Design and Preclinical Evaluation of a Novel B7-H4-Directed Antibody-Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305.

PURPOSE: We evaluated the activity of AZD8205, a B7-H4-directed antibody-drug conjugate (ADC) bearing a novel topoisomerase I inhibitor (TOP1i) payload, alone and in combination with the PARP1-selective inhibitor AZD5305, in preclinical models. EXPERIMENTAL DESIGN: IHC and deep-learning-based image analysis algorithms were used to assess prevalence and intratumoral heterogeneity of B7-H4 expression in human tumors. Several TOP1i-ADCs, prepared with Val-Ala or Gly-Gly-Phe-Gly peptide linkers, with or without a PEG8 spacer, were compared in biophysical, in vivo efficacy, and rat toxicology studies. AZD8205 mechanism of action and efficacy studies were conducted in human cancer cell line and patient-derived xenograft (PDX) models. RESULTS: Evaluation of IHC-staining density on a per-cell basis revealed a range of heterogeneous B7-H4 expression across patient tumors. This informed selection of bystander-capable Val-Ala-PEG8-TOP1i payload AZ14170133 and development of AZD8205, which demonstrated improved stability, efficacy, and safety compared with other linker-payload ADCs. In a study of 26 PDX tumors, single administration of 3.5 mg/kg AZD8205 provided a 69% overall response rate, according to modified RECIST criteria, which correlated with homologous recombination repair (HRR) deficiency (HRD) and elevated levels of B7-H4 in HRR-proficient models. Addition of AZD5305 sensitized very low B7-H4-expressing tumors to AZD8205 treatment, independent of HRD status and in models representing clinically relevant mechanisms of PARPi resistance. CONCLUSIONS: These data provide evidence for the potential utility of AZD8205 for treatment of B7-H4-expressing tumors and support the rationale for an ongoing phase 1 clinical study (NCT05123482). See related commentary by Pommier and Thomas, p. 991.

Efficacy, Tolerability, and Pharmacokinetic Studies of Antibody-Drug Conjugates Containing a Low-Potency Pyrrolobenzodiazepine Dimer.

Antibody-drug conjugate (ADC) research has typically focused on the release of highly potent cytotoxic agents to achieve antitumor efficacy. However, recently approved ADCs trastuzumab deruxtecan and sacituzumab govitecan release lower-potency topoisomerase inhibitors. This has prompted interest in ADCs that release lower-potency cytotoxic drugs to potentially enhance therapeutic index and reduce unwanted toxicity. Pyrrolobenzodiazepine (PBD) dimer ADCs have been widely investigated in human clinical trials, which have focused on high-potency PBDs. In this study, we evaluated five ADCs that release the low-potency PBD dimer SG3650. The relatively low clogD for this agent facilitated higher drug-to-antibody ratio (DAR) conjugation without the need for antibody engineering or functionalization of the drug. The rank order of potency for DAR 2 site-specific ADCs (conjugated at the C239i position) matched the order for the corresponding free drugs in vitro. Despite free drug SG3650 being inactive in vivo, the DAR 2 ADCs derived from the corresponding drug-linker SG3584 showed antitumor efficacy in solid (anti-HER2) and hematologic (anti-CD22) xenograft models. Antitumor activity could be enhanced by conjugating SG3584 to trastuzumab at higher DARs of 4 and 8 and by adjusting dosing and schedule. Higher-DAR conjugates were stable and displayed good rat pharmacokinetic profiles as measured by ELISA and LC/MS-MS. A single intravenous dose of isotype control SG3584 DAR 2 ADC resulted in no mortality in rats or monkeys at doses of up to 25 and 30 mg/kg, respectively. These findings suggest that further investigations of low-potency PBD dimers in ADCs that target hematologic and solid tumors are warranted.

COVID-19 Case Investigation and Contact Tracing Efforts from Health Departments - United States, June 25-July 24, 2020.

