die Grundlagen der Therapiezielfindung und die Eruierung des Patientenwillens kennen und ein palliativmedizinisches Basiswissen besitzen, um auftretende Symptomkrisen adäquat zu beherrschen. Ebenfalls sollten sie Grundkenntnisse in der Kommunikation bei der Überbringung schlechter Nachrichten besitzen.

Objective: To elucidate particular placental pathology findings that are associated with hypoxic ischemic encephalopathy (HIE) and determine which patterns are associated with adverse fetal/neonatal outcomes.Study Design: Multi-institutional retrospective case-control study of newborns with HIE (2002–2022) and controls. Four perinatal pathologists performed gross and histologic evaluation of placentas of cases and controls.Results: A total of 265 placentas of neonates with HIE and 122 controls were examined. Infants with HIE were more likely to have anatomic umbilical cord abnormalities (19.7% vs 7.4%, P= .003), fetal inflammatory response in the setting of amniotic fluid infection (27.7% vs 13.9%, P= .004), and fetal vascular malperfusion (30.6% vs 9.0%, P= <.001) versus controls. Fetal vascular malperfusion with maternal vascular malperfusion was more common in those who died of disease (P= .01).Conclusion: Placental pathology examination of neonates with HIE may improve our understanding of this disorder and its adverse outcomes.

Background: Cataract surgical safety has improved over recent decades, with endophthalmitis rates before 2006 typically 0.13–0.15% compared with the most recent UK national estimate of 0.02%. There remains, however, substantial variation in reported rates from different centres. Due to the low event rate, this disparity may not be noticed and opportunities to improve therefore be missed. We propose a method of monitoring post-cataract endophthalmitis rates that would help centres with higher rates identify this. Methods: A statistical tool, available to download or use online, permits comparison of local endophthalmitis rate with the estimated UK rate of 0.02%. Centres are encouraged to maintain a register of endophthalmitis cases, and when the number reaches a threshold (X cases), either in a certain time period or in a fixed number of procedures, then the centre can consider itself as an outlier and trigger local investigations to improve infection control. Results: Example outputs are offered, such as for a unit doing 5000 cataracts annually, a value of X is suggested such that the third case of endophthalmitis (X= 3) in a 12-month period would give 85% confidence, the fourth case 90% confidence and the fifth case 95% confidence that the true endophthalmitis rate for that unit was higher than the national average. Conclusions: This statistical tool provides a basis for units to set a threshold number of cases of endophthalmitis within a given period that would trigger local processes, thus helping inform local monitoring processes for this rare but potentially catastrophic complication of cataract surgery.

Background/Objectives: The aim of this study was to investigate whether the use of the silicone tipped irrigation/aspiration (I/A) handpiece CapsuleGuard® (Bausch + Lomb, Laval, Canada) reduced rates of posterior capsule rupture (PCR) during cataract surgery. Methods: Royal College of Ophthalmologists’ National Ophthalmology Database (NOD) Cataract Audit data from 01/04/2010 and 31/03/2021 and Bausch + Lomb sales figures were combined to identify centres participating in national cataract audit who have routinely adopted the silicone tipped I/A handpiece, CapsuleGuard®. Data were included only from centres with eligible cataract operations recorded on the NOD both before and after adopting CapsuleGuard®. Review of the literature was undertaken to estimate the proportion of PCR that occurs during I/A, to evaluate the impact of adoption of CapsuleGuard® on PCR occurring in this phase of surgery. Results: Within the study period, 267 371 eligible cataract operations were performed in 14 centres with >50 eligible operations both before and after adopting CapsuleGuard®. Within centres adopting CapsuleGuard®, the rate of PCR occurrence reduction was 16.4%. Before and after the adoption of CapsuleGuard® the median change of PCR was 21.7% reduction (IQR: 4.8% to 37.7% reduction). Conclusions: A reduction in the rate of PCR was seen after regular adoption of CapsuleGuard® during cataract operations. Review of published studies attributing PCR to various components of the cataract operation suggest around 25% of PCR may occur during I/A; adoption of CapsuleGuard may, therefore, be associated with avoidance of a substantial proportion of the PCR during that phase of surgery.

α5 subunit-containing γ-aminobutyric acid type A (GABAA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to neurodevelopmental disorders such as Dup15q and Angelman syndromes, developmental epilepsy and autism. Effective drug action without side effects is dependent on both α5-subtype selectivity and the strength of the positive or negative allosteric modulation (PAM or NAM). Here we solve structures of drugs bound to the α5 subunit. These define the molecular basis of binding and α5 selectivity of the β-carboline, methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), type II benzodiazepine NAMs, and a series of isoxazole NAMs and PAMs. For the isoxazole series, each molecule appears as an ‘upper’ and ‘lower’ moiety in the pocket. Structural data and radioligand binding data reveal a positional displacement of the upper moiety containing the isoxazole between the NAMs and PAMs. Using a hybrid molecule we directly measure the functional contribution of the upper moiety to NAM versus PAM activity. Overall, these structures provide a framework by which to understand distinct modulator binding modes and their basis of α5-subtype selectivity, appreciate structure–activity relationships, and empower future structure-based drug design campaigns.

In his June 2016 Forbes article, 'Physicians and Administrators: Friends or Foes?' Sachin H. Jain asserts, 'We are amidst one of the most dynamic moments in healthcare delivery--and the relationship [...]

