Durable immunity to SARS-CoV-2 in both lower and upper airways achieved with a gorilla adenovirus (GRAd) S-2P vaccine in non-human primates.

SARS-CoV-2 continues to pose a global threat, and current vaccines, while effective against severe illness, fall short in preventing transmission. To address this challenge, there's a need for vaccines that induce mucosal immunity and can rapidly control the virus. In this study, we demonstrate that a single immunization with a novel gorilla adenovirus-based vaccine (GRAd) carrying the pre-fusion stabilized Spike protein (S-2P) in non-human primates provided protective immunity for over one year against the BA.5 variant of SARS-CoV-2. A prime-boost regimen using GRAd followed by adjuvanted S-2P (GRAd+S-2P) accelerated viral clearance in both the lower and upper airways. GRAd delivered via aerosol (GRAd(AE)+S-2P) modestly improved protection compared to its matched intramuscular regimen, but showed dramatically superior boosting by mRNA and, importantly, total virus clearance in the upper airway by day 4 post infection. GrAd vaccination regimens elicited robust and durable systemic and mucosal antibody responses to multiple SARS-CoV-2 variants, but only GRAd(AE)+S-2P generated long-lasting T cell responses in the lung. This research underscores the flexibility of the GRAd vaccine platform to provide durable immunity against SARS-CoV-2 in both the lower and upper airways.

Urinary metabolomic biomarker candidates for skeletal muscle wasting in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints, leading to chronic synovial inflammation and local tissue destruction. Extra-articular manifestations may also occur, such as changes in body composition. Skeletal muscle wasting is often observed in patients with RA, but methods for assessing loss of muscle mass are expensive and not widely available. Metabolomic analysis has shown great potential for identifying changes in the metabolite profile of patients with autoimmune diseases. In this setting, urine metabolomic profiling in patients with RA may be a useful tool to identify skeletal muscle wasting. METHODS: Patients aged 40-70 years with RA have been recruited according to the 2010 ACR/EULAR classification criteria. Further, the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) determined the disease activity. The muscle mass was measured by Dual X-ray absorptiometry (DXA) to generate the appendicular lean mass index (ALMI) by summing the lean mass measurements for both arms and legs and dividing them by height squared (kg/height2 ). Finally, urine metabolomic analysis by 1 H nuclear magnetic resonance (1 H-NMR) spectroscopy was performed and the metabolomics data set analysed using the BAYESIL and MetaboAnalyst software packages. Principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were applied to the 1 H-NMR data, followed by Spearman's correlation analysis. The combined receiver operating characteristic curve (ROC) was calculated, as well as the logistic regression analyses to establish a diagnostic model. The significance level at P < 0.05 was set for all analyses. RESULTS: The total set of subjects investigated included 90 patients with RA. Most patients were women (86.7%), with a mean age of 56.5 ± 7.3 years old and a median DAS28-CRP of 3.0 (IQR 1.0-3.0). Fifteen metabolites were identified in the urine samples with high variable importance in projection (VIP scores) by MetaboAnalyst. Of these, dimethylglycine (r = 0.205; P = 0.053), oxoisovalerate (r = -0.203; P = 0.055), and isobutyric acid (r = -0.249; P = 0.018) were significantly correlated with ALMI. Based on the low muscle mass (ALMI ≤6.0 kg/m2 for women and ≤8.1 kg/m2 for men) a diagnostic model have been established with dimethylglycine (area under the curve [AUC] = 0.65), oxoisovalerate (AUC = 0.49), and isobutyric acid (AUC = 0.83) with significant sensitivity and specificity. CONCLUSIONS: Isobutyric acid, oxoisovalerate, and dimethylglycine from urine samples were associated with low skeletal muscle mass in patients with RA. These findings suggest that this group of metabolites may be further tested as biomarkers for identification of skeletal muscle wasting.

Discovery of BGB-8035, a Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase for B-Cell Malignancies and Autoimmune Diseases.

Bruton's tyrosine kinase (BTK) plays an essential role in B-cell receptor (BCR)-mediated signaling as well as the downstream signaling pathway for Fc receptors (FcRs). Targeting BTK for B-cell malignancies by interfering with BCR signaling has been clinically validated by some covalent inhibitors, but suboptimal kinase selectivity may lead to some adverse effects, which also makes the clinical development of autoimmune disease therapy more challenging. The structure-activity relationship (SAR) starting from zanubrutinib (BGB-3111) leads to a series of highly selective BTK inhibitors, in which BGB-8035 is located in the ATP binding pocket and has similar hinge binding to ATP but exhibits high selectivity over other kinases (EGFR, Tec, etc.). With an excellent pharmacokinetic profile as well as demonstrated efficacy studies in oncology and autoimmune disease models, BGB-8035 has been declared a preclinical candidate. However, BGB-8035 showed an inferior toxicity profile compared to that of BGB-3111.

