Addressing Social Determinants of Health in Primary Care Patients May Reduce Hospital Readmissions: A Quasi-Experimental Study.

BACKGROUND: Health care systems are increasingly partnering with community-based organizations to address social determinants of health (SDH). We established a program that educates and connects patients with SDH needs at a primary care clinic to community services and facilitated referrals. OBJECTIVE: To evaluate the effect of addressing SDH soon after discharge on hospital readmission in a clinic population. DESIGN: Pre/post, quasi-experimental design with longitudinal data analysis for quality improvement. PARTICIPANTS: Clinic patients (n = 754) having at least one hospital discharge between June 1, 2020, and October 31, 2021, were included. Of these, 145 patients received the intervention and 609 served as comparison. INTERVENTIONS: A primary care liaison was employed to assess and educate recently discharged clinic patients for SDH needs and refer them for needed community services from June 1, 2020, to October 31, 2021. MAIN MEASURES: Hospital readmissions within 30, 60, and 90 days of discharge were tracked at 6-month intervals. Covariates included patient age, sex, race/ethnicity, insurance status, income, Hierarchical Condition Category risk scores, and Clinical Classification Software diagnosis groups. Data for all hospital discharges during the intervention period were used for the main analysis and data for the year before the intervention were extracted for comparison. KEY RESULTS: Overall, patients in the intervention group were older, sicker, and more likely to have public insurance. The reductions in 30-, 60-, and 90-day readmissions during the intervention period were 14.39%, 13.28%, and 12.04% respectively in the intervention group, while no significant change was observed in the comparison group. The group difference in reduction over time was statistically significant for 30-day (Diff = 12.54%; p = 0.032), 60-day (Diff = 14.40%; p = 0.012), and 90-day readmissions (Diff = 14.71%; p = 0.036). CONCLUSION: Our findings suggest that screening clinic patients for SDH, and educating and connecting them to community services during post-hospital care may be associated with reductions in hospital readmissions.

A pen pal program during COVID-19 pandemic increases student interest for careers in geriatrics.

Social isolation and loneliness are serious issues facing older adults that have been intensified during COVID-19. Through a pen pal program, we connected 69 healthcare professional students with 180 older adults in our community to help reduce social isolation and loneliness. Participants were connected through letters, e-mails, and phone calls for three months. At the end of the program, we surveyed students (response rate: 62%). Half of the students reported spending less than 20 minutes per week on the project. Of the survey respondents roughly 91% were white, 74.4% were enrolled in the College of Medicine, and 51.1% were in their first year of their respective program. Students increased their knowledge of social isolation and loneliness (p = .0001), their interest in volunteering (p = .018) and working with older adults (p = .028), and their comfort communicating with older adults (p = .002). Students reported that their wellness improved and that they practiced skills that would be used in their future careers. By providing volunteer experiences to students, we can increase their exposure to the geriatric population, hopefully increasing the number of students who enter geriatrics while simultaneously reducing social isolation and loneliness in older adults.

A state-wide audit of unhealthy sponsorship within junior sporting clubs in Victoria, Australia.

OBJECTIVE: To systematically audit the extent of unhealthy sponsorship within junior community sporting clubs and ascertain whether differences exist across geographical areas and sport types. DESIGN: Club sponsorship data were assessed to determine the extent of unhealthy food/beverage, alcohol and gambling sponsorship using a cross-sectional design. Differences across geographical areas were assessed using logistic regressions. SETTING: A stratified random sampling procedure was used to select thirty communities across the state of Victoria, Australia. Within each community, local clubs across the top eight participating junior sports were selected for audit. PARTICIPANTS: Sponsorship data were collected from 191 club websites and Facebook pages in September-November 2019. RESULTS: Unhealthy sponsorships represented 8·9 % of all identified sponsorship arrangements. A quarter of all clubs accepted alcohol (25·6 %) and unhealthy food sponsors (25·9 %), and one-fifth of all clubs accepted high-risk food (unhealthy brands with large market share) (18·1 %) and gambling sponsors (20·4 %). Acceptance of unhealthy sponsorship differed across sport types with football, netball, cricket and soccer clubs having the greatest numbers. Compared with metro areas, a significantly greater proportion of sporting clubs in regional areas were affiliated with unhealthy food (32·7 % v. 19·6 %) and high-risk food sponsors (26·9 % v. 9·8 %). A higher proportion of clubs in low socio-economic status (SES), compared with the high SES areas, were affiliated with alcohol (33·9 % v. 16·5 %) and gambling sponsors (27·4 % v. 12·6 %). CONCLUSION: Victorian children participating in community junior sports are being exposed to marketing of unhealthy brands and products. Public health intervention is necessary to protect children from this exposure.

