Richter's transformation: Transforming the clinical landscape.

Richter transformation (RT) represents an aggressive histological transformation from chronic lymphocytic leukaemia, most often to a large B cell lymphoma. It is characterised by chemo-resistance and subsequent short survival. Drug development has struggled over recent years in light of the aggressive kinetics of the disease, lack of pivotal registrational trials and relative rarity of the phenomenon. In this review we will highlight the diagnostic and therapeutic challenges of managing patients with RT as well as taking a look to the future therapeutic landscape. Highly active therapies developed across B cell malignancies are starting to impact this field, with T-cell activation therapies (CAR-T, bispecific antibodies), antibody-drug conjugates, and novel small molecule inhibitor combinations (e.g. BTKi-BCL2i) being actively studied. We will highlight the data supporting these developments and look to the studies to come to provide hope for patients suffering from this devastating disease.

In Vivo reflectance confocal microscopy of cutaneous acute graft-versus-host disease: concordance with histopathology and interobserver reproducibility of a glossary with representative images.

BACKGROUND: The reliability to non-invasively identify features of inflammatory dermatoses by reflectance confocal microscopy (RCM) remains unknown. Lack of formal training among RCM readers can result in inconsistent assessments, limiting clinical utility. Specific consensus terminology with representative images is necessary to ensure consistent feature-level interpretation among RCM readers. OBJECTIVES: (1) Develop a glossary with representative images of RCM features of cutaneous acute graft-versus-host disease (aGVHD) for consistent interpretation among observers, (2) assess the interobserver reproducibility among RCM readers using the glossary, and (3) determine the concordance between RCM and histopathology for aGVHD features. METHODS: Through an iterative process of refinement and discussion among five international RCM experts, we developed a glossary with representative images of RCM features of aGVHD. From April to November 2018, patients suspected of aGVHD were imaged with RCM and subsequently biopsied. 17 lesions from 12 patients had clinically and pathologically confirmed cutaneous aGVHD. For each of these lesions, four dermatopathologists and four RCM readers independently evaluated the presence of aGVHD features in scanned histopathology slides and 1.5 × 1.5 mm RCM submosaics at 4 depths (blockstacks) respectively. RCM cases were adjudicated by a fifth RCM expert. Interobserver reproducibility was calculated by mean pairwise difference (U statistic). Concordance between modalities was determined by fraction of assignments with agreement. RESULTS: We present a glossary with representative images of 18 aGVHD features by RCM. The average interobserver reproducibility among RCM readers (75%, confidence interval, CI: 71-79%) did not differ significantly from dermatopathologists (80%, 76-85%). The concordance between RCM and histopathology was 59%. CONCLUSIONS: By using the glossary, the interobserver reproducibility among RCM readers was similar to the interobserver reproducibility among dermatopathologists. There was reasonable concordance between RCM and histopathology to visualize aGVHD features. The implementation of RCM can now be advanced in a variety of inflammatory conditions with a validated glossary and representative image set.

A critical appraisal of impact of compounding factors in limb salvage decision making in combat extremity vascular trauma.

OBJECTIVE: For more than half a century, surgeons who managed vascular injuries were guided by a 6-hour maximum ischaemic time dogma in their decision to proceed with vascular reconstruction or not. Contemporary large animal survival model experiments aimed at redefining the critical ischaemic time threshold concluded this to be less than 5 hours. Our clinical experience from recent combat vascular trauma contradicts this dogma with limb salvage following vascular reconstruction with an average ischaemic time of 6 hours. METHODS: During an 8-month period of the Sri Lankan Civil War, all patients with penetrating extremity vascular injuries were prospectively recorded by a single surgeon and retrospectively analysed. A total of 76 arterial injuries was analysed for demography, injury anatomy and physiology, treatment and outcomes. Subsequent statistical analysis was performed to evaluate the impact of independent variables to include; injury anatomy, concomitant venous, skeletal trauma, shock at presentation and time delay from injury to reconstruction. RESULTS: In this study, the 76 extremity arterial injuries had a median ischaemic time of 290 (IQR 225-375) min. Segmental arterial injury (p=0.02), skeletal trauma (p=0.05) and fasciotomy (p=0.03) were found to have a stronger correlation to subsequent amputation than ischaemic time. CONCLUSIONS: Multiple factors affect limb viability following compromised distal circulation and our data show a trend towards various subsets of limbs that are more vulnerable due to inherent or acquired paucity of collateral circulation. Early identification and prioritisation of these limbs could achieve functional limb salvage if recognised. Further prospective research should look into the clinical, biochemical and morphological markers to facilitate selection and prioritisation of limb revascularisation.

