Signalling pathways and transcriptional regulators orchestrating liver development and cancer.

Liver development is controlled by key signals and transcription factors that drive cell proliferation, migration, differentiation and functional maturation. In the adult liver, cell maturity can be perturbed by genetic and environmental factors that disrupt hepatic identity and function. Developmental signals and fetal genetic programmes are often dysregulated or reactivated, leading to dedifferentiation and disease. Here, we highlight signalling pathways and transcriptional regulators that drive liver cell development and primary liver cancers. We also discuss emerging models derived from pluripotent stem cells, 3D organoids and bioengineering for improved studies of signalling pathways in liver cancer and regenerative medicine.

Intravascular Endothelial Hyperplasia of the Foot.

Intravascular endothelial hyperplasia is a benign soft tissue mass rarely reported in the foot. Advanced imaging and confirming a benign diagnosis are critical for any soft tissue mass. This paper identifies 2 patients that developed intravascular endothelial hyperplasia tumors which required surgical excision. A 17-year-old male patient presented to clinic complaining of a painful bump to the arch of his right foot which he related to an injury 9 months prior. Magnetic resonance imaging of the right foot revealed a mass within the plantar subcutaneous fat that was serpiginous in nature similar to adjacent branching vessels favoring a low-flow vascular malformation. A 38-year-old female with Multiple Sclerosis presented with complaints of persistent symptoms of pain to the 1st interspace, difficult ambulation and neuritis. Ultrasound and MRI observed solid, multilobulated mass, with internal vascular malformation, MRI describing intrinsic involvement along the abductor musculature and flexor tendons. Both lesions were surgically excised and sent for pathology. Pathology report indicated a diagnosis of intravascular papillary endothelial hyperplasia or Masson's tumor in both cases. Pathology diagnosis of intravascular papillary endothelial hyperplasia is generally good with wide resection leading to low recurrence rates. Both patients in the current study have progressed postoperatively with resolution of symptoms and without recurrence.

Shigellosis Cases With Bacterial Sexually Transmitted Infections: Population-Based Data From 6 US Jurisdictions, 2007 to 2016.

BACKGROUND: Shigella species, which cause acute diarrheal disease, are transmitted via fecal-oral and sexual contact. To better understand the overlapping populations affected by Shigella infections and sexually transmitted infections (STIs) in the United States, we examined the occurrence of reported STIs within 24 months among shigellosis case-patients. METHODS: Culture-confirmed Shigella cases diagnosed from 2007 to 2016 among residents of 6 US jurisdictions were matched to reports of STIs (chlamydia, gonorrhea, and all stages of syphilis) diagnosed 12 months before or after the shigellosis case. We examined epidemiologic characteristics and reported temporal trends of Shigella cases by sex and species. RESULTS: From 2007 to 2016, 10,430 shigellosis cases were reported. The annual number of reported shigellosis cases across jurisdictions increased 70%, from 821 cases in 2007 to 1398 cases in 2016; males saw a larger increase compared with females. Twenty percent of male shigellosis case-patients had an STI reported in the reference period versus 4% of female case-patients. The percentage of male shigellosis case-patients with an STI increased from 11% (2007) to 28% (2016); the overall percentage among females remained low. CONCLUSIONS: We highlight the substantial proportion of males with shigellosis who were diagnosed with STIs within 24 months and the benefit of matching data across programs. Sexually transmitted infection screening may be warranted for male shigellosis case-patients.

Using pharmacy technicians and electronic health record capabilities to improve outcomes for patients with cardiovascular disease.

