Neutralizing immunity in vaccine breakthrough infections from the SARS-CoV-2 Omicron and Delta variants.

Virus-like particle (VLP) and live virus assays were used to investigate neutralizing immunity against Delta and Omicron SARS-CoV-2 variants in 259 samples from 128 vaccinated individuals. Following Delta breakthrough infection, titers against WT rose 57-fold and 3.1-fold compared with uninfected boosted and unboosted individuals, respectively, versus only a 5.8-fold increase and 3.1-fold decrease for Omicron breakthrough infection. Among immunocompetent, unboosted patients, Delta breakthrough infections induced 10.8-fold higher titers against WT compared with Omicron (p = 0.037). Decreased antibody responses in Omicron breakthrough infections relative to Delta were potentially related to a higher proportion of asymptomatic or mild breakthrough infections (55.0% versus 28.6%, respectively), which exhibited 12.3-fold lower titers against WT compared with moderate to severe infections (p = 0.020). Following either Delta or Omicron breakthrough infection, limited variant-specific cross-neutralizing immunity was observed. These results suggest that Omicron breakthrough infections are less immunogenic than Delta, thus providing reduced protection against reinfection or infection from future variants.

Adeno-associated virus type 2 in US children with acute severe hepatitis.

As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA1,2. Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA3-7, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses.

Limited cross-variant immunity from SARS-CoV-2 Omicron without vaccination.

SARS-CoV-2 Delta and Omicron are globally relevant variants of concern. Although individuals infected with Delta are at risk of developing severe lung disease, infection with Omicron often causes milder symptoms, especially in vaccinated individuals1,2. The question arises of whether widespread Omicron infections could lead to future cross-variant protection, accelerating the end of the pandemic. Here we show that without vaccination, infection with Omicron induces a limited humoral immune response in mice and humans. Sera from mice overexpressing the human ACE2 receptor and infected with Omicron neutralize only Omicron, but not other variants of concern, whereas broader cross-variant neutralization was observed after WA1 and Delta infections. Unlike WA1 and Delta, Omicron replicates to low levels in the lungs and brains of infected animals, leading to mild disease with reduced expression of pro-inflammatory cytokines and diminished activation of lung-resident T cells. Sera from individuals who were unvaccinated and infected with Omicron show the same limited neutralization of only Omicron itself. By contrast, Omicron breakthrough infections induce overall higher neutralization titres against all variants of concern. Our results demonstrate that Omicron infection enhances pre-existing immunity elicited by vaccines but, on its own, may not confer broad protection against non-Omicron variants in unvaccinated individuals.

SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells.

Despite the importance of programmed cell death-1 (PD-1) in inhibiting T cell effector activity, the mechanisms regulating its expression remain poorly defined. We found that the chromatin organizer special AT-rich sequence-binding protein-1 (Satb1) restrains PD-1 expression induced upon T cell activation by recruiting a nucleosome remodeling deacetylase (NuRD) complex to Pdcd1 regulatory regions. Satb1 deficienct T cells exhibited a 40-fold increase in PD-1 expression. Tumor-derived transforming growth factor ß (Tgf-ß) decreased Satb1 expression through binding of Smad proteins to the Satb1 promoter. Smad proteins also competed with the Satb1-NuRD complex for binding to Pdcd1 enhancers, releasing Pdcd1 expression from Satb1-mediated repression, Satb1-deficient tumor-reactive T cells lost effector activity more rapidly than wild-type lymphocytes at tumor beds expressing PD-1 ligand (CD274), and these differences were abrogated by sustained CD274 blockade. Our findings suggest that Satb1 functions to prevent premature T cell exhaustion by regulating Pdcd1 expression upon T cell activation. Dysregulation of this pathway in tumor-infiltrating T cells results in diminished anti-tumor immunity.

In Situ Synthesis and Self-Assembly of Peptide-PEG Conjugates: A Facile Method for the Construction of Fibrous Hydrogels.