Diffuse large B cell lymphoma (DLBCL) in patients older than 65 years: analysis of 3 year Real World data of practice patterns and outcomes in England.

BACKGROUND: We wished to examine treatment and outcome patterns in older diffuse large B-cell lymphoma (DLBCL) patients, with a focus on the effect of route-to-diagnosis to outcome. METHODS: Data were extracted from Public Health England's National Cancer Registration and Analysis Service between 2013 and 2015 included route-to-diagnosis, disease characteristics and survival for 9186 patients ≥65 years. Systemic Anti-Cancer Therapy data identified front-line regimens, cycles and doses. RESULTS: Route-to-diagnosis were emergency (34%), NHS urgent cancer pathway (rapid haemato-oncologist review <2 weeks), (29%) and standard GP referral (25%). The most common regimen was R-CHOP (n = 4392). 313 patients received R-miniCHOP (7% of R-CHOP). For all patients, 3-year overall survival (OS) for 65-79 years was 57% and for ≥80 years was 32%. Three-year OS for R-CHOP-treated patients diagnosed via emergency presentation was 54% (adjusted hazard ratio (HR) 1.63, p < 0.01) and 75% (adjusted HR 0.81, p < 0.01) on the NHS urgent cancer pathway (reference HR:1.00: GP referrals). 3-year OS was 54% for both R-miniCHOP and R-CHOP in ≥80 years. CONCLUSIONS: Our comprehensive population analysis is the first to show that the NHS urgent cancer pathway is associated with a superior survival after adjusting for multiple confounders. Equivalent survival for R-CHOP and R-mini-CHOP was demonstrated in those ≥80 years.

The resilience of the developing reading system: multi-modal evidence of incident and recovery after a pediatric stroke.

Decades of neuroscientific findings have elucidated the highly specialized brain areas involved in reading, especially along the ventral occipitotemporal stream where the critical step of recognizing words occurs. We report on a 14-year-old female with temporary dyslexia after a left ventral occipitotemporal ischemic stroke. Our longitudinal multimodal findings show that the resolution of the reading impairment was associated with heightened activity in the left posterior superior and inferior temporal gyri. Our findings highlight the role of the left inferior temporal gyrus in reading and the importance of perilesional and ipsilateral cortical areas for functional recovery after childhood stroke.

Quality assessment of cancer patient education materials: the current state of systemic therapy patient education in fourteen cancer centres across Ontario, Canada.

PURPOSE: Most patients diagnosed with cancer are administered systemic therapy and these patients are counselled and given printed education (PE) materials. High rates of low health literacy highlight the need to evaluate the quality of these PE materials. METHODS: A current state assessment of the quality of PE materials was conducted in Ontario, Canada. Patient education leaders from 14 cancer centres submitted print materials on the topic of systemic cancer therapy to the assessment team. To report adherence to PE quality and health literacy best practices, the following validated measures were used: readability (FRY, SMOG and Flesch Reading Ease), understandability and actionability (Patient Education Materials Assessment Tool (PEMAT)). Materials at grade level 6 or lower and with PEMAT scores greater than 80% were considered to meet health literacy best practices. RESULTS: A total of 1146 materials were submitted; 366 met inclusion criteria and 83 were selected for assessment. Most materials scored below the 80% target for understandability (x̄ = 73%, 31-100%) and actionability (x̄ = 68%, 20-100%), and above the recommended grade 6 readability level (x̄ = grade 9) meaning that the majority did not meet quality standards or best practices. CONCLUSION: Results suggest that there is significant opportunity to improve the quality of PE materials distributed by cancer centres. The quality of PE materials is a critical safety and equity consideration when these materials convey important safety and self-care directives.