Translating the REACH OUT dementia caregiver intervention into a primary care setting: a pilot study.

OBJECTIVE: The current study translated the Resources for Enhancing Alzheimer's Caregiver Health: Offering Useful Treatments (REACH OUT), a skills-building stress and burden intervention, for the primary care setting and pilot the resulting intervention. METHODS: The 16-week intervention consisted of a combination of clinic-based group and one-on-one sessions offered within a medical home, geriatrics clinic. A quasi-experimental pre- and post-test study design without a control group tested the resulting intervention. Semi-structured qualitative exit interviews evaluated program satisfaction. RESULTS: Twenty-five caregivers participated in one of four intervention groups; 21 caregivers completed the intervention (attended at least five of six group sessions). Caregiver burden on standardized assessments was significantly reduced between pre- and post-intervention, specifically for physical/emotional strain and caregiving uncertainty. Significant reductions were found in the frequency of reported disruptive behaviors; increased caregiver confidence in handling behavior problem frequency, depressive symptoms, disruptive behaviors, and memory-related problems; and decreased bother with respect to behavioral problem frequency and care recipient depression. Program satisfaction was high. CONCLUSION: This work suggests that the REACH OUT program can be successfully modified for use within a primary-care medical home setting.

Unpack the Salt: an evaluation of the Victorian Salt Reduction Partnership's media advocacy activities to highlight the salt content of different foods.

BACKGROUND: Australians are consuming almost double the recommended maximum salt intake. The Victorian Salt Reduction Partnership was established to coordinate efforts to reduce salt intake in the state of Victoria. As part of an intervention strategy, media advocacy strategies were used to raise public awareness and stimulate industry and government action on salt reduction. This study aimed to evaluate the Victorian Salt Reduction Partnership's media advocacy activities by determining the extent to which activities contributed to the overall strategy aims and the effectiveness of the activities in gaining media and industry engagement. METHODS: A framework for evaluating media advocacy strategies used in complex public health interventions was used to guide this evaluation. Media advocacy activities were monitored and documented throughout the intervention period. A content analysis of media release press statements was performed. Indicators of media coverage (media items, cumulative audience reach, advertising space rate) and food industry engagement (number of meetings, number and type of follow up actions) were tracked. RESULTS: Six media releases were issued between March 2017 and November 2018 on different processed food categories including breads, cooking sauces, ready meals, dips and crackers, processed meats and Asian-style sauces. Three main themes were identified in the qualitative analysis of the press statements: general information on salt and health, salt levels in foods, and calls to action for consumers, industry and/or government. These themes were aligned with the overall intervention strategy. Media items (print and online news, radio and TV) generated by each release ranged from 36 to 274, and cumulative audience reach (opportunities to see) ranged from 2.3 to 7.5 million Australians per release. One to three food manufacturers were met with per media release. CONCLUSIONS: Disseminating sodium-monitoring data through media releases can be used as a tool to gain access to the media and reach consumers with salt reduction messages, and to engage food manufacturers in discussions about salt reduction. Characteristics of media advocacy activities, including alignment with the overall strategy, and external factors outside the of control of the program implementers, can influence media and industry engagement. When planning future nutrition interventions that include media advocacy activities, internal and external factors impacting outcomes, should be considered, documented and evaluated.

The Geriatric Workforce Enhancement Program: Review of the Coordinating Center and Examples of the GWEP in Practice.

The Health Resources and Services Administration created the Geriatric Workforce Enhancement Program (GWEP) in 2015 to address future geriatric workforce challenges and redefine the delivery of care to older adults. The John A. Hartford Foundation subsequently funded the GWEP Coordinating Center (GWEP-CC) to offer centralized, strategic support to these 44 diverse GWEP sites. This article outlines the last 3 years of GWEP work done at the national and local levels to transform geriatric care. Dissemination of the innovative Geriatric Interprofessional Team Transformation in Primary Care program, created by the Dartmouth GWEP, demonstrates how the GWEP-CC can benefit local initiatives and inform national perspectives. The GWEP-CC is a change agent in this way, scaling and distributing information and implementation support across the country. The GWEP-CC also serves as an essential repository of data, continuously determining what is working and what could be improved. This informs activity of the GWEP-CC, funders and other stakeholders, and provides the most up-to-date resources to GWEP sites and their partners. The GWEP-CC achieves its objectives through several key pillars: networking opportunities, education and training, advocacy, and evaluation. Although many advances have been made, opportunities to continue paving the way are plenty, especially with regards to mental health. This article discusses the work accomplished to date and presents some future considerations for mental health and overall healthcare transformation.