OBJECTIVE: This study aimed to compare lipid and blood pressure (BP) control before and after implementing a certified pharmacy technician (CPhT) protocol that optimized electronic health record (EHR) capabilities and shifted work from clinical pharmacy specialists (CPSs) to CPhT. SETTING: Kaiser Permanente Colorado's pharmacist-managed cardiac risk reduction service (which manages dyslipidemia, hypertension, and diabetes for all patients with atherosclerotic cardiovascular disease). PRACTICE DESCRIPTION: In 2019, a protocol that optimized EHR capabilities and allowed work to be offloaded from CPS to CPhT was implemented. Filtered views within the EHR were created that bucketed patients with specific lipid results criteria. The CPhT protocol provided guidance to CPhT on determining whether patients were at low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein (non-HDL) goals, on appropriate statin intensity, adherent to medications, and whether the most recent BP was controlled. The CPhT notified CPS of uncontrolled patients who would assess and manage these patients, as necessary. The CPhT notified controlled patients of their results. PRACTICE INNOVATION: Data on the outcomes of incorporating pharmacy technicians to support CPS clinical activities in ambulatory clinical pharmacy are limited. EVALUATION DETHODS: This retrospective study compared a "Pharmacist-Driven" (index date: January 1, 2016) with a "Tech-Enhanced" (index date: January 1, 2019) group. The primary outcome was the proportion of patients at all goals defined as LDL-C < 70 mg/dL, non-HDL < 100 mg/dL, and BP < 140/90 mm Hg at 1 year after the index dates. RESULTS: There were 6813 patients included (mean age: 70.2 ± 11.1 years, 71.4% male): 3130 and 3683 in the "Pharmacist-Driven" and "Tech-Enhanced" groups, respectively. The proportion of patients who attained LDL-C, non-HDL, and BP goals was higher in the "Tech-Enhanced" group (51.1% vs. 39.7%, P < 0.001) than the "Pharmacist-Driven" group. CONCLUSION: A protocol integrating EHR decision support and CPhTs enabled work to shift to from CPS to CPhT and improved clinical outcomes.

Radiographic Analysis of the Lateral Column Lengthening Procedure in Stage II Adult Acquired Flatfoot Deformity.

Adult acquired flat foot deformity (AAFD) is a progressive, tri-planar deformity involving collapse of the medial longitudinal arch, valgus deformity of the rear foot, and abduction of the mid-foot on the rear foot. There are a wide variety of surgical treatment options for this deformity, including lateral column lengthening (LCL) which results in tri-planar correction of AAFD. We retrospectively reviewed weightbearing preoperative radiographs and weight-bearing 6-week postoperative radiographs of 34 patients with stage II AAFD who underwent LCL (with and without concurrent procedures) with a minimum of 1-year of follow up. Outcomes, including complications and postoperative differences in 6 types of angle measurements were evaluated. Radiographic evaluation showed statistically significant differences in preoperative and postoperative measures in the following angles: calcaneal inclination, Meary's, Simmons, talocalcaneal, and metatarsus adductus (each p ≤ .05). Postoperative Engel's angle difference did not reach statistical significance (p = .07). Paired t tests showed TN coverage angles increased greater with LCL plus a Cotton osteotomy as compared to isolated LCL. Additionally, there was no significant difference in TN coverage angle based on LCL graft size (p = .20). Furthermore, the distance of the osteotomy from the calcaneocuboid joint on anteroposterior and lateral radiographs did not significantly predict TN coverage angle change. Our study suggests that LCL corrects AAFD in three planes while decreasing the metatarsus adductus angle. LCL appears to be more effective when performed with a Cotton osteotomy. Wedge size (6 mm, 8 mm, 10 mm) and osteotomy location did not demonstrate a relationship with postoperative TN coverage angle or incidence of lateral column overload.

Influenza Vaccination in Health Centers During the Coronavirus Disease 2019 Pandemic-United States, 7-27 November 2020.