Peptide-based hydrogels have gained considerable attention as a compelling platform for various biomedical applications in recent years. Their attractiveness stems from their ability to seamlessly integrate diverse properties, such as biocompatibility, biodegradability, easily adjustable hydrophilicity/hydrophobicity, and other functionalities. However, a significant drawback is that most of the functional self-assembling peptides cannot form robust hydrogels suitable for biological applications. In this study, we present the synthesis of novel peptide-PEG conjugates and explore their comprehensive hydrogel properties. The hydrogel comprises double networks, with the first network formed through the self-assembly of peptides to create a ß-sheet secondary structure. The second network is established through covalent bond formation via N-hydroxysuccinimide chemistry between peptides and a 4-arm PEG to form a covalently linked network. Importantly, our findings reveal that this hydrogel formation method can be applied to other peptides containing lysine-rich sequences. Upon encapsulation of the hydrogel with antimicrobial peptides, the hydrogel retained high bacterial killing efficiency while showing minimum cytotoxicity toward mammalian cells. We hope that this method opens new avenues for the development of a novel class of peptide-polymer hydrogel materials with enhanced performance in biomedical contexts, particularly in reducing the potential for infection in applications of tissue regeneration and drug delivery.

Analysis of percutaneous nephrostomy exchange intervals: insights from a retrospective Merative MarketScan analysis between 2009-2021.

BACKGROUND: Current practices in nephrostomy exchange are guided by institutional or societal expert-consensus rather than evidence-based recommendations. OBJECTIVE: To examine the temporal distribution of exchanges and assess whether the observed distributions align with institutional, or expert-recommended guidelines where routine exchanges would be expected to occur within 60-89 days. Non-routine exchanges would be expected to occur either after 60 days or after 89 days. METHODS: Data were collected from the Merative™ MarketScan Commercial Claims and Encounters Databases and included all patients who underwent a PCN exchange from 2009 to 2021. The dataset was queried using ICD-9/10 and CPT coding systems. Outpatient exchanges were classified as routine exchanges, whereas inpatient exchanges were classified as non-routine exchanges. Chi-Square Goodness-of-Fit tests were used to compare observed frequencies against expected distributions of routine exchanges within the 59-89 day window, and non-routine exchanges to occur after either 60 or after 89 days. RESULTS: There was a total of 19,689 exchanges: of those, 41% (n = 8,058) exchange encounters occurred within 29 days, 67% (n = 13,213) occurred within 59 days, and 81% (n = 15,899) occurred within 89 days. Routine exchanges accounted for 76% of total exchanges: of those routine exchanges, 39% (n = 5,863) of routine exchanges occurred within 29 days, 67% (n = 10,057) occurred within 59 days, and 82% (n = 12,256) occurred within 89 days. Non-routine exchanges account for 24% of all exchanges in the study cohort. Of all non-routine exchanges (n = 4,737), 46% (n = 2,035) of non-routine exchange encounters occurred within 29 days, 67% (n = 3,156) within 60 days, and 77% (n = 3,643) within 89 days. Chi-square tests indicated significant deviations from the expected distributions for both routine (p < 0.01) and non-routine (p < 0.01) exchanges. CONCLUSION: A significant proportion of routine exchanges occur outside a 60-89 day window, and with a majority of routine exchange observations occurring prior to 59 days. A significant proportion of non-routine exchanges occur prior to 60 days and prior to 89 days. CLINICAL IMPACT: Significant disparities between existing guidelines and clinical practice, underscoring the need for evidence-based guidelines to reduce complication rates, improve patient outcomes, and reduce the burden of cost on the healthcare system.

Reducing Hospitalizations and Multidrug-Resistant Organisms via Regional Decolonization in Hospitals and Nursing Homes.