Case investigation and contact tracing are core public health tools used to interrupt transmission of pathogens, including SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19); timeliness is critical to effectiveness (1,2). In May 2020, CDC funded* 64 state, local, and territorial health departments† to support COVID-19 response activities. As part of the monitoring process, case investigation and contact tracing metrics for June 25-July 24, 2020, were submitted to CDC by 62 health departments. Descriptive analyses of case investigation and contact tracing load, timeliness, and yield (i.e., the number of contacts elicited divided by the number of patients prioritized for interview) were performed. A median of 57% of patients were interviewed within 24 hours of report of the case to a health department (interquartile range [IQR] = 27%-82%); a median of 1.15 contacts were identified per patient prioritized for interview§ (IQR = 0.62-1.76), and a median of 55% of contacts were notified within 24 hours of identification by a patient (IQR = 32%-79%). With higher caseloads, the percentage of patients interviewed within 24 hours of case report was lower (Spearman coefficient = -0.68), and the number of contacts identified per patient prioritized for interview also decreased (Spearman coefficient = -0.60). The capacity to conduct timely contact tracing varied among health departments, largely driven by investigators' caseloads. Incomplete identification of contacts affects the ability to reduce transmission of SARS-CoV-2. Enhanced staffing capacity and ability and improved community engagement could lead to more timely interviews and identification of more contacts.

Preclinical development of a high affinity α-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo.

There are no approved drug therapies that can prevent or slow the progression of Parkinson's disease (PD). Accumulation and aggregation of α-synuclein protein is observed throughout the nervous system in PD. α-Synuclein is a core component of Lewy bodies and neurites that neuropathologically define PD, suggesting that α-synuclein may be a key causative agent in PD. Recent experimental data suggest that PD progression may arise due to spreading of pathological forms of extracellular α-synuclein throughout the brain via a cellular release, uptake and seeding mechanism. We have developed a high affinity α-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo. MEDI1341 binds both monomeric and aggregated forms of α-synuclein. In vitro, MEDI1341 blocks cell-to-cell transmission of pathologically relevant α-synuclein preformed fibrils (pffs). After intravenous injection into rats and cynomolgus monkeys, MEDI1341 rapidly enters the central nervous system and lowers free extracellular α-synuclein levels in the interstitial fluid (ISF) and cerebrospinal fluid (CSF) compartments. Using a novel lentiviral-based in vivo mouse model of α-synuclein spreading in the brain, we show that treatment with MEDI1341 significantly reduces α-synuclein accumulation and propagation along axons. In this same model, we demonstrate that an effector-null version of the antibody was equally as effective as one with effector function. MEDI1341 is now in Phase 1 human clinical trial testing as a novel treatment for α-synucleinopathies including PD with the aim to slow or halt disease progression.

Cough response to aspiration in thin and thick fluids during FEES in hospitalized inpatients.

BACKGROUND: The modifications of fluid viscosity and/or volume are common strategies in dysphagia management, with increased viscosity or reduced volume intended to reduce aspiration. Little attention has been given to whether cough response to aspiration varies across different viscosities and volumes. AIMS: This prospective observational study investigated aspiration prevalence and cough response to aspiration in thin and thick fluids of two different volumes in patients referred for flexible endoscopic evaluation of swallowing (FEES) in an acute hospital setting. METHODS & PROCEDURES: Consecutive inpatients (N = 180) referred for FEES were recruited: stroke 51 (28%); other neurological condition (traumatic brain injury, progressive neurological) 33 (18%); cardiovascular critical care 51 (28%); respiratory illness/condition 23 (13%); spinal injury 9 (5%); and other 13 (7%). A standardized protocol was completed on 268 FEES (180 first FEES, 88 repeat FEES). Penetration-aspiration scale (PAS) scores were obtained for thin and mildly thick fluids at two volumes: 5 ml teaspoon and 50 ml continuous drinking. OUTCOMES & RESULTS: The incidence of aspiration (PAS > 5) was 32% for thin fluids and 18% for thick fluids. There was a significant association between cough response to aspiration and viscosity (p < .001) and volume (p < .001). There was a higher prevalence of silent aspiration in thick fluids than thin fluids. Some patients demonstrated variable cough responsiveness to aspiration across different viscosities and volumes. With 5 ml volumes, 20 patients coughed when they aspirated thin fluids but silently aspirated thick fluids. In comparison, discrepancies in the 50 ml volume were fewer, with three patients coughing when they aspirated thin fluids but silently aspirating thick fluids. CONCLUSIONS & IMPLICATIONS: Cough response to aspiration differs across bolus volumes and viscosities. The finding of inconsistent cough response to aspiration in some patients strongly encourages the use of instrumental assessment to guide decisions regarding diet modifications.

