Integrative clinical genomics of advanced prostate cancer.

Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, ß-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.

Soma-to-germline RNA communication.

More than a century ago, August Weissman defined a distinction between the germline (responsible for propagating heritable information from generation to generation) and the perishable soma. A central motivation for this distinction was to argue against the inheritance of acquired characters, as the germline was partly defined by its protection from external conditions. However, recent decades have seen an explosion of studies documenting the intergenerational and transgenerational effects of environmental conditions, forcing a re-evaluation of how external signals are sensed by, or communicated to, the germline epigenome. Here, motivated by the centrality of small RNAs in paradigms of epigenetic inheritance, we review across species the myriad examples of intercellular RNA trafficking from nurse cells or somatic tissues to developing gametes.

Argonautes promote male fertility and provide a paternal memory of germline gene expression in C. elegans.

During each life cycle, germ cells preserve and pass on both genetic and epigenetic information. In C. elegans, the ALG-3/4 Argonaute proteins are expressed during male gametogenesis and promote male fertility. Here, we show that the CSR-1 Argonaute functions with ALG-3/4 to positively regulate target genes required for spermiogenesis. Our findings suggest that ALG-3/4 functions during spermatogenesis to amplify a small RNA signal that represents an epigenetic memory of male-specific gene expression. CSR-1, which is abundant in mature sperm, appears to transmit this memory to offspring. Surprisingly, in addition to small RNAs targeting male-specific genes, we show that males also harbor an extensive repertoire of CSR-1 small RNAs targeting oogenesis-specific mRNAs. Together, these findings suggest that C. elegans sperm transmit not only the genome but also epigenetic binary signals in the form of Argonaute/small RNA complexes that constitute a memory of gene expression in preceding generations.

Thermophotovoltaic efficiency of 40.

Thermophotovoltaics (TPVs) convert predominantly infrared wavelength light to electricity via the photovoltaic effect, and can enable approaches to energy storage1,2 and conversion3-9 that use higher temperature heat sources than the turbines that are ubiquitous in electricity production today. Since the first demonstration of 29% efficient TPVs (Fig. 1a) using an integrated back surface reflector and a tungsten emitter at 2,000 °C (ref. 10), TPV fabrication and performance have improved11,12. However, despite predictions that TPV efficiencies can exceed 50% (refs. 11,13,14), the demonstrated efficiencies are still only as high as 32%, albeit at much lower temperatures below 1,300 °C (refs. 13-15). Here we report the fabrication and measurement of TPV cells with efficiencies of more than 40% and experimentally demonstrate the efficiency of high-bandgap tandem TPV cells. The TPV cells are two-junction devices comprising III-V materials with bandgaps between 1.0 and 1.4 eV that are optimized for emitter temperatures of 1,900-2,400 °C. The cells exploit the concept of band-edge spectral filtering to obtain high efficiency, using highly reflective back surface reflectors to reject unusable sub-bandgap radiation back to the emitter. A 1.4/1.2 eV device reached a maximum efficiency of (41.1 ± 1)% operating at a power density of 2.39 W cm-2 and an emitter temperature of 2,400 °C. A 1.2/1.0 eV device reached a maximum efficiency of (39.3 ± 1)% operating at a power density of 1.8 W cm-2 and an emitter temperature of 2,127 °C. These cells can be integrated into a TPV system for thermal energy grid storage to enable dispatchable renewable energy. This creates a pathway for thermal energy grid storage to reach sufficiently high efficiency and sufficiently low cost to enable decarbonization of the electricity grid.

Functional analysis and clinical classification of 462 germline BRCA2 missense variants affecting the DNA binding domain.

Variants of uncertain significance (VUSs) in BRCA2 are a common result of hereditary cancer genetic testing. While more than 4,000 unique VUSs, comprised of missense or intronic variants, have been identified in BRCA2, the few missense variants now classified clinically as pathogenic or likely pathogenic are predominantly located in the region encoding the C-terminal DNA binding domain (DBD). We report on functional evaluation of the influence of 462 BRCA2 missense variants affecting the DBD on DNA repair activity of BRCA2 using a homology-directed DNA double-strand break repair assay. Of these, 137 were functionally abnormal, 313 were functionally normal, and 12 demonstrated intermediate function. Comparisons with other functional studies of BRCA2 missense variants yielded strong correlations. Sequence-based in silico prediction models had high sensitivity, but limited specificity, relative to the homology-directed repair assay. Combining the functional results with clinical and genetic data in an American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP)-like variant classification framework from a clinical testing laboratory, after excluding known splicing variants and functionally intermediate variants, classified 431 of 442 (97.5%) missense variants (129 as pathogenic/likely pathogenic and 302 as benign/likely benign). Functionally abnormal variants classified as pathogenic by ACMG/AMP rules were associated with a slightly lower risk of breast cancer (odds ratio [OR] 5.15, 95% confidence interval [CI] 3.43-7.83) than BRCA2 DBD protein truncating variants (OR 8.56, 95% CI 6.03-12.36). Overall, functional studies of BRCA2 variants using validated assays substantially improved the variant classification yield from ACMG/AMP models and are expected to improve clinical management of many individuals found to harbor germline BRCA2 missense VUS.

