Clinical and Histopathologic Characteristics of Acute Severe Hepatitis Associated With Human Herpesvirus 6 Infection.

Acute severe hepatitis associated with active human herpesvirus 6 (HHV-6) infection is a rare life-threatening condition with unclear clinical course and histopathology. In this study, we retrospectively analyzed 5 patients with indeterminate acute severe hepatitis found to have active hepatic HHV-6 infection during care. All patients were previously healthy children presenting with a nonspecific prodrome. Four developed acute liver failure (ALF) and 3 received liver transplantation. The explanted livers and biopsies demonstrated a centrilobular pattern of necroinflammation characterized by moderate to marked central perivenulitis and confluent centrilobular to panlobular necrosis in 4 cases, accompanied by marked hepatocellular swelling and milder portal inflammation in 3. Central perivenulitis was more prominent in comparison to a control of group of ALF without HHV-6 ( P =0.01). When compared with the children with acute severe hepatitis associated with adenovirus encountered in the recent outbreak, both central perivenulitis and centrilobular necrosis were significant predictors for association with HHV-6 ( P <0.01). Liver immunohistochemistry detected HHV-6 structural protein in biliary epithelium in all cases and a predominance of CD8 + T cells in the perivenular inflammatory infiltrate. Among the 4 patients with ALF, one received early anti-HHV-6 therapy and had transplant-free survival, while the other 3 received either general prophylactic antiviral treatment only (n=2) or late anti-HHV-6 therapy (n=1) and needed liver transplantation. Our findings were similar to those in previously reported cases. In summary, acute severe hepatitis associated with HHV-6 tends to affect children, progress to ALF, and exhibit characteristic centrilobular necroinflammation which likely represents an immune-mediated process.

MeCP2 binds to methylated DNA independently of phase separation and heterochromatin organisation.

Correlative evidence has suggested that the methyl-CpG-binding protein MeCP2 contributes to the formation of heterochromatin condensates via liquid-liquid phase separation. This interpretation has been reinforced by the observation that heterochromatin, DNA methylation and MeCP2 co-localise within prominent foci in mouse cells. The findings presented here revise this view. MeCP2 localisation is independent of heterochromatin as MeCP2 foci persist even when heterochromatin organisation is disrupted. Additionally, MeCP2 foci fail to show hallmarks of phase separation in live cells. Importantly, we find that mouse cellular models are highly atypical as MeCP2 distribution is diffuse in most mammalian species, including humans. Notably, MeCP2 foci are absent in Mus spretus which is a mouse subspecies lacking methylated satellite DNA repeats. We conclude that MeCP2 has no intrinsic tendency to form condensates and its localisation is independent of heterochromatin. Instead, the distribution of MeCP2 in the nucleus is primarily determined by global DNA methylation patterns.

Epistasis, core-genome disharmony, and adaptation in recombining bacteria.

Recombination of short DNA fragments via horizontal gene transfer (HGT) can introduce beneficial alleles, create genomic disharmony through negative epistasis, and create adaptive gene combinations through positive epistasis. For non-core (accessory) genes, the negative epistatic cost is likely to be minimal because the incoming genes have not co-evolved with the recipient genome and are frequently observed as tightly linked cassettes with major effects. By contrast, interspecific recombination in the core genome is expected to be rare because disruptive allelic replacement is likely to introduce negative epistasis. Why then is homologous recombination common in the core of bacterial genomes? To understand this enigma, we take advantage of an exceptional model system, the common enteric pathogens Campylobacter jejuni and C. coli that are known for very high magnitude interspecies gene flow in the core genome. As expected, HGT does indeed disrupt co-adapted allele pairings, indirect evidence of negative epistasis. However, multiple HGT events enable recovery of the genome's co-adaption between introgressing alleles, even in core metabolism genes (e.g., formate dehydrogenase). These findings demonstrate that, even for complex traits, genetic coalitions can be decoupled, transferred, and independently reinstated in a new genetic background-facilitating transition between fitness peaks. In this example, the two-step recombinational process is associated with C. coli that are adapted to the agricultural niche.IMPORTANCEGenetic exchange among bacteria shapes the microbial world. From the acquisition of antimicrobial resistance genes to fundamental questions about the nature of bacterial species, this powerful evolutionary force has preoccupied scientists for decades. However, the mixing of genes between species rests on a paradox: 0n one hand, promoting adaptation by conferring novel functionality; on the other, potentially introducing disharmonious gene combinations (negative epistasis) that will be selected against. Taking an interdisciplinary approach to analyze natural populations of the enteric bacteria Campylobacter, an ideal example of long-range admixture, we demonstrate that genes can independently transfer across species boundaries and rejoin in functional networks in a recipient genome. The positive impact of two-gene interactions appears to be adaptive by expanding metabolic capacity and facilitating niche shifts through interspecific hybridization. This challenges conventional ideas and highlights the possibility of multiple-step evolution of multi-gene traits by interspecific introgression.