Are dietary inequalities among Australian adults changing? a nationally representative analysis of dietary change according to socioeconomic position between 1995 and 2011-13.

BACKGROUND: Increasing inequalities in rates of obesity and chronic disease may be partly fuelled by increasing dietary inequalities, however very few nationally representative analyses of socioeconomic trends in dietary inequalities exist. The release of the 2011-13 Australian National Nutrition and Physical Activity Survey data allows investigation of change in dietary intake according to socioeconomic position (SEP) in Australia using a large, nationally representative sample, compared to the previous national survey in 1995. This study examined change in dietary intakes of energy, macronutrients, fiber, fruits and vegetables among Australian adults between 1995 and 2011-13, according to SEP. METHODS: Cross-sectional data were obtained from the 1995 National Nutrition Survey, and the 2011-13 National Nutrition and Physical Activity Survey. Dietary intake data were collected via a 24-h dietary recall (n = 17,484 adults) and a dietary questionnaire (n = 15,287 adults). SEP was assessed according to educational level, equivalized household income, and area-level disadvantage. Survey-weighted linear and logistic regression models, adjusted for age, sex/gender and smoking status, examined change in dietary intakes over time. RESULTS: Dietary intakes remained poor across the SEP spectrum in both surveys, as evidenced by high consumption of saturated fat and total sugars, and low fiber, fruit and vegetable intakes. There was consistent evidence (i.e. according to ≥2 SEP measures) of more favorable changes in dietary intakes of carbohydrate, polyunsaturated and monounsaturated fat in higher, relative to lower SEP groups, particularly in women. Intakes of energy, total fat, saturated fat and fruit differed over time according to a single SEP measure (i.e. educational level, household income, or area-level disadvantage). There were no changes in intake of total sugars, protein, fiber or vegetables according to any SEP measures. CONCLUSIONS: There were few changes in dietary intakes of energy, most macronutrients, fiber, fruits and vegetables in Australian adults between 1995 and 2011-13 according to SEP. For carbohydrate, polyunsaturated and monounsaturated fat, more favorable changes in intakes occurred in higher SEP groups. Despite the persistence of suboptimal dietary intakes, limited evidence of widening dietary inequalities is positive from a public health perspective. TRIAL REGISTRATION: Clinical trials registration: ACTRN12617001045303 .

Streptococcus pneumoniae NanC: STRUCTURAL INSIGHTS INTO THE SPECIFICITY AND MECHANISM OF A SIALIDASE THAT PRODUCES A SIALIDASE INHIBITOR.

Streptococcus pneumoniae is an important human pathogen that causes a range of disease states. Sialidases are important bacterial virulence factors. There are three pneumococcal sialidases: NanA, NanB, and NanC. NanC is an unusual sialidase in that its primary reaction product is 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en, also known as DANA), a nonspecific hydrolytic sialidase inhibitor. The production of Neu5Ac2en from α2-3-linked sialosides by the catalytic domain is confirmed within a crystal structure. A covalent complex with 3-fluoro-ß-N-acetylneuraminic acid is also presented, suggesting a common mechanism with other sialidases up to the final step of product formation. A conformation change in an active site hydrophobic loop on ligand binding constricts the entrance to the active site. In addition, the distance between the catalytic acid/base (Asp-315) and the ligand anomeric carbon is unusually short. These features facilitate a novel sialidase reaction in which the final step of product formation is direct abstraction of the C3 proton by the active site aspartic acid, forming Neu5Ac2en. NanC also possesses a carbohydrate-binding module, which is shown to bind α2-3- and α2-6-linked sialosides, as well as N-acetylneuraminic acid, which is captured in the crystal structure following hydration of Neu5Ac2en by NanC. Overall, the pneumococcal sialidases show remarkable mechanistic diversity while maintaining a common structural scaffold.

Structural characterization of the carbohydrate-binding module of NanA sialidase, a pneumococcal virulence factor.