Establishment of CD8+ T Cell Thymic Central Tolerance to Tissue-Restricted Antigen Requires PD-1.

Highly self-reactive T cells are censored from the repertoire by both central and peripheral tolerance mechanisms upon receipt of high-affinity TCR signals. Clonal deletion is considered a major driver of central tolerance; however, other mechanisms such as induction of regulatory T cells and functional impairment have been described. An understanding of the interplay between these different central tolerance mechanisms is still lacking. We previously showed that impaired clonal deletion to a model tissue-restricted Ag did not compromise tolerance. In this study, we determined that murine T cells that failed clonal deletion were rendered functionally impaired in the thymus. Programmed cell death protein 1 (PD-1) was induced in the thymus and was required to establish cell-intrinsic tolerance to tissue-restricted Ag in CD8+ thymocytes independently of clonal deletion. In bone marrow chimeras, tolerance was not observed in PD-L1-deficient recipients, but tolerance was largely maintained following adoptive transfer of tolerant thymocytes or T cells to PD-L1-deficient recipients. However, CRISPR-mediated ablation of PD-1 in tolerant T cells resulted in broken tolerance, suggesting different PD-1 signaling requirements for establishing versus maintaining tolerance. Finally, we showed that chronic exposure to high-affinity Ag supported the long-term maintenance of tolerance. Taken together, our study identifies a critical role for PD-1 in establishing central tolerance in autoreactive T cells that escape clonal deletion. It also sheds light on potential mechanisms of action of anti-PD-1 pathway immune checkpoint blockade and the development of immune-related adverse events.

Analysis of Clinical Criteria for Discharge Among Patients Hospitalized for COVID-19: Development and Validation of a Risk Prediction Model.

BACKGROUND: Patients hospitalized with COVID-19 can clinically deteriorate after a period of initial stability, making optimal timing of discharge a clinical and operational challenge. OBJECTIVE: To determine risks for post-discharge readmission and death among patients hospitalized with COVID-19. DESIGN: Multicenter retrospective observational cohort study, 2020-2021, with 30-day follow-up. PARTICIPANTS: Adults admitted for care of COVID-19 respiratory disease between March 2, 2020, and February 11, 2021, to one of 180 US hospitals affiliated with the HCA Healthcare system. MAIN MEASURES: Readmission to or death at an HCA hospital within 30 days of discharge was assessed. The area under the receiver operating characteristic curve (AUC) was calculated using an internal validation set (33% of the HCA cohort), and external validation was performed using similar data from six academic centers associated with a hospital medicine research network (HOMERuN). KEY RESULTS: The final HCA cohort included 62,195 patients (mean age 61.9 years, 51.9% male), of whom 4704 (7.6%) were readmitted or died within 30 days of discharge. Independent risk factors for death or readmission included fever within 72 h of discharge; tachypnea, tachycardia, or lack of improvement in oxygen requirement in the last 24 h; lymphopenia or thrombocytopenia at the time of discharge; being ≤ 7 days since first positive test for SARS-CoV-2; HOSPITAL readmission risk score ≥ 5; and several comorbidities. Inpatient treatment with remdesivir or anticoagulation were associated with lower odds. The model's AUC for the internal validation set was 0.73 (95% CI 0.71-0.74) and 0.66 (95% CI 0.64 to 0.67) for the external validation set. CONCLUSIONS: This large retrospective study identified several factors associated with post-discharge readmission or death in models which performed with good discrimination. Patients 7 or fewer days since test positivity and who demonstrate potentially reversible risk factors may benefit from delaying discharge until those risk factors resolve.