Dysphagia and laryngeal pathology in post-surgical cardiothoracic patients.

PURPOSE: Cardiothoracic surgery is known to result in dysphagia and laryngeal injury. While prevalence has been explored, extent, trajectory and longevity of symptoms are poorly understood. This retrospective, observational study explored dysphagia and laryngeal injury in patients following cardiothoracic surgery referred for instrumental swallowing assessment. METHODS: Clinical notes and endoscopic recordings of 106 patients (age range 18-87yrs; mean 63yrs; SD 15yrs) (including 190 endoscopes) at one large tertiary centre were reviewed by two speech-language pathologists and a laryngologist. Standardized measures of laryngeal anatomy and physiology, New Zealand Secretion Scale, Penetration-Aspiration scale and Yale Residue Scale were rated. RESULTS: Prevalence of abnormality included 39% silent aspiration, 65% laryngeal edema and 61% vocal paralysis. The incidence of pneumonia was 36% with a post-operative stroke rate of 14%. Forty percent of patients were receiving a standard diet by discharge from acute care; while, 24% continued to require enteral feeding and 8% received laryngeal surgery within twelve months of discharge. Vocal fold motion impairment was significantly associated with ventilation time and tracheostomy tube duration (p<.05). CONCLUSION: Early endoscopic assessment for identification of dysphagia and laryngeal injury in patients following cardiothoracic surgery may allow early management and prevention of secondary complications.

Predictive Value of the New Zealand Secretion Scale (NZSS) for Pneumonia.

Accumulated pharyngo-laryngeal secretions have been associated with aspiration and pneumonia. While traditional secretion scales evaluate location and amount, the eight-point New Zealand Secretion Scale (NZSS) uniquely encompasses a responsiveness subcomponent. This prospective observational study investigated the predictive value of NZSS for aspiration and pneumonia. Consecutive inpatients (N:180) referred for flexible endoscopic evaluation of swallowing (FEES) were recruited (neurological 49%, critical care 31%, structural 15%, other 5% etiologies). Mean age was 63 years (range 18-95 years, S.D. 18). A standardized protocol was completed on 264 FEES (180 first FEES, 84 repeat FEES). Penetration-aspiration scale (PAS) (ICC = .89) and NZSS (ICC = .91) were independently scored by two raters. Aspiration of food and/or fluids occurred in 36% of FEES; 24% silently. Median NZSS was 3 (range 0-7); with silent aspiration of secretions in 33% of FEES. There was a significant correlation between NZSS and PAS (R = .37, p < .001). Incidence of pneumonia during admission was 46% and was significantly associated with PAS (p < .001), NZSS (p < .001), age (p < .001), and tracheostomy (p < .001). Of those who developed pneumonia, 33% had both high PAS (>5) and high NZSS (>4). Eleven percent of those who developed pneumonia had an elevated NZSS (>4) in the absence of aspiration (PAS < 6). This large study reports the significant relationship between accumulated secretions, airway responsiveness, and pneumonia. This comprehensive scale is a useful tool when carrying out endoscopic evaluation and has the potential to predict pneumonia in patients irrespective of their aspiration status.

Post-stroke dysphagia: A review and design considerations for future trials.