BACKGROUND: Streptococcus pneumoniae Neuraminidase A (NanA) is a multi-domain protein anchored to the bacterial surface. Upstream of the catalytic domain of NanA is a domain that conforms to the sialic acid-recognising CBM40 family of the CAZY (carbohydrate-active enzymes) database. This domain has been identified to play a critical role in allowing the bacterium to promote adhesion and invasion of human brain microvascular endothelial cells, and hence may play a key role in promoting bacterial meningitis. In addition, the CBM40 domain has also been reported to activate host chemokines and neutrophil recruitment during infection. RESULTS: Crystal structures of both apo- and holo- forms of the NanA CBM40 domain (residues 121 to 305), have been determined to 1.8 Å resolution. The domain shares the fold of other CBM40 domains that are associated with sialidases. When in complex with α2,3- or α2,6-sialyllactose, the domain is shown to interact only with the terminal sialic acid. Significantly, a deep acidic pocket adjacent to the sialic acid-binding site is identified, which is occupied by a lysine from a symmetry-related molecule in the crystal. This pocket is adjacent to a region that is predicted to be involved in protein-protein interactions. CONCLUSIONS: The structural data provide the details of linkage-independent sialyllactose binding by NanA CBM40 and reveal striking surface features that may hold the key to recognition of binding partners on the host cell surface. The structure also suggests that small molecules or sialic acid analogues could be developed to fill the acidic pocket and hence provide a new therapeutic avenue against meningitis caused by S. pneumoniae.

HEX17(Neumifil): An intranasal respiratory biotherapeutic with broad-acting antiviral activity.

Broad-acting antiviral strategies to prevent respiratory tract infections are urgently required. Emerging or re-emerging viral diseases caused by new or genetic variants of viruses such as influenza viruses (IFVs), respiratory syncytial viruses (RSVs), human rhinoviruses (HRVs), parainfluenza viruses (PIVs) or coronaviruses (CoVs), pose a severe threat to human health, particularly in the very young or old, or in those with pre-existing respiratory conditions such as asthma or chronic obstructive pulmonary disease (COPD). Although vaccines remain a key component in controlling and preventing viral infections, they are unable to provide broad-spectrum protection against recurring seasonal infections or newly emerging threats. HEX17 (aka Neumifil), is a first-in-class protein-based antiviral prophylactic for respiratory viral infections. HEX17 consists of a hexavalent carbohydrate-binding module (CBM) with high affinity to sialic acids, which are typically present on terminating branches of glycans on viral cellular receptors. This allows HEX17 to block virus engagement of host receptors and inhibit infection of a wide range of viral pathogens and their variants with reduced risk of antiviral resistance. As described herein, HEX17 has demonstrated broad-spectrum efficacy against respiratory viral pathogens including IFV, RSV, CoV and HRV in multiple in vivo and in vitro studies. In addition, HEX17 can be easily administered via an intranasal spray and is currently undergoing clinical trials.

Toward a hepatitis C virus vaccine: the structural basis of hepatitis C virus neutralization by AP33, a broadly neutralizing antibody.

The E2 envelope glycoprotein of hepatitis C virus (HCV) binds to the host entry factor CD81 and is the principal target for neutralizing antibodies (NAbs). Most NAbs recognize hypervariable region 1 on E2, which undergoes frequent mutation, thereby allowing the virus to evade neutralization. Consequently, there is great interest in NAbs that target conserved epitopes. One such NAb is AP33, a mouse monoclonal antibody that recognizes a conserved, linear epitope on E2 and potently neutralizes a broad range of HCV genotypes. In this study, the X-ray structure of AP33 Fab in complex with an epitope peptide spanning residues 412 to 423 of HCV E2 was determined to 1.8 Å. In the complex, the peptide adopts a ß-hairpin conformation and docks into a deep binding pocket on the antibody. The major determinants of antibody recognition are E2 residues L413, N415, G418, and W420. The structure is compared to the recently described HCV1 Fab in complex with the same epitope. Interestingly, the antigen-binding sites of HCV1 and AP33 are completely different, whereas the peptide conformation is very similar in the two structures. Mutagenesis of the peptide-binding residues on AP33 confirmed that these residues are also critical for AP33 recognition of whole E2, confirming that the peptide-bound structure truly represents AP33 interaction with the intact glycoprotein. The slightly conformation-sensitive character of the AP33-E2 interaction was explored by cross-competition analysis and alanine-scanning mutagenesis. The structural details of this neutralizing epitope provide a starting point for the design of an immunogen capable of eliciting AP33-like antibodies.

Use of a Preclinical Natural Transmission Model to Study Antiviral Effects of a Carbohydrate-Binding Module Therapy against SARS-CoV-2 in Hamsters.