ABSTRACT: This article outlines the contemporary history of sectarian conflict in Iraq and identifies the consequences of the US surge strategy in perpetuating the region's violence and strengthening the Islamic [...]

Sean Williams, a third-year middle school teacher of mathematics, has heard the rumblings about the Common Core State Standards. His school district's curriculum director distributed some sample test items of [...]

Evidence on associations between COVID-19 illness and mental health is mixed. We aimed to examine whether COVID-19 is associated with deterioration in mental health while considering pre-pandemic mental health, time since infection, subgroup differences, and confirmation of infection via self-reported test and serology data.

Widely applicable, modified Green–Kubo expressions for the local diffusion coefficient (Dl) are obtained using linear response theory. In contrast to past definitions in use, these expressions are statistical mechanical results. Molecular simulations of systems with anisotropic diffusion and an inhomogeneous density profile confirm the validity of the results. Diffusion coefficients determined from different expressions in terms of currents and velocity correlations agree in the limit of large systems. Furthermore, they apply to arbitrarily small local regions, making them readily applicable to nanoscale and inhomogeneous systems where knowledge of Dlis important.

With the increasing practice of gender-affirming mastectomy as a therapeutic procedure in the setting of gender dysphoria, there has come a profusion of literature on the pathologic findings within these specimens. Findings reported in over 1500 patients have not included either prostatic metaplasia or pilar metaplasia of breast epithelium. We encountered both of these findings in the course of routine surgical pathology practice and therefore aimed to analyze these index cases together with a retrospective cohort to determine the prevalence, anatomic distribution, pathologic features, and associated clinical findings of prostatic metaplasia and pilar metaplasia in the setting of gender-affirming mastectomy. In addition to the 2 index cases, 20 additional archival gender-affirming mastectomy specimens were studied. Before mastectomies, all but 1 patient received testosterone cypionate, 6/22 patients received norethindrone, and 21/22 practiced breast binding. Prostatic metaplasia, characterized by glandular proliferation along the basal layer of epithelium in breast ducts, and in one case, within lobules, was seen in 18/22 specimens; 4/22 showed pilar metaplasia, consisting of hair shafts located within breast ducts, associated with squamoid metaplasia resembling hair matriceal differentiation. By immunohistochemistry, prostatic metaplasia was positive for PSA in 16/20 cases and positive for NKX3.1 in 15/20 cases. Forty-three reduction mammoplasty control cases showed no pilar metaplasia and no definite prostatic metaplasia, with no PSA and NKX3.1 staining observed. We demonstrate that prostatic metaplasia and pilar metaplasia are strikingly common findings in specimens from female-assigned-at-birth transgender patients undergoing gender-affirming mastectomy. Awareness of these novel entities in the breast is important, to distinguish them from other breast epithelial proliferations and to facilitate accrual of follow-up data for better understanding their natural history.

Most postmenopausal women do not enjoy preventive medical care despite their being prone to several late-life disabling diseases. Medical experts believe that to prevent disability in older women, they should be made to avail of or be given access to hormone replacement therapy, regular exercise, balanced diets, mammography/Pap smears and vitamin D and calcium supplements. Doctors should also regularly furnish older women with information on other available community health services and provide referral on other health practitioners., Older women as patients are the mainstay of many primary care practices. Women use more health services than men at all ages, and - because they tend to suffer from [...]

Objective. This study examines the difference between permanent and transitory residence in a nursing home with special emphasis on the extent to which the risk of a long nursing home stay is reduced by the availability of informal help in the community. Data Source. Secondary data were used, taken from the National Long-Term Care Surveys of 1982 and 1984. The 1982 NLTCS samples disabled elderly living in the community. For these community dwellers, the 1984 NLTCS provides information on continued residence in the community and on their nursing home episodes between 1982 and 1984. Method of Analysis. The analysis is based on estimates from a multinomial logit regression with three explicit categories: persons with at least one long nursing home stay (n = 292), persons with only short stays (n = 227), and persons who died without ever having had a nursing home stay (n = 945). The implicit category: persons living in the community in 1984 without having had any nursing home stay (n = 3,368). Principal Findings. This study demonstrates the systematic differences in the personal characteristics that predict the risk of long stays from those that predict short stays in a nursing home. Controlling for limitations in physical and cognitive functioning, the regression analysis shows that indicators of informal help in the community have a statistically significant and relatively large effect on the risk of long stays; but the effects of these indicators on the risk of short stays is numerically smaller and not statistically significant. Specifically, when the burden of caregiving is shared by a spouse and children, the risk of a long stay in a nursing home is reduced by 9.3 percentage points; in contrast, the risk is increased by 18 percentage points for childless elders who are living alone and by 45.8 percentage points for elders living with adults other than a spouse or children. Conclusion. The relatively strong effects of family helpers and living arrangements on the risk of long nursing home stays confirm the hypothesis that, after controlling for the effects of physical and cognitive functioning, adequate help in the community reduces the risk of permanent nursing home residence. But help in the community has no effect on the risk of short nursing home episodes because these episodes are likely to be extensions of acute hospital care. The findings provide essential information for designing a long-term care program because they suggest the magnitudes of the effects that such a program can have on reducing the risk of permanent nursing home residence., I. INTRODUCTION AND BACKGROUND The rising number of very old Americans has increased the number of frail and disabled individuals needing regular help over a long period. For them, the [...]