Implementation science and the Health Resources and Services Administration's Ryan White HIV/AIDS Program's work towards ending the HIV epidemic in the United States.

Demetrios Psihopaidas and co-authors discuss the implementation science framework of an HIV/AIDS program in the United States.

Discussing sexual activities after total hip arthroplasty.

BACKGROUND: Hip pathology can affect functions including sexual activity. Sex after hip replacement (SAHR) is an important subject for patients but rarely discussed. A conversation prior to surgery can be difficult to initiate, and appropriate advice is then not given. This study has set out to find how physicians approach the subject, and how patients would the like the subject to be addressed. Thus, device a process that ensures appropriate discussions take place prior to Total Hip Replacement (THR) in all patients. METHODS: Questionnaires were given to clinicians and patients. The clinicians' questionnaire asked how they dealt with the issue of SAHR. All patients below the age of 80 were asked how the issue was addressed, and how this could be improved. The aim of this study was twofold. Firstly, to address how SAHR should be approached, both by reviewing the clinicians present views and asking the patients their expectations. Secondly, to develop a process that will ensure patients' concerns are appropriately and consistently addressed prior to total hip replacement (THR). RESULTS: All 17 clinicians responded. None used any printed information to give to patients dealing with SAHR nor did they routinely discuss it with patients. 244/340 patients responded. Over 90% of patients wanted the surgeon to discuss sex after THR with them, and would be happy to be asked directly about the subject. CONCLUSION: Clinicians do not routinely raise the subject of SAHR with patients, who often wanted to know, but rarely asked. There is unease around the subject, and therefore there is a need to establish a process that ensures this discussion takes place prior to THR.

Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.

Aberrant activation of Bruton's tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.

Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor.

The DNA damage response (DDR) is a DNA damage surveillance and repair mechanism that can limit the effectiveness of radiotherapy and DNA-damaging chemotherapy, commonly used treatment modalities in cancer. Two related kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3-related kinase (ATR), work together as apical proteins in the DDR to maintain genome stability and cell survival in the face of potentially lethal forms of DNA damage. However, compromised ATM signaling is a common characteristic of tumor cells, which places greater reliance on ATR to mediate the DDR. In such circumstances, ATR inhibition has been shown to enhance the toxicity of DNA damaging chemotherapy to many cancer cells in multiple preclinical studies, while healthy tissue with functional ATM can tolerate ATR inhibition. ATR therefore represents a very attractive anticancer target. Herein we describe the discovery of VX-970/M6620, the first ATR inhibitor to enter clinical studies, which is based on a 2-aminopyrazine core first reported by Charrier ( J. Med. Chem. 2011 , 54 , 2320 - 2330 , DOI: 10.1021/jm101488z ).

Evaluation, validation and refinement of noninvasive diagnostic biomarkers for endometriosis (ENDOmarker): A protocol to phenotype bio-specimens for discovery and validation.

OBJECTIVE: Endometriosis is a chronic, estrogen dependent condition that affects 5-10% of reproductive aged women and is associated with pelvic pain and infertility. As the approach to therapy shifts from surgical ablation to pharmacological control, a non-surgical mode of diagnosis would be desirable. The ENDOmarker study was designed by the NICHD Reproductive Medicine Network (RMN) to obtain well characterized and phenotyped bio specimens in a standardized fashion from women with and without endometriosis. DESIGN: Development of a diagnostic test. SETTING: Academic medical centers. PATIENTS: This study will enroll up to 500 participants, and follow them for up to 5 months. Included subjects are aged 18-44, scheduled to undergo gynecologic surgery (laparoscopy/laparotomy) for clinical reasons. INTERVENTIONS: Presence and stage of endometriosis (or its absence) is characterized by visual examination at the time of surgery. Subjects will undergo extensive clinical evaluation pre-operatively and at visits one and four months postoperatively. Endometrial biopsy, blood, urine and disease specific questionnaires will be collected at each visit. MAIN OUTCOME: Samples will be placed in a bio-repository to be used to validate and optimize the clinical use of genomic classifiers of the endometrium alone or in combination with serum cytokines as a non-surgical composite marker of endometriosis. CONCLUSION: This protocol can serve as a reference for objective collection of high quality bio specimens for discovery or validation of potential nonsurgical diagnosis of presence or severity of disease.

601 metal-on-metal total hip replacements with 36 mm heads a 5 minimum year follow up: Levels of ARMD remain low despite a comprehensive screening program.