The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV-2) and its expansion to a worldwide pandemic resulted in efforts to assess and develop interventions to reduce the disease burden. Despite the introduction of vaccine programmes against SARS-CoV-2, global incidence levels in early 2022 remained high, demonstrating a need for the development of physiologically relevant models, which are essential for the identification of alternative antiviral strategies. The hamster model of SARS-CoV-2 infection has been widely adopted due to similarities with humans in terms of host cell entry mechanism (via ACE2), and aspects of symptomology and virus shedding. We have previously described a natural transmission hamster model that better represents the natural course of infection. In the present study, we have conducted further testing of the model using the first-in-class antiviral Neumifil, which has previously shown promise against SARS-CoV-2 after a direct intranasal challenge. Neumifil is an intranasally delivered carbohydrate-binding module (CBM) which reduces the binding of viruses to their cellular receptor. By targeting the host cell, Neumifil has the potential to provide broad protection against multiple pathogens and variants. This study demonstrates that using a combination of a prophylactic and therapeutic delivery of Neumifil significantly reduces the severity of clinical signs in animals infected via a natural route of transmission and indicates a reduction of viral loads in the upper respiratory tract. Further refinements of the model are required in order to ensure the adequate transmission of the virus. However, our results provide additional data to the evidence base of Neumifil efficacy against respiratory virus infection and demonstrate that the transmission model is a potentially valuable tool for testing antiviral compounds against SARS-CoV-2.

Perceptions towards unhealthy food sponsorship in junior sports in Victoria, Australia.

OBJECTIVE: To explore Victorian parents' and club officials' engagement with, and attitudes towards, the sponsorship of junior sports by unhealthy food and beverage companies. METHODS: We conducted online surveys with 504 parents of children participating in junior sports and 16 semi-structured interviews with junior sports club officials (from clubs that accepted unhealthy food sponsorship) in Victoria, Australia. RESULTS: Most parents were concerned about children's exposure to sponsorship by unhealthy local (58% extremely, very or moderately concerned) and large food companies (63%) in junior sports. The views of sporting club officials were grouped into four themes: (1) the existing funding challenges for junior sports, (2) how junior sports sponsorship is community dependent, (3) how the perceived risks of sponsorship by unhealthy food companies are low and (4) the need for high-level regulations and support to transition towards healthier junior sports sponsorship. CONCLUSIONS: Transitioning towards healthier junior sports sponsorship may be hindered by insufficient funding models and low concern for such actions by community leaders. IMPLICATIONS FOR PUBLIC HEALTH: Policy actions from higher-level sporting governing bodies and governments are likely to be necessary to reduce harmful junior sports sponsorship, alongside restrictions on the marketing of unhealthy foods through other media and settings.

Targeted Telehealth Education Increases Interest in Using Telehealth among a Diverse Group of Low-Income Older Adults.

Telehealth allows older adults to take control over their health and preventive care; however, they are less likely to use telehealth. Minority older adults use telehealth services less than their White counterparts. During COVID-19, the U.S. Medicare system allowed for telehealth delivery of Annual Wellness Visits, which are known to improve use of preventive services. To increase telehealth use, we targeted vulnerable, low-income, minority older adults and provided education to improve knowledge of and identify barriers to telehealth use. Ultimately, this could serve as a means of improving health and preventive care services. Participants resided at independent living facilities, low-income housing, and elders of the Native American coalition; N = 257. Participants received written education materials; a subset attended a 20-min presentation. In this quasi-experimental study, participants completed a pre-post survey. Results were analyzed using Chi-Squared and Fisher's Exact tests. Participants included 54 'in-person' and 203 'at-home' learners. Most were female (79%), single/widowed (51%), and white (65%). At baseline, 39% were familiar with telehealth; following education 73% stated understanding on accessing telehealth. Nearly 40% of participants said they would use telehealth in the future; a larger proportion of "in-person" (73%) learners were willing to use telehealth than "at-home" learners (41%) (p = 0.001). Divorced older adults and Blacks voiced greater likelihoods of using telehealth than their married/widowed and White counterparts, respectively (Χ2(3, N = 195) = 9.693, p = 0.02), (p = 0.01). This education program demonstrates an increase likelihood in health promotion among older adults by increasing confidence in accessing and future use of telehealth; therefore, we achieved our aim of promoting telehealth use and improving health promotion.

Activity of a Carbohydrate-Binding Module Therapy, Neumifil, against SARS-CoV-2 Disease in a Hamster Model of Infection.