In this study, the authors examine the extent to which the characteristics of caregivers or recipients determine the probability that caregivers stop being caregivers. We find that caregivers' characteristics such as working outside their homes, raising children, or having their own health problems do not increase this probability. Nor does the emotional distress of caregiving increase the probability of quitting. However, caregivers are more likely to quit when recipients have six to seven disabilities in activities of daily living and need help on demand around the clock. This study also determines that assistive equipment, home modifications, and attendance at senior centers do not reduce the probability that caregivers quit., Introduction The rapid growth in the number of very old Americans has increased the number of elderly depending on others for the basic daily activities of personal care and household [...]

Alemtuzumab is a CD52-specific lympho-depleting antibody. CD52− T cells emerge under alemtuzumab selection pressure. We sought to investigate the phenotype and function of the CD52− T cell fraction and related their presence to clinical outcome. We obtained longitudinal peripheral blood samples from 67 consecutive patients undergoing allo-HSCT between 2013-2016. Forty-seven patients (70%) had a myeloid disease (acute myelogenous leukemia or myelodysplastic syndrome) whereas 20 patients had lymphoid disease. All patients received in vivo alemtuzumab (10 mg/d from day −5 for 5 days) as part of their conditioning protocol. Sixty-three (94%) received reduced-intensity conditioning chemotherapy, whereas 4 (6%) received a myeloablative regimen. All patients received post-transplantation cyclosporine A for graft-versus-host disease (GVHD) prophylaxis. Six (9%) also received methotrexate, whereas 2 (3%) patients also received mycophenolate mofetil. Overall survival at 2 years was 68%, and relapse-free survival was 48%. Twenty-none percent of patients experienced acute GVHD (grade 2 or above), and 15% developed chronic GVHD. CD52− T cells were detectable in 66 of 67 consecutive patients. CD52− T cells demonstrated low binding of fluorescent aerolysin, indicating downregulation of the glycophosphatidylinositol anchor, although we did not detect any mutations in the PIG-Agene as is typically seen in patients with paroxysmal nocturnal hemoglobinuria. CD52− T cells were almost exclusively CD4+and exhibited a dominant memory phenotype with only small numbers of CD25+CD127lowFoxp3+regulatory T cells. CD52− T cells exhibited alloreactive specificity in vitro and have a distinct TCR repertoire to CD52+ T cells. Early after allo-hematopoietic stem cell transplantation, the presence of a significant population of CD52− T cells (comprising >51% of the T cell fraction) was found to be an independent risk factor for acute GvHD. This was confirmed in a validation cohort of 28 patients obtained between 2017-2018. These data suggest that the CD52− T cell fraction may represent a residual “footprint” of an early CD4+ T cell alloreactive response and may have been rescued from alemtuzumab-mediated lysis by antigen engagement in vivo. These data help to delineate the nature of T cell escape from alemtuzumab surveillance and contribute to increasing interest in the importance of CD4+ T cells in alloreactive immune responses, which could help inform immunotherapy protocols.

In addition to encoding the tertiary fold and stability, the primary sequence of a protein encodes the folding trajectory and kinetic barriers that determine the speed of folding. How these kinetic barriers are encoded is not well understood. Here, we use evolutionary sequence variation in the α-lytic protease (αLP) protein family to probe the relationship between sequence and energy landscape. αLP has an unusual energy landscape: the native state of αLP is not the most thermodynamically favored conformation and, instead, remains folded due to a large kinetic barrier preventing unfolding. To fold, αLP utilizes an N-terminal pro region similar in size to the protease itself that functions as a folding catalyst. Once folded, the pro region is removed, and the native state does not unfold on a biologically relevant time scale. Without the pro region, αLP folds on the order of millennia. A phylogenetic search uncovers αLP homologs with a wide range of pro region sizes, including some with no pro region at all. In the resulting phylogenetic tree, these homologs cluster by pro region size. By studying homologs naturally lacking a pro region, we demonstrate they can be thermodynamically stable, fold much faster than αLP, yet retain the same fold as αLP. Key amino acids thought to contribute to αLP’s extreme kinetic stability are lost in these homologs, supporting their role in kinetic stability. This study highlights how the entire energy landscape plays an important role in determining the evolutionary pressures on the protein sequence.

With the increasing practice of gender-affirming mastectomy as a therapeutic procedure in the setting of gender dysphoria, there has come a profusion of literature on the pathologic findings within these specimens. Findings reported in over 1500 patients have not included either prostatic metaplasia or pilar metaplasia of breast epithelium. We encountered both of these findings in the course of routine surgical pathology practice and therefore aimed to analyze these index cases together with a retrospective cohort to determine the prevalence, anatomic distribution, pathologic features, and associated clinical findings of prostatic metaplasia and pilar metaplasia in the setting of gender-affirming mastectomy. In addition to the 2 index cases, 20 additional archival gender-affirming mastectomy specimens were studied. Before mastectomies, all but 1 patient received testosterone cypionate, 6/22 patients received norethindrone, and 21/22 practiced breast binding. Prostatic metaplasia, characterized by glandular proliferation along the basal layer of epithelium in breast ducts, and in one case, within lobules, was seen in 18/22 specimens; 4/22 showed pilar metaplasia, consisting of hair shafts located within breast ducts, associated with squamoid metaplasia resembling hair matriceal differentiation. By immunohistochemistry, prostatic metaplasia was positive for PSA in 16/20 cases and positive for NKX3.1 in 15/20 cases. Forty-three reduction mammoplasty control cases showed no pilar metaplasia and no definite prostatic metaplasia, with no PSA and NKX3.1 staining observed. We demonstrate that prostatic metaplasia and pilar metaplasia are strikingly common findings in specimens from female-assigned-at-birth transgender patients undergoing gender-affirming mastectomy. Awareness of these novel entities in the breast is important, to distinguish them from other breast epithelial proliferations and to facilitate accrual of follow-up data for better understanding their natural history.

Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging–targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.

Supplemental Digital Content is available in the text.Intraductal carcinoma of the prostate (IDC-P) has been recently recognized by the World Health Organization classification of prostatic tumors as a distinct entity, most often occurring concurrently with invasive prostatic adenocarcinoma (PCa). Whether documented admixed with PCa or in its rare pure form, numerous studies associate this entity with clinical aggressiveness. Despite increasing clinical experience and requirement of IDC-P documentation in protocols for synoptic reporting, the specifics of its potential contribution to assessment of grade group (GG) and cancer quantitation of PCa in both needle biopsies (NBx) and radical prostatectomy (RP) specimens remain unclear. Moreover, there are no standard guidelines for incorporating basal cell marker immunohistochemistry (IHC) in the diagnosis of IDC-P, either alone or as part of a cocktail with AMACR/racemase. An online survey containing 26 questions regarding diagnosis, reporting practices, and IHC resource utilization, focusing on IDC-P, was undertaken by 42 genitourinary subspecialists from 9 countries. The degree of agreement or disagreement regarding approaches to individual questions was classified as significant majority (>75%), majority (51% to 75%), minority (26% to 50%) and significant minority (≤25%). IDC-P with or without invasive cancer is considered a contraindication for active surveillance by the significant majority (95%) of respondents, although a majority (66%) also agreed that the clinical significance/behavior of IDC-P on NBx or RP with PCa required further study. The majority do not upgrade PCa based on comedonecrosis seen only in the intraductal component in NBx (62%) or RP (69%) specimens. Similarly, recognizable IDC-P with GG1 PCa was not a factor in upgrading in NBx (78%) or RP (71%) specimens. The majority (60%) of respondents include readily recognizable IDC-P in assessment of linear extent of PCa at NBx. A significant majority (78%) would use IHC to confirm or exclude intraductal carcinoma if other biopsies showed no PCa, while 60% would use it to confirm IDC-P with invasive PCa in NBx if it would change the overall GG assignment. Nearly half (48%, a minority) would use IHC to confirm IDC-P for accurate Gleason pattern 4 quantitation. A majority (57%) report the percentage of IDC-P when present, in RP specimens. When obvious Gleason pattern 4 or 5 PCa is present in RP or NBx, IHC is rarely to almost never used to confirm the presence of IDC-P by the significant majority (88% and 90%, respectively). Most genitourinary pathologists consider IDC-P to be an adverse prognostic feature independent of the PCa grade, although recommendations for standardization are needed to guide reporting of IDC-P vis a vis tumor quantitation and final GG assessment. The use of IHC varies widely and is performed for a multitude of indications, although it is used most frequently in scenarios where confirmation of IDC-P would impact the GG assigned. Further study and best practices recommendations are needed to provide guidance with regards to the most appropriate indications for IHC use in scenarios regarding IDC-P.

A holistic view of the fate of barley starch, arabinoxylan and β‐glucan throughout malting and brewing is largely missing. Here, an industrial scale malting trial and pilot brewing trial were performed, and the concentration and structural characteristics of carbohydrates were analysed at 28 key points in the process. The barley starch content decreased during malting from 75.0% to 69.7%. During mashing, malt starch was converted to fermentable sugars (75.3%), dextrin (22.8%) or was retained in spent grains (1.8%). Arabinoxylan was partially hydrolysed during malting. Despite mashing‐in at 45°C, no further solubilisation of arabinoxylan was observed during mashing. However, the average degree of polymerisation of the soluble arabinoxylan fraction decreased slightly. During fermentation, the arabinoxylan content decreased to 2.5 g/L. The amount of barley β‐glucan decreased gradually in time during malting. Of the solubilised β‐glucan, 31% was retained in the spent grains during wort filtration, slightly lowering the β‐glucan content in the wort. The β‐glucan content remained at 0.5 g/L during fermentation. Sucrose was hydrolysed during mashing, probably by barley invertases. From the total amount of malt used, 41.0% was converted to fermentable sugars. This mashing yield could have been improved by the full hydrolysis to fermentable sugars of the present β‐glucan (to 41.1%), the remaining starch in spent grains (to 42.0%) and dextrin in wort (to 50.3%). These results provide more insight into the carbohydrate conversions during malting and brewing and can act as a baseline measurement for future work. © 2020 The Institute of Brewing & Distilling

ABSTRACTThis article examines retroactive continuity (or retcon), a fundamental feature of serialized comics, in which a character’s backstory can be effectively rewritten, in order to shed light on the complex question of testimonial production and reception. Specifically, I analyze how the Jewish identity of X- Menvillain Magneto has been overwritten. While Magneto first appeared in Uncanny X-Men1 (1963), his origins as a survivor of Auschwitz were only written into the story much later, in Uncanny X-Men150 (1981). More recently, Greg Pak’s X-Men: Magneto Testament(2008), a five-issue origin story, confirmed Magneto’s Jewish background. Retconning reveals how comics are constantly reinvented to meet new market demands, but it is also a feature that challenges the internal logic of a text while being an extension of it. Magneto is repeatedly retconned (i.e. the number on his arm tattoo, his given name), as is Holocaust discourse at large. How, then, are we to read (into) his pasts? In the case of Magneto, retroactive continuity calls attention to the relations between the character, the story world, and cultural and political contexts by generating multiple, parallel stories. Rather than undermining or deforming the ‘truth,’ to read retroactive continuity back into testimony is to allow for the relations that necessarily condition the ‘truth’ in the first place to come to the fore.