Importance: Infections due to multidrug-resistant organisms (MDROs) are associated with increased morbidity, mortality, length of hospitalization, and health care costs. Regional interventions may be advantageous in mitigating MDROs and associated infections. Objective: To evaluate whether implementation of a decolonization collaborative is associated with reduced regional MDRO prevalence, incident clinical cultures, infection-related hospitalizations, costs, and deaths. Design, Setting, and Participants: This quality improvement study was conducted from July 1, 2017, to July 31, 2019, across 35 health care facilities in Orange County, California. Exposures: Chlorhexidine bathing and nasal iodophor antisepsis for residents in long-term care and hospitalized patients in contact precautions (CP). Main Outcomes and Measures: Baseline and end of intervention MDRO point prevalence among participating facilities; incident MDRO (nonscreening) clinical cultures among participating and nonparticipating facilities; and infection-related hospitalizations and associated costs and deaths among residents in participating and nonparticipating nursing homes (NHs). Results: Thirty-five facilities (16 hospitals, 16 NHs, 3 long-term acute care hospitals [LTACHs]) adopted the intervention. Comparing decolonization with baseline periods among participating facilities, the mean (SD) MDRO prevalence decreased from 63.9% (12.2%) to 49.9% (11.3%) among NHs, from 80.0% (7.2%) to 53.3% (13.3%) among LTACHs (odds ratio [OR] for NHs and LTACHs, 0.48; 95% CI, 0.40-0.57), and from 64.1% (8.5%) to 55.4% (13.8%) (OR, 0.75; 95% CI, 0.60-0.93) among hospitalized patients in CP. When comparing decolonization with baseline among NHs, the mean (SD) monthly incident MDRO clinical cultures changed from 2.7 (1.9) to 1.7 (1.1) among participating NHs, from 1.7 (1.4) to 1.5 (1.1) among nonparticipating NHs (group × period interaction reduction, 30.4%; 95% CI, 16.4%-42.1%), from 25.5 (18.6) to 25.0 (15.9) among participating hospitals, from 12.5 (10.1) to 14.3 (10.2) among nonparticipating hospitals (group × period interaction reduction, 12.9%; 95% CI, 3.3%-21.5%), and from 14.8 (8.6) to 8.2 (6.1) among LTACHs (all facilities participating; 22.5% reduction; 95% CI, 4.4%-37.1%). For NHs, the rate of infection-related hospitalizations per 1000 resident-days changed from 2.31 during baseline to 1.94 during intervention among participating NHs, and from 1.90 to 2.03 among nonparticipating NHs (group × period interaction reduction, 26.7%; 95% CI, 19.0%-34.5%). Associated hospitalization costs per 1000 resident-days changed from $64 651 to $55 149 among participating NHs and from $55 151 to $59 327 among nonparticipating NHs (group × period interaction reduction, 26.8%; 95% CI, 26.7%-26.9%). Associated hospitalization deaths per 1000 resident-days changed from 0.29 to 0.25 among participating NHs and from 0.23 to 0.24 among nonparticipating NHs (group × period interaction reduction, 23.7%; 95% CI, 4.5%-43.0%). Conclusions and Relevance: A regional collaborative involving universal decolonization in long-term care facilities and targeted decolonization among hospital patients in CP was associated with lower MDRO carriage, infections, hospitalizations, costs, and deaths.

Unravelling the Link between the Gut Microbiome and Autoimmune Kidney Diseases: A Potential New Therapeutic Approach.

The gut microbiota and short chain fatty acids (SCFA) have been associated with immune regulation and autoimmune diseases. Autoimmune kidney diseases arise from a loss of tolerance to antigens, often with unclear triggers. In this review, we explore the role of the gut microbiome and how disease, diet, and therapy can alter the gut microbiota consortium. Perturbations in the gut microbiota may systemically induce the translocation of microbiota-derived inflammatory molecules such as liposaccharide (LPS) and other toxins by penetrating the gut epithelial barrier. Once in the blood stream, these pro-inflammatory mediators activate immune cells, which release pro-inflammatory molecules, many of which are antigens in autoimmune diseases. The ratio of gut bacteria Bacteroidetes/Firmicutes is associated with worse outcomes in multiple autoimmune kidney diseases including lupus nephritis, MPO-ANCA vasculitis, and Goodpasture's syndrome. Therapies that enhance SCFA-producing bacteria in the gut have powerful therapeutic potential. Dietary fiber is fermented by gut bacteria which in turn release SCFAs that protect the gut barrier, as well as modulating immune responses towards a tolerogenic anti-inflammatory state. Herein, we describe where the current field of research is and the strategies to harness the gut microbiome as potential therapy.