The rapid global spread of severe acute respiratory coronavirus 2 (SARS-CoV-2) has resulted in an urgent effort to find efficacious therapeutics. Broad-spectrum therapies which could be used for other respiratory pathogens confer advantages, as do those based on targeting host cells that are not prone to the development of resistance by the pathogen. We tested an intranasally delivered carbohydrate-binding module (CBM) therapy, termed Neumifil, which is based on a CBM that has previously been shown to offer protection against the influenza virus through the binding of sialic acid receptors. Using the recognised hamster model of SARS-CoV-2 infection, we demonstrate that Neumifil significantly reduces clinical disease severity and pathological changes in the nasal cavity. Furthermore, we demonstrate Neumifil binding to the human angiotensin-converting enzyme 2 (ACE2) receptor and spike protein of SARS-CoV-2. This is the first report describing the testing of this type of broad-spectrum antiviral therapy in vivo and provides evidence for the advancement of Neumifil in further preclinical and clinical studies.

A Robotic Device to Enhance Nursing Home Provider Telepresence During and After the COVID-19 Pandemic.

The COVID-19 pandemic presented significant challenges to face-to-face communication with people residing in post-acute and long-term care (PALTC) settings. Telemedicine is an alternative, but facility staff may be overburdened with the management of the equipment. Here we introduce the use of a mobile HIPPA-compliant telepresence robot (MTR) to bridge this barrier, which may be beneficial to reimagine options for PALTC in the future.

Transitions experienced by older survivors of critical care.

The transition from hospital to home is complicated for older adults who experience a serious or life-threatening illness. The specific aims of this prospective, observational cohort study were to determine the number of older adults who experience a change in their functional ability and residence after an intensive care unit (ICU) stay and to explore risk factors for functional decline and new institutionalization at hospital discharge. We found high rates of unrecognized preexisting cognitive impairment, delirium, complications, functional decline, and new institutionalization in this sample (N = 43). A number of variables were associated with functional decline or new institutionalization, including narcotic agent use (p = 0.03), ICU complications (p = 0.05), comorbidities (p = 0.01), depression (p = 0.05), and severity of illness (p = 0.05). We identified device self-removal, admission type, and ICU delirium as also potentially associated with these outcomes (p ≤ 0.25). There are a number of important and potentially modifiable factors that influence an older adult's ability to recover after a critical illness.

System Redesign: The Value of a Primary Care Liaison Model to Address Unmet Social Needs among Older Primary Care Patients.

Assessing and addressing social determinants of health can improve health outcomes of older adults. The Nebraska Geriatrics Workforce Enhancement Program implemented a primary care liaison (PCL) model of care, including training primary care staff to assess and address unmet social needs, patient counseling to identify unmet needs, and mapping referral services through cross-sectoral partnerships. A PCL worked with three patient-centered medical homes (PCMHs) that are part of a large integrative health system. A mixed-methods approach using a post-training survey and a patient tracking tool, was used to understand the reach, adoption, and implementation of the PCL model. From June 2020 to May 2021, the PCL trained 61 primary care staff to assess and address unmet social needs of older patients. A total of 327 patients, aged 65 years and older and within 3-5 days of acute-care hospital discharges, were counseled by the PCL. For patients with unmet needs, support services were arranged through community agencies: transportation (37%), in-home care (33%), food (16%), caregiver support (2%), legal (16%), and other (16%). Our preliminary results suggest that the PCL model is feasible and implementable within PCMH settings to address unmet social needs of older patients to improve their health outcomes.

Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design.

HCV vaccine development is stymied by the high genetic diversity of the virus and the variability of the envelope glycoproteins. One strategy to overcome this is to identify conserved, functionally important regions-such as the epitopes of broadly neutralizing antibodies (bNAbs)-and use these as a basis for structure-based vaccine design. Here, we report an anti-idiotype approach that has generated an antibody that mimics a highly conserved neutralizing epitope on HCV E2. Crucially, a mutagenesis screen was used to identify the antibody, designated B2.1 A, whose binding characteristics to the bNAb AP33 closely resemble those of the original antigen. Protein crystallography confirmed that B2.1 A is a structural mimic of the AP33 epitope. When used as an immunogen B2.1 A induced antibodies that recognized the same epitope and E2 residues as AP33 and most importantly protected against HCV challenge in a mouse model.

Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease.

BACKGROUND: Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access. RESULTS: We describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT-multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition. CONCLUSION: We describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.