Transplantation is an effective treatment of many clinical disorders, but the mechanisms that regulate immunological tolerance are uncertain and remain central to improving patient outcome. Hemopoietic stem cell transplantation (SCT) often establishes “mixed chimerism” in which immune cells from both the donor and patient coexist in vivo in a setting of immunological tolerance. We studied immune function in 69 patients within 2 months following SCT; 37 were fully donor and 32 displayed mixed chimerism. The proportion of T regulatory (Treg) cells was increased during mixed chimerism and comprised equal numbers of donor and host-derived regulatory cells. This was associated with a tolerogenic PD-L1+ profile on dendritic cells. Importantly, effector T cells from patients with mixed chimerism exhibited reduced cytotoxicity against host target cells in vitro, but this was restored following depletion of CD4+ Treg cells. These data show that Treg cells play a major role in sustaining immunological tolerance during mixed chimerism. These insights should help to guide novel interventions to improve clinical transplantation.

A personal narrative is presented which explores the author's experience of visiting the Aachen Cathedral in Germany.

Aggregation-induced emission (AIE) has been meanwhile observed for many dye classes and particularly for fluorophores containing propeller-like groups. Herein, we report on the AIE characteristics of a series of four hydrophobic pyrrolidinylvinylquinoxaline (PVQ) derivatives with phenyl, pyrrolyl, indolyl, and methoxythienyl substituents used to systematically vary the torsion angle between this substituent at the quinoxaline C2 position and the planar PVQ moiety. These molecules, which are accessible via four- or five-component one-pot syntheses, were spectroscopically studied in organic solvents and solvent–water mixtures, as dye aggregates, solids, and entrapped in polystyrene particles (PSP). Steady-state and time-resolved fluorescence measurements revealed a strong fluorescence enhancement for all dyes in ethanol–water mixtures of high water content, accompanying the formation of dye aggregates with sizes of a few hundred nm, overcoming polarity and H-bonding-induced fluorescence quenching of the charge-transfer-type emission of these PVQ dyes. The size and shape of these dye aggregates and the size of the AIE effect are controlled by the water content and the substituent-dependent torsion angle that influences the nucleation process and the packing of the molecules during aggregation. Staining of 1 μm-sized carboxy-functionalized PSP with the PVQ dyes resulted also in a considerable increase in the fluorescence quantum yield and lifetime, reflecting the combined influence of the restricted molecular motion and the reduced polarity of the dye microenvironment.

Angiosarcoma is a rare type of soft tissue sarcoma that accounts for less than 1% of all sarcomas and only 2% of all primary hepatic tumours. Thorotrast, arsenic, and vinyl chloride monomer are frequently listed as occupational exposure risks. The estimated latency is long (10–40 years) in occupational cases and very long (60 years or more) in non-occupational cases. The symptoms and CT-scan appearance of hepatic angiosarcoma (HAS) are non-specific. We present a case of a 65-year-old Caucasian male with history of cryptogenic cirrhosis, low alpha-foetoprotein levels and a single, 4-cm nodule of potential atypical hepatocellular carcinoma (no washout at MRI and CT-scan) in segment VIII. Laparoscopic radiofrequency ablation (a biopsy of the neoplastic lesion was technically impossible) was performed, followed by liver transplantation (LT) 6 months later. High-grade multifocal HAS was found in the explanted liver, with extensive involvement of the venous portal structures. No complications were observed during the postoperative course, and initial immunosuppression included tacrolimus, mycophenolate mofetil and corticosteroids. Because of the histological findings, tacrolimus was switched to everolimus as the main immunosuppressive drug one month after LT. Despite this conversion, the patient developed bone metastases 3 months after LT and peritoneal carcinosis one month later. This case report suggests that everolimus conversion does not inhibit the development of tumour metastases. Consequently, HAS remains an absolute contraindication to LT because of the poor outcome. If LT has been performed for incidental HAS, new molecular therapies (e.g. vascular endothelial growth factor antagonists) should be considered immediately after LT to improve the outcome.

On first seeing Rembrandt's self-portrait as St. Paul Was it Rembrandt or was it Saint Paul who raised his brows in doubt about that time when ecstasy embraced him in [...]