Transforming growth factor ß-mediated suppression of antitumor T cells requires FoxP1 transcription factor expression.

Tumor-reactive T cells become unresponsive in advanced tumors. Here we have characterized a common mechanism of T cell unresponsiveness in cancer driven by the upregulation of the transcription factor Forkhead box protein P1 (Foxp1), which prevents CD8⁺ T cells from proliferating and upregulating Granzyme-B and interferon-γ in response to tumor antigens. Accordingly, Foxp1-deficient lymphocytes induced rejection of incurable tumors and promoted protection against tumor rechallenge. Mechanistically, Foxp1 interacted with the transcription factors Smad2 and Smad3 in preactivated CD8⁺ T cells in response to microenvironmental transforming growth factor-ß (TGF-ß), and was essential for its suppressive activity. Therefore, Smad2 and Smad3-mediated c-Myc repression requires Foxp1 expression in T cells. Furthermore, Foxp1 directly mediated TGF-ß-induced c-Jun transcriptional repression, which abrogated T cell activity. Our results unveil a fundamental mechanism of T cell unresponsiveness different from anergy or exhaustion, driven by TGF-ß signaling on tumor-associated lymphocytes undergoing Foxp1-dependent transcriptional regulation.

Neutralizing Immunity Induced Against the Omicron BA.1 and BA.2 Variants in Vaccine Breakthrough Infections.

BACKGROUND: As of early 2022, the Omicron variants are the predominant circulating lineages globally. Understanding neutralizing antibody responses against Omicron BA.1 and BA.2 after vaccine breakthrough infections will provide insights into BA.2 infectivity and susceptibility to subsequent reinfection. METHODS: Live virus neutralization assays were used to study immunity against Delta and Omicron BA.1 and BA.2 variants in samples from 86 individuals, 24 unvaccinated (27.9%) and 62 vaccinated (72.1%), who were infected with Delta (n = 42, 48.8%) or BA.1 (n = 44, 51.2%). Among the 62 vaccinated individuals, 39 were unboosted (62.9%), whereas 23 were boosted (37.1%). RESULTS: In unvaccinated infections, neutralizing antibodies (nAbs) against the three variants were weak or undetectable, except against Delta for Delta-infected individuals. Both Delta and BA.1 breakthrough infections resulted in strong nAb responses against ancestral wild-type and Delta lineages, but moderate nAb responses against BA.1 and BA.2, with similar titers between unboosted and boosted individuals. Antibody titers against BA.2 were generally higher than those against BA.1 in breakthrough infections. CONCLUSIONS: These results underscore the decreased immunogenicity of BA.1 compared to BA.2, insufficient neutralizing immunity against BA.2 in unvaccinated individuals, and moderate to strong neutralizing immunity induced against BA.2 in Delta and BA.1 breakthrough infections.

Urinary Biomarkers of Polycyclic Aromatic Hydrocarbons and Timing of Pubertal Development: The California PAH Study.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are endocrine-disrupting chemicals. Few studies have evaluated the association between pubertal development in girls and PAH exposures quantified by urinary biomarkers. METHODS: We examined associations of urinary PAH metabolites with pubertal development in 358 girls 6-16 years of age from the San Francisco Bay Area enrolled in a prospective cohort from 2011 to 2013 and followed until 2020. Using baseline data, we assessed associations of urinary PAH metabolites with pubertal development stage. In prospective analyses limited to girls who at baseline had not yet started breast (N = 176) or pubic hair (N = 179) development or menstruation (N = 267), we used multivariable Cox proportional hazards regression to assess associations of urinary PAH metabolites with the onset of breast and pubic hair development, menstruation, and pubertal tempo (interval between the onset of breast development and menstruation). RESULTS: We detected PAH metabolites in >98% of girls. In cross-sectional analyses using baseline data, PAH metabolites were not associated with the pubertal development stage. In prospective analyses, higher concentrations (≥ median) of some PAH metabolites were associated with two-fold higher odds of earlier breast development (2-hydroxy naphthalene, 1-hydroxy phenanthrene, summed hydroxy phenanthrenes) or pubic hair development (1-hydroxy naphthalene) among girls overweight at baseline (body mass index-for-age percentile ≥85) compared with nonoverweight girls with lower metabolites concentrations. PAH metabolites were not associated with age at menarche or pubertal tempo. CONCLUSIONS: PAH exposures were widespread in our sample. Our results support the hypothesis that, in overweight girls, PAHs impact the timing of pubertal development, an important risk factor for breast cancer.