BACKGROUND: We conducted a retrospective study to assess the clinical outcome, failure rate, and reason for failure of a large consecutive series of 36 mm MoM Corail/Pinnacle total hip replacements (THRs). METHODS: Between 2006 and 2011, 601 consecutive 36 mm MoM THRs were performed (585 patients). Patients were followed according to the UK Medicines and Healthcare Products Regulatory Agency (MHRA) guidelines. All patients were accounted for and 469 patients (78%) were clinically and radiographically assessed. 328 females and 141 males with a median age of 73 (range 36-94 years) and a median follow up of 7.2 years (range 5.2-9.7 years) were followed. Clinical data included blood cobalt and chromium, Oxford Hip Score (OHS), plain radiograph, ultrasound of hip and intra-operative findings in those patients who had revision surgery. RESULTS: 56 patients died of causes unrelated to their hip replacement. The mean survivorship of the implant was 92.8% (range 91.6-94%, 95% CI) at a median time to follow up of 84 months (62-113 months). The functional outcome was good with a median OHS of 38 out of 48 (23-44). The dislocation rate was 0.99%, with all these 6 cases requiring revision. 476 patients had blood tests. 100 patients (21%) had elevated levels of either cobalt above MHRA guidelines of 7 parts per billion (120 and 135 nmol/L respectively for cobalt and chromium). Cobalt was elevated independently of chromium in 75% of the cases (but never vice versa). The mean cup inclination angle was 42°. Each incremental stem size increase resulted in a decrease in cobalt by 11 nmol/L. The most common reason for revision was adverse reaction to metal debris (ARMD) (12 cases). CONCLUSION: This paper is the largest and longest follow up of 36 mm MoM THRs. Using the MHRA guidelines for follow up, the revision rates of this cohort has remained low compared to other studies, but unacceptably higher than that of other bearing surfaces. LEVEL OF EVIDENCE: III.

Decreased Notch pathway signaling in the endometrium of women with endometriosis impairs decidualization.

CONTEXT: Endometriosis is a common gynecological disease affecting one in 10 women of reproductive age and is a major cause of pelvic pain and impaired fertility. Endometrial stromal cells of women with endometriosis exhibit a reduced response to in vitro decidualization. NOTCH1 is critical for decidualization of both mouse and human uterine stromal cells. OBJECTIVE: This study aimed to determine whether decidualization failure in women with endometriosis is a consequence of impaired Notch signaling. SETTING AND DESIGN: We investigated expression levels of Notch signaling components in the endometrium of women and baboons with or without endometriosis. We identified NOTCH1-regulated genes during decidualization of human uterine fibroblast (HuF) cells by microarray and quantified their expression levels in in vitro-decidualized endometrial stromal cells isolated from women with or without endometriosis. RESULTS: Notch signaling receptors NOTCH1 and NOTCH4, ligands JAGGED2 and DLL4, as well as direct target genes HES5 and HEY1 were decreased in the eutopic endometrium of women and baboons with endometriosis. Notch signaling was decreased in stromal cells isolated from women with endometriosis, which was associated with impaired in vitro decidualization. Genes that were down-regulated by NOTCH1 silencing in decidualized HuF cells were also decreased in decidualized endometrial stromal cells of women with endometriosis. FOXO1 acts as a downstream target of Notch signaling and endometriosis is associated with decreased expression of NOTCH1-regulated, FOXO1-responsive genes during decidualization. CONCLUSIONS: Decreased Notch signaling is associated with endometriosis and contributes to impaired decidualization through the down-regulation of FOXO1.

Spectral analysis of the sound produced during femoral broaching and implant insertion in uncemented total hip arthroplasty.

Preparation of the proximal femur using incremental broaches to create the ideal cancellous bone envelope is an important technique to perfect in uncemented hip arthroplasty. To guide broaching adequacy and final implant position, the surgeon can use audible pitch changes produced by the femoral broach and definitive implant. The aim of this study was to characterise these pitch changes by analysing the sound spectra created by the first broach, last broach and implant using spectral analysis software. The last broach and implant introduction spectra demonstrated low-frequency (400-1200 Hz) spectral peaks that were not detected when using the first broach. These frequencies corresponded to the natural resonant frequency of a standing sound wave within the femoral bone canal (approximately 894 Hz) that was estimated using acoustic physics theory. The remaining spectral peaks were associated with transverse vibration modes produced by striking the metal broach handle and implant introducer and were a function of the constructs geometry and material properties.

The articular surface replacement implant recall: a United Kingdom district hospital experience.