Scalable and Consolidated Microbial Platform for Rare Earth Element Leaching and Recovery from Waste Sources.

Chemical methods for the extraction and refinement of technologically critical rare earth elements (REEs) are energy-intensive, hazardous, and environmentally destructive. Current biobased extraction systems rely on extremophilic organisms and generate many of the same detrimental effects as chemical methodologies. The mesophilic methylotrophic bacterium Methylobacterium extorquens AM1 was previously shown to grow using electronic waste by naturally acquiring REEs to power methanol metabolism. Here we show that growth using electronic waste as a sole REE source is scalable up to 10 L with consistent metal yields without the use of harsh acids or high temperatures. The addition of organic acids increases REE leaching in a nonspecific manner. REE-specific bioleaching can be engineered through the overproduction of REE-binding ligands (called lanthanophores) and pyrroloquinoline quinone. REE bioaccumulation increases with the leachate concentration and is highly specific. REEs are stored intracellularly in polyphosphate granules, and genetic engineering to eliminate exopolyphosphatase activity increases metal accumulation, confirming the link between phosphate metabolism and biological REE use. Finally, we report the innate ability of M. extorquens to grow using other complex REE sources, including pulverized smartphones, demonstrating the flexibility and potential for use as a recovery platform for these critical metals.

Stability of the cytosine methylome during post-testicular sperm maturation in mouse.

Beyond the haploid genome, mammalian sperm carry a payload of epigenetic information with the potential to modulate offspring phenotypes. Recent studies show that the small RNA repertoire of sperm is remodeled during post-testicular maturation in the epididymis. Epididymal maturation has also been linked to changes in the sperm methylome, suggesting that the epididymis might play a broader role in shaping the sperm epigenome. Here, we characterize the genome-wide methylation landscape in seven germ cell populations from throughout the male reproductive tract. We find very few changes in the cytosine methylation landscape between testicular germ cell populations and cauda epididymal sperm, demonstrating that the sperm methylome is stable throughout post-testicular maturation. Although our sequencing data suggested that caput epididymal sperm exhibit a highly unusual methylome, follow-up studies revealed that this resulted from contamination of caput sperm by extracellular DNA. Extracellular DNA formed web-like structures that ensnared sperm, and was present only in sperm samples obtained from the caput epididymis and vas deferens of virgin males. Curiously, contaminating extracellular DNA was associated with citrullinated histone H3, potentially resulting from a PAD-driven genome decondensation process. Taken together, our data emphasize the stability of cytosine methylation in mammalian sperm, and identify a surprising, albeit transient, period during which sperm are associated with extracellular DNA.

Should We Wait for Bone-on-Bone Arthritis? Equivalent Clinical Outcomes in Patients Requiring Advanced Imaging Before Primary Total Hip Arthroplasty.

BACKGROUND: Plain radiographs remain the standard for diagnosing osteoarthritis (OA). Total hip arthroplasty (THA) is generally offered only for advanced OA by plain radiographs. Advanced imaging is used as an adjunct to assess OA severity in cases of progressive symptoms with less advanced OA by plain radiographs. The objective of this study was to compare outcomes following THA in patients who have advanced OA visualized by plain radiographs to patients who have less severe OA visualized by plain radiographs. METHODS: From February 2016 to February 2020, 93 patients who had Kellgren-Lawrence (KL) grade 0 to 2 OA and underwent THA were identified. The median age was 65 years, and 55% were women. They were matched 1:3 to patients who underwent THA for KL 4 OA based on age, sex, body mass index, and Charlson Comorbidity Index. The primary outcome was achievement of the Hip Injury and Osteoarthritis Outcome Score for Joint Replacement (HOOS JR) minimum clinically important difference, substantial clinical benefit, and patient-acceptable symptom state at 1 year postoperatively. RESULTS: There was no difference between the KL 0 to 2 and KL 4 cohorts in the achievement of HOOS JR minimum clinically important difference (86 versus 85.6%, P = .922), substantial clinical benefit (81.7 versus 80.2%, P = .751), or patient-acceptable symptom state (89.2 versus 85.6%, P = .374). The KL 0 to 2 cohort had a similar improvement in their 2-year HOOS JR (42.5 versus 38.6, P = .019). CONCLUSIONS: In this series, there was no difference in outcomes following primary THA between patients who have severe OA on plain radiographs (KL 4) compared to those who have less severe OA (KL 0 to 2). In the setting of severe symptoms and the absence of advanced OA on radiographs, advanced imaging can be used to guide treatment and select patients who could benefit from THA.