Relative increase of grade 4 and presence of invasive cribriform and/or intraductal carcinoma have individually been associated with adverse outcome of Gleason score 7 (GS 7) prostate cancer. The objective of this study was to investigate the relation of Gleason grade 4 tumor percentage (%GG4) and invasive cribriform and/or intraductal carcinoma in GS 3+4=7 prostate cancer biopsies. We reviewed 1031 prostate cancer biopsies from the European Randomized Study of Screening for Prostate Cancer. In total 370 men had G3+4=7. The relation of invasive cribriform and/or intraductal carcinoma and %GG4 with biochemical recurrence-free survival (BCRFS) after radical prostatectomy (n=146) and radiation therapy (n=195) was analyzed using Cox regression. Invasive cribriform and/or intraductal carcinoma occurred in 7/121 (6%) patients with 1–10% GG4, 29/131 (22%) with 10–25%, and 52/118 (44%) with 25–50% GG4 (P<0.001). In crude analysis, both invasive cribriform and/or intraductal carcinoma (HR 2.72; 95% CI: 1.33–5.95; P=0.006) and 10–50% GG4 (HR 2.43; 95% CI: 1.10–5.37; P=0.03) were associated with BCRFS after prostatectomy. In adjusted analysis, invasive cribriform and/or intraductal carcinoma was an independent predictor for BCRFS (HR 2.40; 95% CI: 1.03–5.60; P=0.04) after prostatectomy, whereas percentage %GG4 (HR 1.00; 95% CI: 0.97–1.03; P=0.80) was not. While invasive cribriform and/or intraductal carcinoma (HR 2.58; 95% CI: 1.59–4.21; P<0.001) performed better than 10–50% GG4 (HR 1.24; 95% CI: 0.67–2.29; P=0.49) for prediction of BCRFS after radiation therapy, both parameters were insignificant in analysis adjusted for prostate-specific antigen (P=0.001), positive biopsies (P<0.001) and tumor volume (P=0.05). In conclusion, increased %GG4 is associated with invasive cribriform and/or intraductal carcinoma in GS 3+4=7 prostate cancer biopsies. Invasive cribriform and/or intraductal carcinoma is an independent parameter for BCR after prostatectomy, whereas %GG4 is not. The presence of invasive cribriform and/or intraductal carcinoma has to be included in pathology reports and should act as exclusion criterion for active surveillance.

Supplemental Digital Content is available in the text

Copper(II) hydroxide (as the rarely occurring mineral spertiniite) is formed under alkaline, oxidising conditions. It has been observed as a naturally occurring corrosion product of brass in sea water. But most occurrences on copper alloys are due to conservation treatments using basic solutions (sodium hydroxide or ammonia) or to intentional patination. Classical brass centrepieces (c. 1800), ‘cleaned’ with ammonia solution, developed a blue spertiniite patina in gaps, where evaporation was hindered. Additional to the danger of stress corrosion cracking this is another reason now outlawing this treatment. Copper pigment layers will transform to copper hydroxide when exposed to bases. The treatment of basic copper salts with bases has been used intentionally in the production of Bremen blue and similar pigments which can be composed of copper hydroxide as well.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5–10, 2011), 12th (Comandatuba, Brazil, August 19–23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5–10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Invasive cribriform and intraductal carcinoma in radical prostatectomy specimens have been associated with an adverse clinical outcome. Our objective was to determine the prognostic value of invasive cribriform and intraductal carcinoma in pre-treatment biopsies on time to disease-specific death. We pathologically revised the diagnostic biopsies of 1031 patients from the first screening round of the European Randomized Study of Screening for Prostate Cancer (1993–2000). Ninety percent of all patients (n=923) had received active treatment, whereas 10% (n=108) had been followed by watchful waiting. The median follow-up was 13 years. Patients who either had invasive cribriform growth pattern or intraductal carcinoma were categorized as CR/IDC+. The outcome was disease-specific survival. Relationships with outcome were analyzed using multivariable Cox regression and log-rank analysis. In total, 486 patients had Gleason score 6 (47%) and 545 had ≥7 (53%). The 15-year disease-specific-survival probabilities were 99% in Gleason score 6 (n=486), 94% in CR/IDC− Gleason score ≥7 (n=356) and 67% in CR/IDC+ Gleason score ≥7 (n=189). CR/IDC− Gleason score 3+4=7 patients did not have statistically different survival probabilities from those with Gleason score 6 (P=0.30), while CR/IDC+ Gleason score 3+4=7 patients did (P<0.001). In multivariable analysis, CR/IDC+ status was independently associated with a poorer disease-specific survival (HR 2.6, 95% CI 1.4–4.8, P=0.002). We conclude that CR/IDC+ status in prostate cancer biopsies is associated with a worse disease-specific survival. Our findings indicate that men with biopsy CR/IDC− Gleason score 3+4=7 prostate cancer could be candidates for active surveillance, as these patients have similar survival probabilities to those with Gleason score 6.

Context:Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterized by infiltration of foamy histiocytes in multiple organs. Endocrine involvement has mostly been described in case reports.Objective:We performed systematic endocrine evaluation in a large cohort of patients with ECD.Design:This was a single-center observational study conducted between October 2007 and May 2013.Setting:The evaluation was conducted in Pitié-Salpêtrière Hospital (Paris, France), a tertiary care hospital.Patients:Sixty-four consecutive patients with ECD (sex ratio, 3.6; mean age, 57.6 years [range, 20–80 years]). Thirty-six patients had follow-up assessments.Interventions:There were no interventions.Main Outcome Measures:Clinical, biological, and morphological evaluations of pituitary, gonadal, adrenal, and thyroid functions, as well as metabolic evaluation, were performed.Results:Diabetes insipidus was found in 33.3% of patients, frequently as the first manifestation of ECD. Anterior pituitary dysfunction was found in 91.3% of patients with full anterior pituitary evaluation, including somatotropic deficiency (78.6%), hyperprolactinemia (44.1%), gonadotropic deficiency (22.2%), thyrotropic deficiency (9.5%), and corticotropic deficiency (3.1%). Thirty-five patients (54.7%) had ≥2 anterior pituitary dysfunctional axes, rising to 69.6% (16 of 23) when only patients with complete evaluations were considered. Two patients had panhypopituitarism. Infiltration of the pituitary and stalk was found with magnetic resonance imaging in 24.4% of patients. Testicular insufficiency was found in 53.1% of patients, with sonographic testicular infiltration in 29% of men, mostly bilateral. Computed tomography adrenal infiltration was found in 39.1% of patients, and 1 case of adrenal insufficiency was observed. No patient was free of endocrine hormonal or morphological involvement. Endocrine dysfunctions were most often permanent, and new deficits appeared during follow-up.Conclusion:Endocrine involvement is very frequent in ECD and should be evaluated carefully at diagnosis and during follow-up.