Provincial Veterinary Services respond to drought in South Africa.

In 2018, Cape Town, South Africa, nearly ran out of water. That this has not yet happened is in large part due to the water-saving efforts of its citizens. It is highly likely that this situation will be repeated in Cape Town and that similar situations will be experienced by major cities in other parts of the world. Efforts to save water should thus continue and the lessons learned in Cape Town should be shared. The functioning of Veterinary Services during a drought is affected in the same way as any business, in terms of running an office, but veterinary professionals face an increased risk of exposure to pathogens, compared to that of many occupations, and of veterinary officials becoming disease vectors. One component of Veterinary Services is veterinary laboratory services. Laboratory procedures rely heavily on water and, without advance planning, a laboratory's function can be severely limited by a restricted water supply. In many cases, innovative water-saving techniques can be used to reduce water use substantially without compromising the quality of the services offered. Here, the authors share their experiences and some lessons learned while working in Veterinary Services in the Western Cape province of South Africa.

En 2018, la ville du Cap en Afrique du Sud a failli manquer d'eau. Si la pénurie totale a pu être évitée, ce fut en grande partie grâce aux efforts déployés par les habitants pour économiser l'eau. Or, il est très probable que cette situation se reproduise au Cap et que des situations analogues surviennent dans nombre de grandes métropoles d'autres régions du monde. C'est pourquoi il convient de poursuivre les efforts d'économie d'eau et de partager avec d'autres les enseignements tirés dans la ville du Cap. L'impact de la sécheresse sur le fonctionnement des Services vétérinaires est similaire à celui de toute organisation en termes de gestion administrative ; en revanche, par rapport à d'autres professionnels, les vétérinaires de terrain sont davantage exposés à des agents pathogènes et au risque de devenir eux-mêmes vecteurs de maladies. Les laboratoires vétérinaires sont l'une des composantes des Services vétérinaires. Les procédures de laboratoire sont amplement tributaires de l'eau ; or, en l'absence d'une planification préalable, les activités d'un laboratoire pourraient être gravement mises à mal par des restrictions de l'approvisionnement en eau. Dans bien des cas, il est possible d'utiliser des techniques innovantes pour économiser l'eau afin d'en diminuer la consommation sans pour autant compromettre la qualité des services rendus. Les auteurs font part de leur expérience et de certains enseignements tirés lorsqu'ils travaillaient dans les Services vétérinaires de la province du Cap-Occidental en Afrique du Sud.

En 2018 faltó poco para que Ciudad del Cabo (Sudáfrica) se quedara sin agua. Si las cosas aún no han llegado a este extremo es, en gran parte, gracias a los esfuerzos de los habitantes por economizar agua. Es muy probable que en el futuro Ciudad del Cabo vuelva a sufrir esta situación y que grandes metrópolis de otras partes del mundo conozcan dificultades parecidas. Por ello hay que perseverar en los esfuerzos de ahorro de agua y se deben compartir las enseñanzas extraídas en Ciudad del Cabo. Durante una sequía, el funcionamiento de los Servicios Veterinarios se ve afectado del mismo modo que cualquier otra actividad, por lo que respecta al trabajo de oficina, pero además los profesionales del ramo, en comparación con los de otros muchos sectores, corren mayor peligro de exposición a patógenos, lo que a su vez entraña el riesgo de que los propios veterinarios ejerzan de vectores de la enfermedad. Uno de los puntales de los Servicios Veterinarios son los laboratorios veterinarios, cuyo quehacer depende en gran medida del uso de agua. Por ello, cuando no se ha planificado con antelación la eventualidad de una penuria de agua, esta puede imponer graves cortapisas a las funciones de laboratorio. En muchos casos es posible emplear innovadoras técnicas de ahorro de agua para reducir sustancialmente las cantidades utilizadas sin menoscabo de la calidad de los servicios dispensados. Los autores comparten su experiencia y algunas de las lecciones que extrajeron de su trabajo en los Servicios Veterinarios de la provincia sudafricana del Cabo Occidental.