Rapid response of thyroid eye disease, peripheral edema, and acropathy to teprotumumab infusion.

Purpose: We present a case of rapid improvement in symptoms of thyroid eye disease and amelioration of worsening peripheral edema and acropathy with infusion of teprotumumab, a monoclonal antibody targeting the insulin-like growth factor-1 receptor. Observations: A 66 year old female with history of Hashimoto thyroiditis developed progressive thyroid eye disease (TED), peripheral edema, and acropathy attributable to acute Graves disease. Her signs and symptoms, refractory to oral steroid and diuretic therapy, rapidly improved following a standard dosing regimen of teprotumumab (one infusion 10 mg/kg then seven infusions 20 mg/kg) to resolution. Conclusions & importance: Teprotumumab, a monoclonal antibody targeting the insulin-like growth factor-1 receptor, is the first medication approved by the FDA for use in TED. Teprotumumab may contribute to the treatment of extraocular manifestations of Graves disease, chief among these peripheral soft tissue manifestations.

Do players with superior physiological attributes outwork their less-conditioned counterparts? A study in Gaelic football.

This study investigated the association of physiological attributes with in-game workload measures during competitive Gaelic football match-play. Fifty-two male developmental level Gaelic football players (mean ± SD; age: 22.9 ± 3.8 years) underwent measurements of anthropometric characteristics, running speed, muscular strength and power, blood lactate (BLa), running economy and aerobic capacity during two separate testing visits. Global Positioning System units (18-Hz) were used to record players in-game workloads during a competitive match 1-week following the baseline physiological assessments. Results indicated that players body fat percentage, drop jump height (DJ) and running velocity at 4 mmol · L-1 BLa were significantly associated with the number of high-speed runs completed (Adjusted R2 26.8% to 39.5%; p < 0.05) while 20 m running speed, running velocity at 2 mmol · L-1 BLa and DJ were significantly associated with the number of accelerations completed (Adjusted R2 17.2% to 22.0%; p < 0.05) during match-play. Additionally, aerobic capacity and body fat percentage were significantly associated with total distance (Adjusted R2 14.4% to 22.4%; p < 0.05) while body fat percentage, DJ and 20 m running speed were significantly associated with high-speed distance (Adjusted R2 17.8% to 22.0%; p < 0.05). Players were also divided into higher-standard and lower-standard groups using a median split of these physiological attributes. Players in the higher-standard groups completed significantly more high-speed runs and accelerations and covered significantly larger total and high-speed distances (+10.4% to +36.8%; ES = 0.67 to 0.88; p < 0.05) when compared to the lower-standard groups. This study demonstrates that superior levels of physical conditioning are associated with larger in-game workloads during Gaelic football match-play.

Correction: Wet market biosecurity reform: Three social narratives influence stakeholder responses in Vietnam, Kenya, and the Philippines.

[This corrects the article DOI: 10.1371/journal.pgph.0001704.].

Students experienced near peer-led simulation in physiotherapy education as valuable and engaging: a mixed methods study.

QUESTIONS: What is the student experience of near peer-led simulation in physiotherapy education from the perspectives of students (near peer learners and near peer teachers)? What are their expectations, perceptions and engagement in this as a teaching and learning activity? Are there any short-term benefits? DESIGN: Convergent mixed-methods study. PARTICIPANTS: From a graduate entry Doctor of Physiotherapy course, 111 first-year and 20 second-year students participated. INTERVENTION: Near peer-led simulation was delivered within first-year cardiorespiratory, musculoskeletal and neurological physiotherapy curricula and as a precursor to second-year clinical placements. First-year students were near peer learners. Second-year students were near peer teachers and the simulated patients. OUTCOME MEASURES: Focus groups, pre/post-simulation questionnaires and direct observation. Data were triangulated and presented in overall themes. RESULTS: Five themes emerged: near peer-led simulation improved the students' confidence and the opportunity to make mistakes in a supportive and safe environment was valued; peer feedback was an integral part of the learning process that enriched the learning experience; the authenticity and realism created seriousness, promoted engagement and facilitated perceived knowledge transfer; there were benefits for learning for both peer learners and peer teachers; and the anticipation and emotional impact was evident. CONCLUSION: Near peer-led simulation was viewed by students as a valuable and engaging activity. Students perceived a broad range of benefits on their learning, especially from peer feedback (giving and receiving) on their performance, and had increased confidence following simulation. Peer-led simulation is an authentic and valuable component of entry-to-practice physiotherapy education.