F-BAR domain proteins regulate and sense membrane curvature by interacting with negatively charged phospholipids and assembling into higher-order scaffolds. However, regulatory mechanisms controlling these interactions are poorly understood. Here, we show that DrosophilaNervous Wreck (Nwk) is autoregulated by a C-terminal SH3 domain module that interacts directly with its F-BAR domain. Surprisingly, this autoregulation does not mediate a simple “on-off” switch for membrane remodeling. Instead, the isolated Nwk F-BAR domain efficiently assembles into higher-order structures and deforms membranes only within a limited range of negative membrane charge, and autoregulation elevates this range. Thus, autoregulation could either reduce membrane binding or promote higher-order assembly, depending on local cellular membrane composition. Our findings uncover an unexpected mechanism by which lipid composition directs membrane remodeling.

Patients with Gleason score 7 prostate cancer on radical prostatectomy demonstrate a wide range in clinical outcome. Gleason grade 4 prostate cancer encompasses a heterogeneous group of tumor growth patterns including fused, ill-defined, cribriform, and glomeruloid glandular structures. Our objective was to determine the prognostic value of different Gleason grade 4 growth patterns. We performed a nested case–control study among 535 patients with Gleason score 7 prostate cancer at radical prostatectomy, treated between March 1985 and July 2013 at a university hospital in the Netherlands. We analyzed 52 cases (with metastasis, disease-specific mortality or both) and 109 controls, matched for age, PSA level, and pT stage. Presence of the following Gleason grade 4 patterns was recorded: fused, ill-defined, cribriform, and glomeruloid. Intraductal carcinoma of the prostate and tertiary Gleason grade 5 were additionally assessed. Outcomes were metastasis-free survival and disease-specific survival. We used Cox proportional hazards regression to determine the predictive value of Gleason grade 4 patterns for survival time. The overall prevalence of Gleason grade 4 patterns was as follows: fused 75% (n=121), ill-defined 64% (n=102), cribriform 48% (n=83), and glomeruloid 25% (n=40). Cribriform pattern was the only pattern with an unequal distribution between cases and controls. Forty-two out of 52 cases (81%) had cribriform growth pattern versus41/109 controls (38%). In multivariate analysis, presence of cribriform growth was an adverse independent predictor for distant metastasis-free survival (HR 8.0, 95% CI 3.0–21; P<0.001) and disease-specific survival (HR 5.4, 95% CI 2.0–15, P=0.001). In conclusion, cribriform growth in Gleason grade 4 is a strong prognostic marker for distant metastasis and disease-specific death in patients with Gleason score 7 prostate cancer at radical prostatectomy.

Numerous systemic treatment options exist for patients with mycosis fungoides (MF) and Sézary syndrome (SS), but no large comparative studies are published. To study the efficacy of treatments, a retrospective analysis of our cutaneous lymphoma database was undertaken, with 198 MF/SS patients undergoing systemic therapies. The primary end point was time to next treatment (TTNT). Patients with advanced-stage disease made up 53%. The median follow-up time from diagnosis for all alive patients was 4.9 years (range 0.3-39.6), with a median survival of 11.4 years. Patients received a median of 3 lines of therapy (range 1-13), resulting in 709 treatment episodes. Twenty-eight treatment modalities were analyzed. The median TTNT for single- or multiagent chemotherapy was only 3.9 months (95% confidence interval [CI] 3.2-5.1), with few durable remissions. α-interferon gave a median TTNT of 8.7 months (95% CI 6.0-18.0), and histone deacetylase inhibitors (HDACi) gave a median TTNT of 4.5 months (95% CI 4.0-6.1). When compared directly with chemotherapy, interferon and HDACi both had greater TTNT (P < .00001 and P = .01, respectively). This study confirms that all chemotherapy regimens assessed have very modest efficacy; we recommend their use be restricted until other options are exhausted.

The article explores the connection between the U.S. Common Core State Standards (CCSS) and teachers' performance evaluation. An explanation on the discrepancy in state educational standards is offered. Also discussed are the effects of the CCSS on student literacy, core subjects and instructional decisions, the need to incorporate elements of the instructional program in curriculum planning, and the capacity of teachers to understand and convey the CCSS to their students.