Persistent leukocytosis in polycythemia vera is associated with disease evolution but not thrombosis.

There are unresolved questions regarding the association between persistent leukocytosis and risk of thrombosis and disease evolution in polycythemia vera (PV), as much of the published literature on the topic does not appropriately use repeated-measures data or time-dependent modeling to answer these questions. To address this knowledge gap, we analyzed a retrospective database of 520 PV patients seen at 10 academic institutions across the United States. Taking hematologic laboratory data at ∼3-month intervals (or as available) for all patients for duration of follow-up, we used group-based trajectory modeling to identify latent clusters of patients who follow distinct trajectories with regard to their leukocyte, hematocrit, and platelet counts over time. We then tested the association between trajectory membership and hazard of 2 major outcomes: thrombosis and disease evolution to myelofibrosis, myelodysplastic syndrome, or acute myeloid leukemia. Controlling for relevant covariates, we found that persistently elevated leukocyte trajectories were not associated with the hazard of a thrombotic event (P = .4163), but were significantly associated with increased hazard of disease evolution in an ascending stepwise manner (overall P = .0002). In addition, we found that neither hematocrit nor platelet count was significantly associated with the hazard of thrombosis or disease evolution.

Predictors of urinary polycyclic aromatic hydrocarbon metabolites in girls from the San Francisco Bay Area.

BACKGROUND: Polycyclic aromatic hydrocarbon (PAH) exposures from tobacco smoke, automobile exhaust, grilled or smoked meat and other sources are widespread and are a public health concern, as many are classified as probable carcinogens and suspected endocrine-disrupting chemicals. PAH exposures can be quantified using urinary biomarkers. METHODS: Seven urinary metabolites of naphthalene, fluorene, phenanthrene, and pyrene were measured in two samples collected from girls aged 6-16 years from the San Francisco Bay Area. We used Spearman correlation coefficients (SCC) to assess correlations among metabolite concentrations (corrected for specific gravity) separately in first (n = 359) and last (N = 349) samples, and to assess consistency of measurements in samples collected up to 72 months apart. Using multivariable linear regression, we assessed variation in mean metabolites across categories of participant characteristics and potential outdoor, indoor, and dietary sources of PAH exposures. RESULTS: The detection rate of PAH metabolites was high (4 metabolites in ≥98% of first samples; 5 metabolites in ≥95% of last samples). Correlations were moderate to strong between fluorene, phenanthrene and pyrene metabolites (SCC 0.43-0.82), but weaker between naphthalene and the other metabolites (SCC 0.18-0.36). SCC between metabolites in first and last samples ranged from 0.15 to 0.49. When classifying metabolite concentrations into tertiles based on single samples (first or last samples) vs. the average of the two samples, agreement was moderate to substantial (weighted kappa statistics 0.52-0.65). For specific metabolites, concentrations varied by age, race/ethnicity, and body mass index percentile, as well as by outdoor sources (season of sample collection, street traffic), indoor sources (heating with gas, cigarette smoke), and dietary sources (frequent use of grill, consumption of smoked meat or fish) of PAH exposures. CONCLUSIONS: Urinary PAH exposure was widespread in girls aged 6-16 years and associated with several sources of exposure. Tertile classification of a single urine sample provides reliable PAH exposure ranking.