BACKGROUND: Influenza vaccination is the most effective way to prevent influenza and influenza-associated complications including those leading to hospitalization. Resources otherwise used for influenza could support caring for patients with coronavirus disease 2019 (COVID-19). The Health Resources and Services Administration (HRSA) Health Center Program serves 30 million people annually by providing comprehensive primary healthcare, including influenza vaccination, to demographically diverse and historically underserved communities. Because racial and ethnic minority groups have been disproportionately affected by COVID-19, the objective of this analysis was to assess disparities in influenza vaccination at HRSA-funded health centers during the COVID-19 pandemic. METHODS: The Centers for Disease Control and Prevention and HRSA analyzed cross-sectional data on influenza vaccinations from a weekly, voluntary health center COVID-19 survey after addition of an influenza-related question covering 7-11 November 2020. RESULTS: During the 3-week period, 1126 of 1385 health centers (81%) responded to the survey. Most of the 811 738 influenza vaccinations took place in urban areas and in the Western US region. There were disproportionately more health center influenza vaccinations among racial and ethnic minorities in comparison with county demographics, except among non-Hispanic blacks and American Indian/Alaska Natives. CONCLUSIONS: HRSA-funded health centers were able to quickly vaccinate large numbers of mostly racial or ethnic minority populations, disproportionately more than county demographics. However, additional efforts might be needed to reach specific racial populations and persons in rural areas. Success in influenza vaccination efforts can support success in severe acute respiratory syndrome coronavirus 2 vaccination efforts.

Management of COVID-19 infection in organic acidemias.

The COVID-19 pandemic has affected the health and healthcare of individuals of all ages worldwide. There have been multiple reports and reviews documenting a milder effect and decreased morbidity and mortality in the pediatric population, but there have only been a small number of reports discussing the SARS-CoV-2 infection in the setting of an inborn error of metabolism (IEM). Here, we report two patients with underlying metabolic disorders, propionic acidemia and glutaric aciduria type 1, and discuss their clinical presentation, as well as their infectious and metabolic management. Our report demonstrates that individuals with an underlying IEM are at risk of metabolic decompensation in the setting of a COVID-19 infection. The SARS-CoV-2 virus does not appear to cause a more severe metabolic deterioration than is typical.

Trends in Use of Telehealth Among Health Centers During the COVID-19 Pandemic - United States, June 26-November 6, 2020.

Telehealth can facilitate access to care, reduce risk for transmission of SARS-CoV-2 (the virus that causes coronavirus disease 2019 [COVID-19]), conserve scarce medical supplies, and reduce strain on health care capacity and facilities while supporting continuity of care. Health Resources and Services Administration (HRSA)-funded health centers* expanded telehealth† services during the COVID-19 pandemic (1). The Centers for Medicare & Medicaid Services eliminated geographic restrictions and enhanced reimbursement so that telehealth services-enabled health centers could expand telehealth services and continue providing care during the pandemic (2,3). CDC and HRSA analyzed data from 245 health centers that completed a voluntary weekly HRSA Health Center COVID-19 Survey§ for 20 consecutive weeks to describe trends in telehealth use. During the weeks ending June 26-November 6, 2020, the overall percentage of weekly health care visits conducted via telehealth (telehealth visits) decreased by 25%, from 35.8% during the week ending June 26 to 26.9% for the week ending November 6, averaging 30.2% over the study period. Weekly telehealth visits declined when COVID-19 cases were decreasing and plateaued as cases were increasing. Health centers in the South and in rural areas consistently reported the lowest average percentage of weekly telehealth visits over the 20 weeks, compared with health centers in other regions and urban areas. As the COVID-19 pandemic continues, maintaining and expanding telehealth services will be critical to ensuring access to care while limiting exposure to SARS-CoV-2.

Adolescent psychopathology and psychological wellbeing: a network analysis approach.