Early Periprosthetic Femur Fractures After Primary Cementless Total Hip Arthroplasty: High Risk of Periprosthetic Joint Infection and Subsequent Reoperation.

BACKGROUND: Periprosthetic femur fracture (PFF) following total hip arthroplasty (THA) is a leading cause of early reoperation. The objective of this study was to compare rates of periprosthetic joint infection (PJI) and reoperation following PFFs occurring early postoperatively to those that occurred late. METHODS: We retrospectively identified 173 consecutive surgically managed PFFs following primary THA. Cases were categorized as "early" if they occurred within 90 days of THA (n = 117) or "late" if they occurred following the initial 90 days (n = 56). Mean age at time of PFF was 68 years (range, 26 to 96) and 60% were women. Mean body mass index was 29 (range, 16 to 52). Mean follow-up was 2 years (range, 0 to 13). Kaplan-Meier survival analysis estimated cumulative incidences of PJI and reoperation. RESULTS: Early PFFs had higher 2-year cumulative incidence of PJI (11% versus 0%, P < .001) and reoperation (24% versus 13%, P = .110). Following early PFF, 27 patients required reoperation (ie, 13 for PJI, 5 for instability, 2 for re-fracture, 2 for painful hardware, 2 for non-union, 1 for adverse local tissue reaction, 1 for aseptic loosening, and 1 for leg-length discrepancy). Following late PFF, 5 patients required reoperation (ie, 3 for instability, 1 for re-fracture, and 1 for non-union). CONCLUSIONS: There are greater incidences of PJIs and overall reoperations following early PFFs compared to late PFFs after THA. In addition to focusing efforts on prevention of early PFFs, surgeons should consider antiseptic interventions to mitigate the increased risk of PJI after treatment of early PFF.

High Rate of Unplanned Reoperation for Interprosthetic Femur Fractures After Total Hip and Knee Arthroplasty.

BACKGROUND: Interprosthetic femur fractures (IPFFs) are a rare, but devastating complication following total joint arthroplasty. There is limited evidence to help guide their management. The purpose of this study was to describe the features, treatment, and outcomes of surgically managed IPFFs. METHODS: We retrospectively identified 75 patients who had 76 IPFFs. The mean age at the time of IPFF was 75 years (range, 29 to 94), and 78% were women. The mean body mass index was 30 (range, 19 to 51), and the mean follow-up was 3 years (range, 0 to 14). There were 16 Vancouver B1 fractures, 28 Vancouver B2 fractures, 2 Vancouver B3 fractures, and 30 Vancouver C fractures. All B1 fractures underwent open reduction internal fixation (ORIF). All Vancouver B2 and B3 fractures underwent revision arthroplasty, including 1 proximal femur replacement and 1 total femur replacement. Vancouver C fractures were treated with ORIF (n = 20), distal femoral replacement (n = 9), and in 1 case, total femur replacement (n = 1). Kaplan-Meier survivorship was used to calculate 2-year survival free from all-cause reoperation and periprosthetic joint infection (PJI). RESULTS: The 2-year survivorship-free rate from reoperation was 71%. There were 18 reoperations following initial surgical management of the IPFF, including 9 for infection, 3 for refracture, 3 for nonunion, 2 for hardware failure, and 1 for instability. An initial IPFF involving a stemmed femoral total knee arthroplasty component was associated with increased risk for reoperation (P = .007) and PJI (P = .044). There was no difference in survivorship free of reoperation between IPFFs managed with ORIF or revision arthroplasty (P = .72). CONCLUSIONS: An IPFF is a devastating complication following total joint arthroplasty with high reoperation rates, most commonly secondary to PJI. Those IPFFs that occurred between 2 stemmed components were at the highest risk for reoperation.

Does Approach Matter in Robotic-Assisted Total Hip Arthroplasty? A Comparison of Early Reoperations Between Direct Anterior and Postero-Lateral Approach.