Human epidermal growth factor receptor 2 (HER2) is an important biomarker for breast and gastric cancer prognosis and patient treatment decisions. HER2 positivity, as defined by IHC or fluorescent in situhybridization testing, remains an imprecise predictor of patient response to HER2-targeted therapies. Challenges to correct HER2 assessment and patient stratification include intratumoral heterogeneity, lack of quantitative and/or objective assays, and differences between measuring HER2 amplification at the protein versus gene level. We developed a novel immunofluorescence method for quantitation of HER2 protein expression at the single-cell level on FFPE patient samples. Our assay uses automated image analysis to identify and classify tumor versus non-tumor cells, as well as quantitate the HER2 staining for each tumor cell. The HER2 staining level is converted to HER2 protein expression using a standard cell pellet array stained in parallel with the tissue sample. This approach allows assessment of HER2 expression and heterogeneity within a tissue section at the single-cell level. By using this assay, we identified distinct subgroups of HER2 heterogeneity within traditional definitions of HER2 positivity in both breast and gastric cancers. Quantitative assessment of intratumoral HER2 heterogeneity may offer an opportunity to improve the identification of patients likely to respond to HER2-targeted therapies. The broad applicability of the assay was demonstrated by measuring HER2 expression profiles on multiple tumor types, and on normal and diseased heart tissues.

Nwk is a neuronal F-BAR/SH3 protein that deforms membranes into positively curved ridges using a novel zigzag assembly of the crescent-shaped F-BAR domain. Membrane between adjacent ridges forms a negatively curved scallop that can be amplified by the cytoskeleton into cellular protrusions.

Chemokines regulate the migration of hemopoietic cells and play an important role in the pathogenesis of many immune-mediated diseases. Intradermal recruitment of CD8+ T cells by CXCL10 is a central feature of the pathogenesis of cutaneous acute GVHD (aGVHD), but very little is known about the pathogenesis of chronic GVHD (cGVHD). Serum concentrations of the 3 CXCR3-binding chemokines, CXCL9, CXCL10, and CXCL11, were found to be markedly increased in patients with active cGVHD of the skin (n = 8). An 80% decrease in CD4+ cells expressing CXCR3 was seen in the blood of these patients (n = 5), whereas CD4+ cells were increased in tissue biopsies and were clustered around the central arterioles of the dermis. The well-documented increase in expression of CXCL10 in aGVHD therefore diversifies in cGVHD to include additional members of the CXCR3-binding family and leads to preferential recruitment of CD4+ T cells. These observations reveal a central role for chemokine-mediated recruitment of CXCR3+ T cells in cGVHD.

Chemokines regulate the migration of hemopoietic cells and play an important role in the pathogenesis of many immune-mediated diseases. Intradermal recruitment of CD8+T cells by CXCL10 is a central feature of the pathogenesis of cutaneous acute GVHD (aGVHD), but very little is known about the pathogenesis of chronic GVHD (cGVHD). Serum concentrations of the 3 CXCR3-binding chemokines, CXCL9, CXCL10, and CXCL11, were found to be markedly increased in patients with active cGVHD of the skin (n = 8). An 80% decrease in CD4+cells expressing CXCR3 was seen in the blood of these patients (n = 5), whereas CD4+cells were increased in tissue biopsies and were clustered around the central arterioles of the dermis. The well-documented increase in expression of CXCL10 in aGVHD therefore diversifies in cGVHD to include additional members of the CXCR3-binding family and leads to preferential recruitment of CD4+T cells. These observations reveal a central role for chemokine-mediated recruitment of CXCR3+T cells in cGVHD.

Although malaria is widely considered a major cause of death in young children born with sickle cell anemia (SCA) in sub-Saharan Africa, this is poorly quantified. We attempted to investigate this question through 4 large case-control analyses involving 7164 children living on the coast of Kenya. SCA was associated with an increased risk of admission to hospital both with nonmalaria diseases in general (odds ratio [OR] = 4.17; 95% confidence interval [CI], 1.95-8.92; P< .001) and with invasive bacterial diseases in particular (OR = 8.73; 95% CI, 4.51-16.89; P< .001). We found no evidence for a strongly increased risk of either uncomplicated malaria (OR = 0.43; 95% CI, 0.09-2.10; P= .30) or malaria complicated by a range of well-described clinical features of severity (OR = 0.80; 95% CI, 0.25-2.51; P= .70) overall; nevertheless, mortality was considerably higher among SCA than non-SCA children hospitalized with malaria. Our findings highlight both the central role that malaria plays in the high early mortality seen in African children with SCA and the urgent need for better quantitative data. Meanwhile, our study confirms the importance of providing all children living with SCA in malaria-endemic areas with effective prophylaxis.

Although malaria is widely considered a major cause of death in young children born with sickle cell anemia (SCA) in sub-Saharan Africa, this is poorly quantified. We attempted to investigate this question through 4 large case-control analyses involving 7164 children living on the coast of Kenya. SCA was associated with an increased risk of admission to hospital both with nonmalaria diseases in general (odds ratio [OR] = 4.17; 95% confidence interval [CI], 1.95-8.92; P < .001) and with invasive bacterial diseases in particular (OR = 8.73; 95% CI, 4.51-16.89; P < .001). We found no evidence for a strongly increased risk of either uncomplicated malaria (OR = 0.43; 95% CI, 0.09-2.10; P = .30) or malaria complicated by a range of well-described clinical features of severity (OR = 0.80; 95% CI, 0.25-2.51; P = .70) overall; nevertheless, mortality was considerably higher among SCA than non-SCA children hospitalized with malaria. Our findings highlight both the central role that malaria plays in the high early mortality seen in African children with SCA and the urgent need for better quantitative data. Meanwhile, our study confirms the importance of providing all children living with SCA in malaria-endemic areas with effective prophylaxis.