BACKGROUND: The extent to which psychological wellbeing may play a preventive and therapeutic role in the development and maintenance of adolescent emotional disorders depends, in part, on the nature of the overlap between these two constructs. We estimated network analysis to examine the relationship between adolescent psychopathology (measured by depression and anxiety symptoms) and psychological wellbeing (measured by happiness, optimism, social support, perceived control, and gratitude). METHODS: This was a cross-sectional study with a large community sample of Kenyan adolescents (N = 2192, aged 13-18). Network analyses were conducted to examine the topology, stability, centrality, and bridge nodes of a network of psychopathology and psychological wellbeing measures. RESULTS: Two distinct community clusters emerged, one for psychopathology nodes and another for wellbeing nodes, suggesting that these are two distinct but connected concepts. Central and bridge nodes of the wellbeing and psychopathology network were identified. The most central nodes in the network were family provides emotional help and support and self-blame; the strongest negative edges between psychopathology and psychological wellbeing were depressed mood-I love life and irritability-I am a joyful person; the main bridge nodes were family helps me and I can talk to family about problems. CONCLUSIONS: Our findings expand understanding of the relationship between psychopathology and wellbeing in an understudied population and are suggestive of how psychological wellbeing can inform psychopathological treatment and preventive efforts in low-income regions such as those in Sub Saharan Africa.

Telehealth Practice Among Health Centers During the COVID-19 Pandemic - United States, July 11-17, 2020.

Early in the coronavirus disease 2019 (COVID-19) pandemic, in-person ambulatory health care visits declined by 60% across the United States, while telehealth* visits increased, accounting for up to 30% of total care provided in some locations (1,2). In March 2020, the Centers for Medicare & Medicaid Services (CMS) released updated regulations and guidance changing telehealth provisions during the COVID-19 Public Health Emergency, including the elimination of geographic barriers and enhanced reimbursement for telehealth services† (3-6). The Health Resources and Services Administration (HRSA) administers a voluntary weekly Health Center COVID-19 Survey§ to track health centers' COVID-19 testing capacity and the impact of COVID-19 on operations, patients, and staff. CDC and HRSA analyzed data from the weekly COVID-19 survey completed by 1,009 HRSA-funded health centers (health centers¶) for the week of July 11-17, 2020, to describe telehealth service use in the United States by U.S. Census region,** urbanicity,†† staffing capacity, change in visit volume, and personal protective equipment (PPE) supply. Among the 1,009 health center respondents, 963 (95.4%) reported providing telehealth services. Health centers in urban areas were more likely to provide >30% of health care visits virtually (i.e., via telehealth) than were health centers in rural areas. Telehealth is a promising approach to promoting access to care and can facilitate public health mitigation strategies and help prevent transmission of SARS-CoV-2 and other respiratory illnesses, while supporting continuity of care. Although CMS's change of its telehealth provisions enabled health centers to expand telehealth by aligning guidance and leveraging federal resources, sustaining expanded use of telehealth services might require additional policies and resources.

Health Center Testing for SARS-CoV-2 During the COVID-19 Pandemic - United States, June 5-October 2, 2020.

Long-standing social inequities and health disparities have resulted in increased risk for coronavirus disease 2019 (COVID-19) infection, severe illness, and death among racial and ethnic minority populations. The Health Resources and Services Administration (HRSA) Health Center Program supports nearly 1,400 health centers that provide comprehensive primary health care* to approximately 30 million patients in 13,000 service sites across the United States.† In 2019, 63% of HRSA health center patients who reported race and ethnicity identified as members of racial ethnic minority populations (1). Historically underserved communities and populations served by health centers have a need for access to important information and resources for preventing exposure to SARS-CoV-2, the virus that causes COVID-19, to testing for those at risk, and to follow-up services for those with positive test results.§ During the COVID-19 public health emergency, health centers¶ have provided and continue to provide testing and follow-up care to medically underserved populations**; these centers are capable of reaching areas disproportionately affected by the pandemic.†† HRSA administers a weekly, voluntary Health Center COVID-19 Survey§§ to track health center COVID-19 testing capacity and the impact of COVID-19 on operations, patients, and personnel. Potential respondents can include up to 1,382 HRSA-funded health centers.¶¶ To assess health centers' capacity to reach racial and ethnic minority groups at increased risk for COVID-19 and to provide access to testing, CDC and HRSA analyzed survey data for the weeks June 5-October 2, 2020*** to describe all patients tested (3,194,838) and those who received positive SARS-CoV-2 test results (308,780) by race/ethnicity and state of residence. Among persons with known race/ethnicity who received testing (2,506,935), 36% were Hispanic/Latino (Hispanic), 38% were non-Hispanic White (White), and 20% were non-Hispanic Black (Black); among those with known race/ethnicity with positive test results, 56% were Hispanic, 24% were White, and 15% were Black. Improving health centers' ability to reach groups at increased risk for COVID-19 might reduce transmission by identifying cases and supporting contact tracing and isolation. Efforts to improve coordination of COVID-19 response-related activities between state and local public health departments and HRSA-funded health centers can increase access to testing and follow-up care for populations at increased risk for COVID-19.