The peripheral immune response in hyperglycemic stroke.

OBJECTIVES: Hyperglycemia is common in acute ischemic stroke patients and is associated with poor clinical outcome. However, aggressive reduction of post-stroke hyperglycemia did not improve clinical outcome, suggesting that other mechanisms are playing a detrimental role in hyperglycemic stroke. We hypothesize that the acute post-stroke immune response is altered in the hyperglycemic state leading to higher mortality and morbidity. The objective of this study was to characterize temporal changes in circulating immune cells after stroke and their association with clinical outcomes in hyperglycemic compared to euglycemic patients. PATIENTS AND METHODS: This retrospective study included 97 (58 % euglycemic, 42 % hyperglycemic) patients presenting within 12 h of symptom onset of stroke. Blood neutrophil, monocyte and lymphocyte concentrations were measured sequentially for 96 h post stroke. Primary clinical outcome was the difference in the NIH stroke scale at admission compared to discharge. Secondary outcome measures included discharge disposition and the modified Rankin Scale (mRS) at 90 days. RESULTS: Circulating neutrophils were significantly higher in hyperglycemic than in euglycemic patients within the first 48 h post stroke, while lymphocyte counts trended to be lower. Hyperglycemic patients had higher mortality rates, less favorable discharge disposition and worse neurological function at 90 days. In both groups, the neutrophil to lymphocytes ratio ((NLR) remained strongly associated with neurological function at discharge within the first 24 h (p < 0.001), and remained significant in hyperglycemic patients up to 48 h (p < 0.001). Multivariate regression analysis showed no confounding by other factors and a significant correlation with differences in NIHSS score (CI; - 9.287 to -1.46, p = 0.0077**) and NLR (CL; 0.6058-6.901, p = 0.0203*) in hyperglycemic patients. CONCLUSIONS: Our data suggests that circulating immune cells play an important role in mediating poor clinical outcome in hyperglycemic patients following stroke. The NLR is a strong predictor of neurological outcomes in hyperglycemic patients. Thus, the modulation of immune cells may be a viable therapeutic approach to improve outcomes for this high risk group.

American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults.

BACKGROUND: Central nervous system (CNS) complications are among the most common, devastating sequelae of sickle cell disease (SCD) occurring throughout the lifespan. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology are intended to support the SCD community in decisions about prevention, diagnosis, and treatment of the most common neurological morbidities in SCD. METHODS: The Mayo Evidence-Based Practice Research Program supported the guideline development process, including updating or performing systematic evidence reviews. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations. RESULTS: The panel placed a higher value on maintaining cognitive function than on being alive with significantly less than baseline cognitive function. The panel developed 19 recommendations with evidence-based strategies to prevent, diagnose, and treat CNS complications of SCD in low-middle- and high-income settings. CONCLUSIONS: Three of 19 recommendations immediately impact clinical care. These recommendations include: use of transcranial Doppler ultrasound screening and hydroxyurea for primary stroke prevention in children with hemoglobin SS (HbSS) and hemoglobin Sß0 (HbSß0) thalassemia living in low-middle-income settings; surveillance for developmental delay, cognitive impairments, and neurodevelopmental disorders in children; and use of magnetic resonance imaging of the brain without sedation to detect silent cerebral infarcts at least once in early-school-age children and once in adults with HbSS or HbSß0 thalassemia. Individuals with SCD, their family members, and clinicians should become aware of and implement these recommendations to reduce the burden of CNS complications in children and adults with SCD.

Survey of Dental Researchers' Perceptions of Sexual Harassment at AADR Conferences: 2015 to 2018.