BACKGROUND: There is no consensus on whether direct anterior approach (DAA) or postero-lateral approach (PLA) total hip arthroplasty (THA) confers a lower risk of postoperative complications. Robotic assistance in THA results in a more consistently accurate component position compared to manual THA. The objective of this study was to compare rates of dislocation, reoperation, revision, and patient-reported outcome measures between patients undergoing DAA and PLA robotic-assisted primary THA. METHODS: We identified 2,040 consecutive robotic-assisted primary THAs performed for primary osteoarthritis, using DAA (n = 497) or PLA (n = 1,542) between 2017 and 2020. The mean follow-up was 18 months. Kaplan-Meier analysis estimated survivorship free of dislocation, reoperation, and revision. Achievement of patient acceptable symptom state and minimum clinically important difference were used to compare changes in the Hip Disability and Osteoarthritis Outcome Score, Joint Replacement (HOOS JR) and Visual Analog Scale. RESULTS: Dislocation was rare in this series (14 in 2,040, 0.7%), including 1 of 497 (0.2%) in the DAA cohort and 13 of 1,542 (0.8%) in the PLA cohort (P = .210). There was no difference in 2-year reoperation-free survivorship (97.8 versus 98.6%, P = .59) or revision-free survivorship (98.8 versus 99.0%, P = .87) at any time point. After controlling for age, sex, and body mass index, there was no difference in dislocation, reoperation, or revision. At 6-week follow-up, after controlling for age, sex, and body mass index, patients in the DAA cohort had higher odds of achieving HOOS JR minimum clinically important difference (odds ratio = 2.01, P = .012) and HOOS JR patient acceptable symptom state (odds ratio = 1.72, P = .028). There were no differences in patient-reported outcome measures by 3 months. CONCLUSIONS: For robotic-assisted primary THA, DAA may confer enhanced early (<6 weeks) functional recovery compared to the PLA, but there was no significant difference in postoperative dislocation, reoperation, or revision rates.

Tackling cancer cell dormancy: Insights from immune models, and transplantation.

Disseminated non-dividing (dormant) cancer cells as well as those in equilibrium with the immune response remain the major challenge for successful treatment of cancer. The equilibrium between disseminated dormant cancer cells and the immune system is reminiscent of states that can occur during infection or allogeneic tissue and cell transplantation. We discuss here the major competing models of how the immune system achieves a self nonself discrimination (pathogen/danger patterns, quorum, and coinhibition/tuning models), and suggest that taking advantage of a combination of the proposed mechanisms in each model may lead to increased efficacy in tackling cancer cell dormancy.

Clinical, pathologic, and molecular features of amphicrine prostate cancer.

BACKGROUND: Amphicrine prostate carcinoma (AMPC) is a poorly defined subset of prostate cancer in which cells co-express luminal prostate epithelial and neuroendocrine markers. The optimal treatment strategy is unknown. We sought to further characterize the clinical, histomorphologic, and molecular characteristics of AMPC and to identify areas of potential future treatment investigations. METHODS: We retrospectively identified 17 cases of AMPC at a single institution, defined as synaptophysin expression in >70% of cells and co-expression of androgen receptor (AR) signaling markers (either AR, PSA, or NKX3.1) in >50% of cells. Clinical and histologic features of AMPC cases as well as response to treatment and clinical outcomes were described. RESULTS: Five AMPC cases arose de novo in the absence of prior systemic treatment and behaved distinctly from cases that were treatment-emergent. In these de novo cases, despite expression of neuroendocrine markers, prognosis appeared more favorable than high-grade neuroendocrine carcinoma, with two (40%) patients with de novo metastatic disease, universal response to androgen deprivation therapy, and no deaths at a median follow-up of 12.3 months. Treatment-emergent AMPC arose a median of 41.1 months after androgen deprivation therapy initiation and was associated with poor response to therapy. CONCLUSIONS: We show that amphicrine prostate cancer is a unique entity and differs in clinical and molecular features from high-grade neuroendocrine carcinomas of the prostate. Our study highlights the need to recognize AMPC as a unique molecularly defined subgroup of prostate cancer.

Endothelial phosphoinositide 3-kinase-ß inactivation confers protection from immune-mediated vascular injury.

Heart transplant and recipient survival are limited by immune cell-mediated injury of the graft vasculature. We examined the role of the phosphoinositide 3-kinase-ß (PI3Kß) isoform in endothelial cells (EC) during coronary vascular immune injury and repair in mice. In minor histocompatibility-antigen mismatched allogeneic heart grafts, a robust immune response was mounted to each wild-type, PI3Kß inhibitor-treated, or endothelial-selective PI3Kß knockout (ECßKO) graft transplanted to wild-type recipients. However, microvascular EC loss and progressive occlusive vasculopathy only developed in control, but not PI3Kß-inactivated hearts. We observed a delay in inflammatory cell infiltration of the ECßKO grafts, particularly in the coronary arteries. Surprisingly, this was accompanied by an impaired display of proinflammatory chemokine and adhesion molecules by the ECßKO ECs. In vitro, tumor necrosis factor α-stimulated endothelial ICAM1 and VCAM1 expression was blocked by PI3Kß inhibition or RNA interference. Selective PI3Kß inhibition also blocked tumor necrosis factor α-stimulated degradation of inhibitor of nuclear factor kappa Bα and nuclear translocation of nuclear factor kappa B p65 in EC. These data identify PI3Kß as a therapeutic target to reduce vascular inflammation and injury.