Engaging Expectant and Parenting Adolescents: Lessons from the Massachusetts Pregnant and Parenting Teen Initiative.

INTRODUCTION: Programs supporting adolescent parents have been shown to increase socio-economic opportunities and promote healthy child development for young families, but retaining young parents is challenging. The Massachusetts Pregnant and Parenting Teen Initiative (MPPTI) offers case management and linkages to community and clinical services to young families. We examine engagement strategies identified by MPPTI participants and staff members in relation to participant retention by program site to identify potential strategies for increasing program engagement. METHODS: We employed a mixed-methods approach incorporating quantitative data on program participant characteristics and program retention by site with qualitative data from staff and participant interviews and focus groups. RESULTS: Key program engagement strategies identified by both MPPTI staff and youth participants were social-emotional supports, staffing model, and concrete supports. We found significant differences in program retention by site; the two sites with the highest levels of program retention offered all engagement strategies identified. DISCUSSION: Quantitative data on program retention coupled with qualitative data from staff and youth interviews suggests that in our program, there may be an association between the engagement strategies identified and levels of program retention.

A National Survey of Assertive Outreach Treatment Services for People Who Frequently Attend Hospital due to Alcohol-Related Reasons in England.

AIMS: To characterize England's alcohol assertive outreach treatment (AAOT) services for people who frequently attend hospital due to alcohol-related reasons according to their concordance with six core AAOT components. METHODS: A cross-sectional national survey using structured telephone interviews with health professionals examining 6 essential AAOT components. High-level AAOT services were those that delivered 5 or more components, mid-level 3 to 4 components, low-level AAOT services 2 or less. RESULTS: The analysis included 37 services that were classified according to their concordance with the 6 AAOT components. Six were identified as high-level AAOT services, 13 as mid-level AAOT services and 18 as low-level services. Extended support covering housing, mental and physical health over and above alcohol consumption was the most commonly delivered AAOT component provided. Having a multidisciplinary team was the least observed component, delivered in 33% high-level AAOT services and in 15% mid-level AAOT services. None of the low-level AAOT services had a multidisciplinary team. CONCLUSIONS: Access to AAOT services developed to support high-cost and high-needs frequent hospital attenders varies across the nation. Further research, service evaluation and AAOT implementation should focus on essential AAOT components rather than self-defined labels of AAOT. SHORT SUMMARY: The study investigated alcohol assertive outreach treatment (AAOT) services in England. The study found variability in service provision across AAOT services when measured against six essential AAOT components. Improvement of AAOT in England's hospitals should focus on the implementation of essential AAOT components.

The N Terminus of the Vaccinia Virus Protein F1L Is an Intrinsically Unstructured Region That Is Not Involved in Apoptosis Regulation.