The American Association for Dental Research (AADR) is committed to providing a collegial, safe, and welcoming environment for all. As part of this effort, we assessed perceptions and experiences related to sexual, gender-based, and non-gender-based harassment among registrants at AADR annual meetings from 2015 to 2018 (n = 10,495); examined demographic factors associated with reported experiences; and identified facilitators and potential solutions concerning these types of harassment. Registrants were emailed an invitation to an anonymous online survey. Demographics were assessed categorically, and response distributions to close-ended survey items were evaluated by these variables. Bivariate analyses of participant demographics were conducted with 8 types of perceived harassment. To determine the demographic distribution of reporters, along with bivariate associations among them, restricted analyses were performed among individuals reporting any type of harassment. Qualitative data analysts conducted content analysis of the open-ended responses to questions asking participants to reflect on the topic. Peer debriefing was used to refine the coding schema. A total of 824 responses were received, of which 172 individuals reported experiencing ≥1 of the 8 types of harassment surveyed. Among those, reports of condescending remarks occurred most frequently (70%). Reported harassment of a more sexual nature was less common by comparison. Reporters of harassment were more likely to be women, members of the AADR/CADR (Canadian Association for Dental Research) divisions, and/or frequent meeting attendees. A total of 229 respondents answered at least 1 of the open-ended questions. While the majority of survey respondents reported no personal experience with harassment at AADR meetings, the fact that 1 in 5 did should be cause for concern. In 2018, AADR introduced a "Professional Conduct at Meetings Policy" delineating unacceptable behaviors, including intimidating or harassing speech and actions. Results of this survey form an important baseline from which its impact may be monitored to ensure that future AADR meetings are respectful, supportive, and safe environments for all.

Contamination in complex healthcare trials: the falls in care homes (FinCH) study experience.

BACKGROUND: Trials are at risk of contamination bias which can occur when participants in the control group are inadvertently exposed to the intervention. This is a particular risk in rehabilitation studies where it is easy for trial interventions to be either intentionally or inadvertently adopted in control settings. The Falls in Care Homes (FinCH) trial is used in this paper as an example of a large randomised controlled trial of a complex intervention to explore the potential risks of contamination bias. We outline the FinCH trial design, present the potential risks from contamination bias, and the strategies used in the design of the trial to minimise or mitigate against this. The FinCH trial was a multi-centre randomised controlled trial, with embedded process evaluation, which evaluated whether systematic training in the use of the Guide to Action Tool for Care Homes reduced falls in care home residents. Data were collected from a number of sources to explore contamination in the FinCH trial. Where specific procedures were adopted to reduce risk of, or mitigate against, contamination, this was recorded. Data were collected from study e-mails, meetings with clinicians, research assistant and clinician network communications, and an embedded process evaluation in six intervention care homes. During the FinCH trial, there were six new falls prevention initiatives implemented outside the study which could have contaminated our intervention and findings. Methods used to minimise contamination were: cluster randomisation at the level of care home; engagement with the clinical community to highlight the risks of early adoption; establishing local collaborators in each site familiar with the local context; signing agreements with NHS falls specialists that they would maintain confidentiality regarding details of the intervention; opening additional research sites; and by raising awareness about the importance of contamination in research among participants. CONCLUSION: Complex rehabilitation trials are at risk of contamination bias. The potential for contamination bias in studies can be minimized by strengthening collaboration and dialogue with the clinical community. Researchers should recognise that clinicians may contaminate a study through lack of research expertise.

Assessing the Translation of Research and Innovation into Dental Practice.