We present our experience of the articular surface replacement (ASR) hip and the implant recall process. One hundred and twenty-one ASR components were implanted (21 resurfacing hip arthroplasty (RHA) and 100 ASR/XL modular total hip replacements). At the time of the implant recall in August 2010 there were 111 surviving hips (92%) with a mean follow-up of 44 months. Nine hips had been revised and one had been listed for revision surgery. Ninety-two percent of surviving implants were reviewed in the recall clinics, and blood metal ion levels or ultrasound scans were indicated in 38 hips (34%). Immediately after the recall process seven hips (6 ASR/XL and 1 RHA) were listed for revision and a further 9 were kept under close surveillance. One year after completion of the recall process 23 hips (19 ASR/XL and 4 RHA's) had been revised. A diagnosis of adverse reaction to metal debris (ARMD) was made at surgery in all but two hips. Our current revision rate for ASR RHA is 19% (mean follow-up 62 months, range 29-80) and for the ASR/XL is 19% (mean follow-up 53 months, range 10-80). The 5-year cumulative survival rates with revision for any reason for the ASR/XL, was 80.8% (95% confidence interval 72.0 - 89.5). Given experience elsewhere we expect this rate may increase significantly with time.

Reducing the rate of early primary hip dislocation by combining a change in surgical technique and an increase in femoral head diameter to 36 mm.

INTRODUCTION: We report how changes to our total hip arthroplasty (THA) surgical practise lead to a decrease in early hip dislocation rates. METHODS: Group B consisted of 421 consecutive primary THA operations performed via a posterior approach. The operative technique included a meticulous repair of the posterior capsule, alignment of the acetabular cup with the transverse acetabular ligament (TAL) and a 36-mm-diameter femoral head. We compared the dislocation rates and cost implications of this technique to a historical control Group A consisting of 389 patients. The control group had their THA performed with no repair of the capsule, no identification of the TAL and all received a 28-mm-diameter head. Our primary outcome is the rate of early hip dislocation and we hypothesised that we can reduce the rate of early hip dislocation with this new regime. RESULTS: In Group B there were no early dislocations (within 6 months) and two (0.5 %) dislocations within 18 months; minimum follow-up time was 18 months with a range of (18-96 months). This compared to a 1.8 % early dislocation rate and a 2.6 % rate at 18 months in Group A; minimum follow-up time was 60 months with a range of (60-112 months). These results were statistically significant (p = 0.006). CONCLUSION: We suggest that when primary hip arthroplasty is performed through a posterior approach, a low early dislocation rate can be achieved using the described methods.

Hepatitis B among Pacific Islanders in Southern California: how is health information associated with screening and vaccination?

We measured Hepatitis B virus (HBV) transmission knowledge and self-reported screening/testing behavior among Pacific Islanders (Guamanians/Chamorros, Samoans, and Tongans) in Southern California. We also examined access and trust by Pacific Islanders of varying health information sources. We administered and analyzed survey data (N = 297), using a convenience sample in Los Angeles, Orange, and San Diego Counties in spring 2009. We found that while Pacific Islander respondents reported that they receive health information from physicians, and largely trust this source, information from and trust in physicians were not statistically significant in explaining whether respondents sought HBV screening or vaccination.

Has packing sinus wounds become a ritualistic practice?

Wound healing is both a science and an art, and modern advances in wound management are ensuring that advanced clinicians use both clinical knowledge and experience when deciding on wound dressings and therapies. When there is a lack of evidence, then selection of dressings or therapies becomes extremely difficult and inappropriate treatment can occur. This is generally the situation with sinus wounds. There is very little evidence available to help decide on suitable dressings for these intractable wounds. The use of high frequency ultrasound (HFU) can help to guide practice on whether or not to pack sinus wounds. This article will explore the potential of ultrasound use by describing a case study of a patient with a sinus wound where HFU was used to examine the sinus and inform the practitioners on the appropriate choice of wound dressing.

High throughput screening for protein kinase inhibitors.

The pivotal role of kinases in signal transduction and cellular regulation has lent them considerable appeal as pharmacological targets across a broad spectrum of pathologies. Since the discovery that the v-Src oncogene encoded a protein kinase in 1978, kinases have remained a focus of research for pharmaceutical laboratories and academic groups alike. Many have sought to develop orally available low molecular weight synthetic kinase modulators (predominantly inhibitors) and thus capitalize on the links between aberrant regulation and disease. This interest in kinases as drug targets was fueled in recent years by the success of several kinase inhibitors in the clinic, primarily Gleevec for the treatment of chronic myelogenous leukemia and Iressa for the treatment of advanced non-small cell lung cancer. This review focuses on the development of small molecule drugs, most of them binding in or close to the ATP binding pocket. After some general considerations regarding the selection of a particular kinase for drug discovery, we will discuss the encouraging lessons learned from some of the kinase inhibitors currently in various stages of development. The majority of this review is dedicated to a detailed description and discussion of the various assay formats currently being employed for high throughput screening.