Subversion of host cell apoptotic responses is a prominent feature of viral immune evasion strategies to prevent premature clearance of infected cells. Numerous poxviruses encode structural and functional homologs of the Bcl-2 family of proteins, and vaccinia virus harbors antiapoptotic F1L that potently inhibits the mitochondrial apoptotic checkpoint. Recently F1L has been assigned a caspase-9 inhibitory function attributed to an N-terminal α helical region of F1L spanning residues 1-15 (1) preceding the domain-swapped Bcl-2-like domains. Using a reconstituted caspase inhibition assay in yeast we found that unlike AcP35, a well characterized caspase-9 inhibitor from the insect virus Autographa californica multiple nucleopolyhedrovirus, F1L does not prevent caspase-9-mediated yeast cell death. Furthermore, we found that deletion of the F1L N-terminal region does not impede F1L antiapoptotic activity in the context of a viral infection. Solution analysis of the F1L N-terminal regions using small angle x-ray scattering indicates that the region of F1L spanning residues 1-50 located N-terminally from the Bcl-2 fold is an intrinsically unstructured region. We conclude that the N terminus of F1L is not involved in apoptosis inhibition and may act as a regulatory element in other signaling pathways in a manner reminiscent of other unstructured regulatory elements commonly found in mammalian prosurvival Bcl-2 members including Bcl-xL and Mcl-1.

Structural insight into BH3 domain binding of vaccinia virus antiapoptotic F1L.

UNLABELLED: Apoptosis is a tightly regulated process that plays a crucial role in the removal of virus-infected cells, a process controlled by both pro- and antiapoptotic members of the Bcl-2 family. The proapoptotic proteins Bak and Bax are regulated by antiapoptotic Bcl-2 proteins and are also activated by a subset of proteins known as BH3-only proteins that perform dual functions by directly activating Bak and Bax or by sequestering and neutralizing antiapoptotic family members. Numerous viruses express proteins that prevent premature host cell apoptosis. Vaccinia virus encodes F1L, an antiapoptotic protein essential for survival of infected cells that bears no discernible sequence homology to mammalian cell death inhibitors. Despite the limited sequence similarities, F1L has been shown to adopt a novel dimeric Bcl-2-like fold that enables hetero-oligomeric binding to both Bak and the proapoptotic BH3-only protein Bim that ultimately prevents Bak and Bax homo-oligomerization. However, no structural data on the mode of engagement of F1L and its Bcl-2 counterparts are available. Here we solved the crystal structures of F1L in complex with two ligands, Bim and Bak. Our structures indicate that F1L can engage two BH3 ligands simultaneously via the canonical Bcl-2 ligand binding grooves. Furthermore, by structure-guided mutagenesis, we generated point mutations within the binding pocket of F1L in order to elucidate the residues responsible for both Bim and Bak binding and prevention of apoptosis. We propose that the sequestration of Bim by F1L is primarily responsible for preventing apoptosis during vaccinia virus infection. IMPORTANCE: Numerous viruses have adapted strategies to counteract apoptosis by encoding proteins responsible for sequestering proapoptotic components. Vaccinia virus, the prototypical member of the family Orthopoxviridae, encodes a protein known as F1L that functions to prevent apoptosis by interacting with Bak and the BH3-only protein Bim. Despite recent structural advances, little is known regarding the mechanics of binding between F1L and the proapoptotic Bcl-2 family members. Utilizing three-dimensional structures of F1L bound to host proapoptotic proteins, we generated variants of F1L that neutralize Bim and/or Bak. We demonstrate that during vaccinia virus infection, engagement of Bim and Bak by F1L is crucial for subversion of host cell apoptosis.

Intimate partner violence and new-onset depression: a longitudinal study of women's childhood and adult histories of abuse.