INTRODUCTION: Over the past 100 y, there have been an unprecedented number of innovations that have improved oral health and functioning. Variations in lag times between discovery and clinical adoption are related to dentist education, the clinical availability of technology, and the perceived value of an innovation. OBJECTIVES: The purposes of this cross-sectional study were 1) catalogue research discoveries and innovations over the past 30 y and 2) from that list identify those which practicing dentists believe have maximally affected patient care. METHODS: Thirty International Association for Dental Research leaders identified innovations over the past 30 y that have significantly affected dental care. The 30 most cited innovations were included in a questionnaire that was sent to a random sample of US dentists who graduated dental school during or before 1995 (before the recency of identified discoveries) and devoted ≥50% of their time to patient care. Eighty-two percent of respondents identified as general dentists and 18% as specialists. Respondents were asked to identify 5 to 7 items whose loss would have the most adverse effects on patient care. RESULTS: The most cited advances were adhesive dental materials (74.5%), dental implants (71.9%), direct bonding systems (71.2%), dental loupes (54.7%), universal precautions for infection control (48.6%), and digital imaging (46.0%). There were differences in the ranking of responses between generalists and specialists. For the oral surgeons and periodontists (OMSPER, n = 51), top choices were dental implants (82%), cone beam computed tomography (CBCT) imaging (74%), regenerative dentistry and tissue engineering (68%), universal precautions (58%), digital imaging (56%), and dental loupes (48%). CONCLUSIONS: There was agreement among generalists and specialists about the importance of dental implants, digital imaging, use of dental loupes, and universal precautions in improving patient care. However, generalists also cited the importance of adhesive dental materials and bonding, and OMSPER cited CBCT and biological-based tissue restoration as major advances. KNOWLEDGE TRANSFER STATEMENT: Many advances in dental patient care capitalize on innovations and technologies that have emerged after dentists graduate from dental school. Adoption of new technologies is influenced by information acquired from professional journals, continuing education, industry marketing activities, and interactions with colleagues. The results of this study suggest that innovations that are directly related to clinical procedures were rated most impactful. Future research should consider cost-effectiveness and patient perceptions on the impact of innovations and technologies.

Gender Inequalities in the Dental Workforce: Global Perspectives.

The aim of this review is to investigate the growth of diversity and inclusion in global academic dental research with a focus on gender equality. A diverse range of research methodologies were used to conduct this review, including an extensive review of the literature, engagement of key informants in dental academic leadership positions around the world, and review of current data from a variety of national and international organizations. Results provide evidence of gender inequalities that currently persist in dental academics and research. Although the gender gap among graduating dental students in North America and the two most populous countries in Europe (the United Kingdom and France) has been narrowed, women make up 30% to 40% of registered dentists in countries throughout Europe, Oceania, Asia, and Africa. In academic dentistry around the globe, greater gender inequality was found to correlate with higher ranking academic and leadership positions in the United States, United Kingdom, several countries in European Union, Japan, and Saudi Arabia. Further disparities are noted in the dental research sector, where women make up 33% of dental researchers in the European Union, 35% in North America, 55% in Brazil, and 25% in Japan. Family and societal pressures, limited access to research funding, and lack of mentoring and leadership training opportunities are reported as also contributing to gender inequalities. To continue advancing gender equality in dental academia and research, efforts should be geared toward the collection and public dissemination of data on gender-specific distributions. Such evidence-driven information will guide the selection of future strategies and best practices for promoting gender equity in the dental workforce, which provides a major pipeline of researchers and scholars for the dental profession.

Empowering Women Researchers in the New Century: IADR's Strategic Direction.

Gender inequality in science, medicine, and dentistry remains a central concern for the biomedical research workforce today. Although progress in areas of inclusivity and gender diversity was reported, growth has been slow. Women still face multiple challenges in reaching higher ranks and leadership positions while maintaining holistic success in these fields. Within dental research and academia, we might observe trends toward a more balanced pipeline. However, women continue to face barriers in seeking leadership roles and achieving economic equity and scholarship recognition. In an effort to evaluate the status of women in dental research and academia, the authors examined the role of the International Association for Dental Research (IADR), a global research organization, which has improved awareness on gender inequality. The goal of this article is to review five crucial issues of gender inequality in oral health research and academics-workforce pipeline, economic inequality, workplace harassment, gender bias in scholarly productivity, and work-life balance-and to discuss proactive steps that the IADR has taken to promote gender equality. Providing networking and training opportunities through effective mentoring and coaching for women researchers, the IADR has developed a robust pipeline of women leaders while promoting gender equality for women in dental academia through a culture shift. As knowledge gaps remained on the levels of conscious and unconscious bias and sexist culture affecting women advancement in academics, as well as the intersectionality of gender with race, gender identity, ability status, sexual orientation, and cultural backgrounds, the IADR has recognized that further research is warranted.