Age-dependent loss of cohesion protection in human oocytes.

Aneuploid human eggs (oocytes) are a major cause of infertility, miscarriage, and chromosomal disorders. Such aneuploidies increase greatly as women age, with defective linkages between sister chromatids (cohesion) in meiosis as a common cause. We found that loss of a specific pool of the cohesin protector protein, shugoshin 2 (SGO2), may contribute to this phenomenon. Our data indicate that SGO2 preserves sister chromatid cohesion in meiosis by protecting a "cohesin bridge" between sister chromatids. In human oocytes, SGO2 localizes to both sub-centromere cups and the pericentromeric bridge, which spans the sister chromatid junction. SGO2 normally colocalizes with cohesin; however, in meiosis II oocytes from older women, SGO2 is frequently lost from the pericentromeric bridge and sister chromatid cohesion is weakened. MPS1 and BUB1 kinase activities maintain SGO2 at sub-centromeres and the pericentromeric bridge. Removal of SGO2 throughout meiosis I by MPS1 inhibition reduces cohesion protection, increasing the incidence of single chromatids at meiosis II. Therefore, SGO2 deficiency in human oocytes can exacerbate the effects of maternal age by rendering residual cohesin at pericentromeres vulnerable to loss in anaphase I. Our data show that impaired SGO2 localization weakens cohesion integrity and may contribute to the increased incidence of aneuploidy observed in human oocytes with advanced maternal age.

Wellbeing-responsive community: a growth target for intentional mental health promotion.

With mental illness remaining a significant burden of disease, there is an ongoing need for community-based health promotion, prevention, and responses (or "mental health promotion activities"). The health promotion, community development, and positive psychology literature identifies significant heterogeneity in the design and delivery of these activities. This variability spans: (1) individual vs. group outcomes, (2) psychological vs. sociological determinants of change, (3) promoting wellbeing vs. reducing mental health symptoms, and (4) the degree activities are contextualized vs. standardized in design and delivery. Mental health promotion activities do not easily accomplish this level of complexity within design and implementation. This has led to the emergence of the complexity-informed health promotion literature and the need for innovative tools, methods, and theories to drive this endeavor. This article directly responds to this call. It introduces "wellbeing-responsive community": a vision and outcome hierarchy (or growth target) for intentionally delivered mental health promotion. The construct enables the design and implementation of interventions that intentionally respond to complexity and contextualization through the drivers of co-creation, intentionality, and local empowerment. It represents a community (support team, programme, agency, network, school, or region) that has the shared language, knowledge, methods, and skills to work together in shared intent. In other words, to integrate best-practice science with their local knowledge systems and existing strengths, and intentionally co-create and deliver contextualized wellbeing solutions at both the individual and community levels that span the "system" (e.g., whole-of-community) to the "moment" (e.g., intentional support and care). Co-creation, as applied through a transdisciplinary lens, is emerging as an evidence-based method to respond to complexity. This article describes the rationale and evidence underpinning the conceptualization of a wellbeing-responsive community through the integration of three key disciplines: (1) positive psychology, (2) ecological or systems approaches, and (3) intentional practice (implementation science). A definitional, contextual, and applied overview of the wellbeing-responsive community is provided, including a hierarchy of outcomes and associated definitions. Its purported application across education, mental health, community service, and organizational settings is discussed, including its potential role in making complexity-informed health promotion practical for all knowledge users.

Are vectors able to learn about their hosts? A case study with Aedes aegypti mosquitoes

The way in which vectors distribute themselves amongst their hosts has important epidemiological consequences. While the role played by active host choice is largely unquestioned, current knowledge relates mostly to the innate response of vectors towards stimuli signalling the presence or quality of their hosts. Many of those cues, however, can be unpredictable, and therefore prevent the incorporation of the appropriate response into the vector's behavioural repertoire unless some sort of associative learning is possible. We performed a wide range of laboratory experiments to test the learning abilities of the mosquito, Aedes aegypti. Mosquitoes were exposed to choice procedures in (1) an olfactomenter and (2) a 'visual arena'. Our goal was to determine whether the mosquitoes were able to associate unconditional stimuli (blood feeding, human breath, vibration and electrical shock) with particular odours (citral, carvone, citronella oil and eugenol) and visual patterns (horizontal or vertical black bars) to which they had been previously observed to be responsive. We found no evidence supporting the hypothesis that associative learning abilities are present in adult Ae. aegypti. We discuss the possibilities that the assays employed were either inappropriate or insufficient to detect associative learning, or that associative learning is not possible in this species