BACKGROUND: Studies indicate that women victims of intimate partner violence are at increased risk for poor mental health. This research disentangled the effect of partner violence on new-onset depression and psychosis spectrum symptoms from effects of child maltreatment and other confounding factors, including substance abuse and antisocial personality. METHODS: Participants were 1,052 mothers involved in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative cohort of families followed prospectively. To test the directionality of associations between partner violence and depression, only women without a history of depression at the beginning of the study were considered (n = 978). Partner violence and mental health were assessed during face-to-face interviews with women across three time points. RESULTS: Four of 10 women reported being the victim of violence from their partner in a 10-year period. They represent 33% of our cohort and they account for 51% of new-onset depression. These women had a twofold increase in their risk of suffering from new-onset depression once the effect of childhood maltreatment, socioeconomic deprivation, antisocial personality, and young motherhood were controlled. Women who were abused both in childhood and adulthood were four to seven times more likely to suffer from depression than never-abused women. We observed similar associations with psychosis spectrum symptoms. CONCLUSIONS: Women victims of partner violence account for more than their share of depression. Findings strengthen existing evidence that partner violence independently contributes to women's poor mental health. Psychological difficulties among a considerable number of women could be reduced by stopping partner violence.

A lab-on-chip for malaria diagnosis and surveillance.

BACKGROUND: Access to timely and accurate diagnostic tests has a significant impact in the management of diseases of global concern such as malaria. While molecular diagnostics satisfy this need effectively in developed countries, barriers in technology, reagent storage, cost and expertise have hampered the introduction of these methods in developing countries. In this study a simple, lab-on-chip PCR diagnostic was created for malaria that overcomes these challenges. METHODS: The platform consists of a disposable plastic chip and a low-cost, portable, real-time PCR machine. The chip contains a desiccated hydrogel with reagents needed for Plasmodium specific PCR. Chips can be stored at room temperature and used on demand by rehydrating the gel with unprocessed blood, avoiding the need for sample preparation. These chips were run on a custom-built instrument containing a Peltier element for thermal cycling and a laser/camera setup for amplicon detection. RESULTS: This diagnostic was capable of detecting all Plasmodium species with a limit of detection for Plasmodium falciparum of 2 parasites/µL of blood. This exceeds the sensitivity of microscopy, the current standard for diagnosis in the field, by ten to fifty-fold. In a blind panel of 188 patient samples from a hyper-endemic region of malaria transmission in Uganda, the diagnostic had high sensitivity (97.4%) and specificity (93.8%) versus conventional real-time PCR. The test also distinguished the two most prevalent malaria species in mixed infections, P. falciparum and Plasmodium vivax. A second blind panel of 38 patient samples was tested on a streamlined instrument with LED-based excitation, achieving a sensitivity of 96.7% and a specificity of 100%. CONCLUSIONS: These results describe the development of a lab-on-chip PCR diagnostic from initial concept to ready-for-manufacture design. This platform will be useful in front-line malaria diagnosis, elimination programmes, and clinical trials. Furthermore, test chips can be adapted to detect other pathogens for a differential diagnosis in the field. The flexibility, reliability, and robustness of this technology hold much promise for its use as a novel molecular diagnostic platform in developing countries.

Parent-focused treatment for adolescent anorexia nervosa: a study protocol of a randomised controlled trial.

BACKGROUND: Family-based treatment is an efficacious outpatient intervention for medically stable adolescents with anorexia nervosa. Previous research suggests family-based treatment may be more effective for some families when parents and adolescents attend separate therapy sessions compared to conjoint sessions. Our service developed a novel separated model of family-based treatment, parent-focused treatment, and is undertaking a randomised controlled trial to compare parent-focused treatment to conjoint family-based treatment. METHODS/DESIGN: This randomised controlled trial will recruit 100 adolescents aged 12-18 years with DSM-IV anorexia nervosa or eating disorder not otherwise specified (anorexia nervosa type). The trial commenced in 2010 and is expected to be completed in 2015. Participants are recruited from the Royal Children's Hospital Eating Disorders Program, Melbourne, Australia. Following a multidisciplinary intake assessment, eligible families who provide written informed consent are randomly allocated to either parent-focused treatment or conjoint family-based treatment. In parent-focused treatment, the adolescent sees a clinical nurse consultant and the parents see a trained mental health clinician. In conjoint family-based treatment, the whole family attends sessions with the mental health clinician. Both groups receive 18 treatment sessions over 6 months and regular medical monitoring by a paediatrician. The primary outcome is remission at end of treatment and 6 and 12 month follow up, with remission defined as being ≥ 95% expected body weight and having an eating disorder symptom score within one standard deviation of community norms. The secondary outcomes include partial remission and changes in eating pathology, depressive symptoms and self-esteem. Moderating and mediating factors will also be explored. DISCUSSION: This will be first randomised controlled trial of a parent-focused model of family-based treatment of adolescent anorexia nervosa. If found to be efficacious, parent-focused treatment will offer an alternative approach for clinicians who treat adolescents with anorexia nervosa. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12610000216011.