Molecular testing of DNA damage response pathways in prostate cancer patients.

PURPOSE OF REVIEW: Personalizing prostate cancer therapy requires germline and tumor molecular tests that predict who will respond to specific treatments and who may not. The review covers molecular testing of DNA damage response pathways, the first biomarker-driven precision target with clinical utility for treatment selection in patients with castration resistant prostate cancer (CRPC). RECENT FINDINGS: Recurrent somatic and germline variants cause deficiency of the mismatch repair (MMR) or homologous recombination (HR) pathways in about a quarter of CRPC patients. In prospective clinical trials, patients with deleterious variants in the MMR pathway more frequently experience a therapeutic response to immune checkpoint inhibitors (ICI). Similarly, somatic and germline events affecting HR predict response to poly(ADP) ribose polymerase inhibitor (PARPi) therapy. Molecular testing of these pathways currently involves assaying for loss of function variants in individual genes and for the genome-wide consequences of repair deficiency. SUMMARY: DNA damage response pathways are the first major area of molecular genetic testing in CRPC settings and offer insights into this new paradigm. Our hope is that eventually an arsenal of molecularly-guided therapies will be developed across many pathways to enable precision medicine options for most men with prostate cancer.

On antigen-specific signals, immune class regulation and energetics: Report III from the workshops on foundational concepts of immune regulation.

This is a report from a one-week workshop held in Athens, Greece in July of 2022. The workshop aimed to identify emerging concepts relevant to the fundamentals of immune regulation and areas for future research. Theories of immune regulation emphasize the role of T cell help or co-stimulation (signal 2). The workshop participants considered how new data on the characteristics of agonist antigens, the role of the antigen receptor signals (signal 1) in driving fate decisions, the effect of energetics on immunity and a better understanding of class-control in the immune response, may impact theories of immune regulation. These ideas were discussed in the context of tumour immunology, autoimmunity, pregnancy and transplantation. Here we present the discussions as a narrative of different viewpoints to allow the reader to join the conversation. These discussions highlight the evolving understanding of the nature of specific antigen recognition and how both antigen-specific and non-specific mechanisms impact immune responses.

Early initiation of short-term emollient use for the prevention of atopic dermatitis in high-risk infants-The STOP-AD randomised controlled trial.

BACKGROUND: Protecting the skin barrier in early infancy may prevent atopic dermatitis (AD). We investigated if daily emollient use from birth to 2 months reduced AD incidence in high-risk infants at 12 months. METHODS: This was a single-center, two-armed, investigator-blinded, randomized controlled clinical trial (NCT03871998). Term infants identified as high risk for AD (parental history of AD, asthma or allergic rhinitis) were recruited within 4 days of birth and randomised 1:1 to either twice-daily emollient application for the first 8 weeks of life (intervention group), using an emollient specifically formulated for very dry, AD-prone skin, or to standard routine skin care (control group). The primary outcome was cumulative AD incidence at 12 months. AD <6 months was diagnosed based on clinical presence of AD. The UK Working Party Diagnostic Criteria were applied when diagnosing AD between 6 and 12 months. RESULTS: Three hundred twenty-one were randomised (161 intervention and 160 control), with 61 withdrawals (41 intervention, 20 control). The cumulative incidence of AD at 12 months was 32.8% in the intervention group vs. 46.4% in the control group, p = 0.036 [Relative risk (95%CI): 0.707 (0.516, 0.965)]. One infant in the intervention group was withdrawn from the study following development of a rash that had a potential relationship with the emollient. There was no significant difference in the incidence of skin infections between the intervention and control groups during the intervention period (5.0% vs. 5.7%, p > 0.05). CONCLUSIONS: This study has demonstrated that early initiation of daily specialized emollient use until 2 months reduces the incidence of AD in the first year of life in high-risk infants.