Predicting Housing Related Delayed Discharge from Mental Health Inpatient Units: A Case Control Study.

The aims of this study were to identify factors that a) predict whether people experience housing related discharge delay (HRDD) from a mental health inpatient unit; and b) predict the length of HRDD for people affected. By identifying the groups most affected by HRDD, clinicians and policy makers can prioritise and address barriers to timely discharge at both an individual and systemic level. A case control study using a detailed medical record review was conducted in one Australian mental health service. Demographic, clinical, contextual and systemic variables were collected for patients with HRDD in one calendar year (n = 55) and a random comparison sample (n = 55). Logistical and multiple regression analyses were conducted to identify variables that predict HRDD and length of HRDD. A model that correctly predicted 92% of HRDD and 78% of non-HRDD cases using five variables was developed. These variables were: diagnosis of schizophrenia or other psychotic disorder, physical comorbidity, having a history of violence or aggressive behaviour, being employed and being involved as a defendant in the justice system. The first three variables increased the likelihood of HRDD, while the second two reduced the likelihood of HRDD. For people who experienced HRDD, the only variable that predicted length of delay was staff reported difficulty finding appropriate support services. This model can be used to rapidly identify patients who might be at risk of HRDD and commence coordinated actions to secure appropriate housing and supports to facilitate timely discharge, thereby addressing a current practice gap. These findings highlight the intersection between health, housing and disability services in the lives of people with serious mental illness, and the need for a whole of government approach to investment and integration to address systemic barriers to suitable housing and supports.

A Dynamic Variation of Pulmonary ACE2 Is Required to Modulate Neutrophilic Inflammation in Response to Pseudomonas aeruginosa Lung Infection in Mice.

Angiotensin-converting enzyme 2 (ACE2) is a potent negative regulator capable of restraining overactivation of the renin-angiotensin system, which contributes to exuberant inflammation after bacterial infection. However, the mechanism through which ACE2 modulates this inflammatory response is not well understood. Accumulating evidence indicates that infectious insults perturb ACE2 activity, allowing for uncontrolled inflammation. In the current study, we demonstrate that pulmonary ACE2 levels are dynamically varied during bacterial lung infection, and the fluctuation is critical in determining the severity of bacterial pneumonia. Specifically, we found that a pre-existing and persistent deficiency of active ACE2 led to excessive neutrophil accumulation in mouse lungs subjected to bacterial infection, resulting in a hyperinflammatory response and lung damage. In contrast, pre-existing and persistent increased ACE2 activity reduces neutrophil infiltration and compromises host defense, leading to overwhelming bacterial infection. Further, we found that the interruption of pulmonary ACE2 restitution in the model of bacterial lung infection delays the recovery process from neutrophilic lung inflammation. We observed the beneficial effects of recombinant ACE2 when administered to bacterially infected mouse lungs following an initial inflammatory response. In seeking to elucidate the mechanisms involved, we discovered that ACE2 inhibits neutrophil infiltration and lung inflammation by limiting IL-17 signaling by reducing the activity of the STAT3 pathway. The results suggest that the alteration of active ACE2 is not only a consequence of bacterial lung infection but also a critical component of host defense through modulation of the innate immune response to bacterial lung infection by regulating neutrophil influx.

Updates in the management of relapsed/refractory multiple myeloma.

Multiple myeloma, a malignant neoplasm of plasma cells that accumulate in bone marrow, accounts for approximately 18% of hematologic malignancies in the United States. Patients are often treated with triplet therapy and may undergo stem cell transplantation. Despite effective therapies, multiple myeloma remains incurable. Patients often require maintenance therapy, and many will progress or relapsed following upfront treatment. Selection of treatment in the relapse/refractory setting is complex due numerous active therapeutic agents and combinations. Treatment is often tailored to prior exposure and duration. In 2020, three novel pharmacological agents were approved in the relapsed setting. We highlight the clinical safety and efficacy of selinexor, isatuximab-irfc, and belantamab mafodotin for patients with multiple myeloma.

Two-Stage Treatment of a Large Premaxillary Defect.