A 22-mer segment in the structurally pliable regulatory domain of metazoan CTP: phosphocholine cytidylyltransferase facilitates both silencing and activating functions.

CTP:phosphocholine cytidylyltransferase (CCT), an amphitropic enzyme that regulates phosphatidylcholine synthesis, is composed of a catalytic head domain and a regulatory tail. The tail region has dual functions as a regulator of membrane binding/enzyme activation and as an inhibitor of catalysis in the unbound form of the enzyme, suggesting conformational plasticity. These functions are well conserved in CCTs across diverse phyla, although the sequences of the tail regions are not. CCT regulatory tails of diverse origins are composed of a long membrane lipid-inducible amphipathic helix (m-AH) followed by a highly disordered segment, reminiscent of the Parkinson disease-linked protein, α-synuclein, which we show shares a novel sequence motif with vertebrate CCTs. To unravel features required for silencing, we created chimeric enzymes by fusing the catalytic domain of rat CCTα to the regulatory tail of CCTs from Drosophila, Caenorhabditis elegans, or Saccharomyces cerevisiae or to α-synuclein. Only the tail domains of the two invertebrate CCTs were competent for both suppression of catalytic activity and for activation by lipid vesicles. Thus, both silencing and activating functions of the m-AH can tolerate significant changes in length and sequence. We identified a highly amphipathic 22-residue segment in the m-AH with features conserved among animal CCTs but not yeast CCT or α-synuclein. Deletion of this segment from rat CCT increased the lipid-independent V(max) by 10-fold, equivalent to the effect of deleting the entire tail, and severely weakened membrane binding affinity. However, membrane binding was required for additional increases in catalytic efficiency. Thus, full activation of CCT may require not only loss of a silencing conformation in the m-AH but a gain of an activating conformation, promoted by membrane binding.

Sheeppox virus SPPV14 encodes a Bcl-2-like cell death inhibitor that counters a distinct set of mammalian proapoptotic proteins.

Many viruses express inhibitors of programmed cell death (apoptosis), thereby countering host defenses that would otherwise rapidly clear infected cells. To counter this, viruses such as adenoviruses and herpesviruses express recognizable homologs of the mammalian prosurvival protein Bcl-2. In contrast, the majority of poxviruses lack viral Bcl-2 (vBcl-2) homologs that are readily identified by sequence similarities. One such virus, myxoma virus, which is the causative agent of myxomatosis, expresses a virulence factor that is a potent inhibitor of apoptosis. In spite of the scant sequence similarity to Bcl-2, myxoma virus M11L adopts an almost identical 3-dimensional fold. We used M11L as bait in a sequence similarity search for other Bcl-2-like proteins and identified six putative vBcl-2 proteins from poxviruses. Some are potent inhibitors of apoptosis, in particular sheeppox virus SPPV14, which inhibited cell death induced by multiple agents. Importantly, SPPV14 compensated for the loss of antiapoptotic F1L in vaccinia virus and acts to directly counter the cell death mediators Bax and Bak. SPPV14 also engages a unique subset of the death-promoting BH3-only ligands, including Bim, Puma, Bmf, and Hrk. This suggests that SPPV14 may have been selected for specific biological roles as a virulence factor for sheeppox virus.