ABSTRACT: Bilateral cleft lip and palate (CLP) patients commonly require surgical management to treat maxillary hypoplasia following the primary repair. Rarer is the CLP patient who also presents with a missing premaxillary segment. Here the authors present the case of a 19-year-old female with a history of bilateral CLP who demonstrated significant maxillary hypoplasia in addition to a large premaxillary defect. To correct this deformity, LeFort I advancement with fibular reconstruction of the maxilla and dental implant placement was performed as a single surgical procedure. The authors discuss the advantages of undergoing this single-staged operation. By utilizing virtual surgical planning (VSP) and incorporating a multidisciplinary team within the operating room, the patient was able to successfully undergo maxillary reconstruction and dental implant placement in a single operation.

A systematic review of global surgery partnerships and a proposed framework for sustainability.

Background: Building surgical capacity through global surgery partnerships (GSPs) between high and low- and middle-income countries (LMICs) is a rising global health focus. Our aim was to conduct a systematic review to characterize strategies employed by GSPs to build capacity and promote sustainability and to propose a novel reproducible model for sustainability. Methods: We conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We searched PubMed, EMBASE, Medline and African Journals Online to identify all peer-reviewed articles published between 2000 and 2016 that described GSPs between partners from the United States or Canada or both and partners from LMICs. We excluded papers that described nonsurgical GSPs, unilateral GSPs (e.g., humanitarian missions) or military initiatives. Descriptive features were analyzed, with a focus on attributes that promote sustainability. We then proposed criteria for sustainability on the basis of the themes that emerged from our review. Results: Our search retrieved 3580 abstracts, which were then independently reviewed by 4 authors. A total of 128 papers (3.6%) met the inclusion criteria. They described GSPs in 68 countries on 5 continents. Among the GSPs, 21.9% demonstrated community engagement and 51.6% included multidisciplinary collaboration. Surgical training or education was provided in 81.3% of GSPs. Although 64.8% of GSPs collected data, only 53.1% reported project-related outcomes. A total of 55.5% had bilateral authorship for publications, and 28.9% had multisource funding. Only 1 GSP fulfilled all 6 of our criteria for sustainability. Conclusion: In this systematic review we identified 6 pillars that are indicators of sustainability: community engagement, multidisciplinary collaboration, education and training, outcomes reporting, bilateral authorship and multisource funding. We propose that future GSPs should build on a foundation of bilateral ideas and expertise exchange, that they should have defined and measurable objectives, that they should engage in continuous evaluation of program outcomes and that they should take a thoughtful and transparent approach to sustained capacity building.

Contexte: Le renforcement de la capacité chirurgicale au moyen de partenariats internationaux en chirurgie (PIC) entre les pays à revenu élevé et ceux à revenu faible ou intermédiaire (PRFI) prend de plus en plus de place en santé mondiale. Nous avons donc réalisé une revue systématique pour caractériser les stratégies de renforcement de la capacité et de promotion de la pérennité employées dans le cadre des PIC, ainsi que pour proposer un modèle de pérennité novateur et reproductible. Méthodes: Pour notre revue systématique, nous avons suivi le modèle Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Nous avons interrogé les bases de données PubMed, Embase, MEDLINE et African Journals Online pour trouver tous les articles évalués par des pairs publiés entre 2000 et 2016 présentant des PIC conclus entre des organismes des États-Unis ou du Canada (ou les 2) et des organismes de PRFI. Nous avons exclu les articles portant sur des partenariats internationaux dans un domaine autre que la chirurgie, les PIC unilatéraux (p. ex., missions humanitaires) et les initiatives militaires. Nous avons analysé les caractéristiques descriptives des partenariats, en particulier les attributs favorisant leur pérennité. Nous avons ensuite proposé des critères de pérennité en fonction des thèmes dégagés dans la revue systématique. Résultats: Les 3580 résumés recensés lors de la recherche initiale ont été évalués de façon indépendante par 4 auteurs. Au total, 128 articles (3,6 %) répondaient aux critères d'inclusion. Ces articles présentaient des PIC impliquant 68 pays de 5 continents. De ces PIC, 21,9 % comportaient une mobilisation communautaire, et 51,6 %, une collaboration multidisciplinaire. Une formation ou un enseignement relatif à la chirurgie était fourni dans 81,3 % des cas. Si 64,8 % des PIC comprenaient une collecte de données, seuls 53,1 % ont produit des rapports sur les issues du projet. En tout, 55,5 % des PIC avaient conclu une entente de paternité bilatérale pour la publication, et 28,9 % avaient bénéficié d'un financement multisource. Un seul PIC répondait aux 6 critères de pérennité établis. Conclusion: Six indicateurs de pérennité ont été dégagés dans le cadre de cette revue systématique : mobilisation communautaire, collaboration multidisciplinaire, éducation et formation, production de rapports sur les issues, entente de paternité bilatérale et financement multisource. Les futurs PIC devraient reposer sur un échange d'idées et de connaissances, avoir des objectifs définis et mesurables, évaluer sans cesse les issues du programme et adopter une approche réfléchie et transparente quant au renforcement continu de la capacité.

Chimeric Antigen Receptors Targeting Human Cytomegalovirus.

Human cytomegalovirus (CMV) is a ubiquitous pathogen that causes significant morbidity in some vulnerable populations. Individualized adoptive transfer of ex vivo expanded CMV-specific CD8+ T cells has provided proof-of-concept that immunotherapy can be highly effective, but a chimeric antigen receptor (CAR) approach would provide a feasible method for broad application. We created 8 novel CARs using anti-CMV neutralizing antibody sequences, which were transduced via lentiviral vector into primary CD8+ T cells. All CARs were expressed. Activity against CMV-infected target cells was assessed by release of cytokines (interferon-γ and tumor necrosis factor-α), upregulation of surface CD107a, proliferation, cytolysis of infected cells, and suppression of viral replication. While some CARs showed varying functional activity across these assays, 1 CAR based on antibody 21E9 was consistently superior in all measures. These results support development of a CMV-specific CAR for therapeutic use against CMV and potentially other applications harnessing CMV-driven immunotherapies.

Environmental influences on placental programming and offspring outcomes following maternal immune activation.

Adverse experiences during pregnancy induce placental programming, affecting the fetus and its developmental trajectory. However, the influence of 'positive' maternal experiences on the placenta and fetus remain unclear. In animal models of early life stress, environmental enrichment (EE) has ameliorated and even prevented associated impairments in brain and behavior. Here, using a maternal immune activation (MIA) model in rats, we test whether EE attenuates maternal, placental and/or fetal responses to an inflammatory challenge, thereby offering a mechanism by which fetal programming may be prevented. Moreover, we evaluate life-long EE exposure on offspring development and examine a constellation of genes and epigenetic writers that may protect against MIA challenges. In our model, maternal plasma corticosterone and interleukin-1ß were elevated 3 h after MIA, validating the maternal inflammatory response. Evidence for developmental programming was demonstrated by a simultaneous decrease in the placental enzymes Hsd11b2 and Hsd11b2/Hsd11b1, suggesting disturbances in glucocorticoid metabolism. Reductions of Hsd11b2 in response to challenge is thought to result in excess glucocorticoid exposure to the fetus and altered glucocorticoid receptor expression, increasing susceptibility to behavioral impairments later in life. The placental, but not maternal, glucocorticoid implications of MIA were attenuated by EE. There were also sustained changes in epigenetic writers in both placenta and fetal brain as a consequence of environmental experience and sex. Following MIA, both male and female juvenile animals were impaired in social discrimination ability. Life-long EE mitigated these impairments, in addition to the sex specific MIA associated disruptions in central Fkbp5 and Oprm1. These data provide the first evidence that EE protects placental functioning during stressor exposure, underscoring the importance of addressing maternal health and well-being throughout pregnancy. Future work must evaluate critical periods of EE use to determine if postnatal EE experience is necessary, or if prenatal exposure alone is sufficient to confer protection.