Post-stroke dysphagia (a difficulty in swallowing after a stroke) is a common and expensive complication of acute stroke and is associated with increased mortality, morbidity, and institutionalization due in part to aspiration, pneumonia, and malnutrition. Although most patients recover swallowing spontaneously, a significant minority still have dysphagia at six months. Although multiple advances have been made in the hyperacute treatment of stroke and secondary prevention, the management of dysphagia post-stroke remains a neglected area of research, and its optimal management, including diagnosis, investigation and treatment, have still to be defined.

Sexually Transmitted Infection Testing Among Adolescents and Young Adults in the United States.

PURPOSE: Persons aged 15-25 years have high sexually transmitted infection (STI) rates and suboptimal screening. There has been limited research analyzing barriers to STI testing at a national level. We examined STI testing among 15-25 year olds and reasons for not testing. METHODS: We used data from a national survey of youth. Bivariate and multivariable analyses examined differences in testing behaviors by demographics, separately by sex. Among sexually experienced respondents who reported never being tested, health system-related reasons for not testing were examined in bivariate and multivariable analyses. RESULTS: Females (16.6%) were more likely to have ever been tested compared with males (6.1%, p < .01) in the last 12 months. Among sexually experienced respondents who were never tested, 41.8% did not seek testing because they felt they were not at risk for STIs. Males (60.1%) had significantly higher reports of foregoing testing for confidentiality reasons compared with females (39.9%, p < .01). Non-Hispanic whites (44.9%) the highest reports of this compared with other ethnic/racial groups (p < .01). CONCLUSIONS: This national-level study found that most of the 15-25 year olds never received an STI test. In addition, confidentiality concerns may deter youth from seeking STI testing. Appropriate strategies to minimize these concerns may be useful. Potential strategies to ameliorate these issues may include engaging clinicians who frequently serve adolescents and young adults to address confidentiality issues with youth patients.

Health Communication and Social Marketing Campaigns for Sexually Transmitted Disease Prevention and Control: What Is the Evidence of their Effectiveness?

BACKGROUND: Despite the ubiquity of sex in the media, a culture of silence surrounds sexual health in the United States, serving as a barrier to sexually transmitted disease (STD) prevention, testing, and treatment. Campaigns can increase STD-related knowledge, communication, and protective behaviors. This review assesses the effectiveness of STD prevention and testing campaigns in the United States to inform the field on their use as a strategy for affecting behavior change. METHODS: A comprehensive literature search was conducted to identify original research articles, published between 2000 and 2014, which report on US media campaigns promoting community- or population-level STD testing or prevention behaviors and are evaluated for impact on one or more behavioral outcomes. Titles and abstracts were independently reviewed by 2 researchers. RESULTS: The review yielded 26 articles representing 16 unique STD testing and/or prevention campaigns. Most campaigns were developed using formative research and social marketing or behavioral theory. Most campaigns (68.75%) used posttest-only or pretest-posttest designs without comparison groups for evaluation; only 5 campaigns used control groups, and these proved challenging (i.e., achieving necessary exposure and avoiding contamination). Nearly all campaigns found differences between exposed and unexposed individuals on one or more key behavioral outcomes. Several campaigns found dose-response relationships. Among evaluations with uncontaminated control groups whose campaigns achieved sufficient exposure, sustained campaign effects were observed among targeted populations. CONCLUSIONS: Current findings suggest that campaigns can impact targeted STD-related behaviors and add to the evidence that greater exposure is associated with greater behavior change.

Assessing Relationship and Sexual Satisfaction in Adolescent Relationships Formed Online and Offline.

PURPOSE: Using the Internet to meet new people is becoming more common; however, such behavior is often considered risky, particularly for adolescents. Nevertheless, adolescents are meeting people through online venues and some are forming romantic/sexual relationships. The purpose of this study was to examine the relationship and sexual satisfaction reported by teens in online- and offline-initiated relationships. METHODS: Data were collected from 273 13-19 year olds visiting a publicly funded clinic through 2010 and 2011. Questions included where respondents met the partner (online vs. offline), time between meeting and first sex, how well they knew the partner, and relationship and sexual (R&S) satisfaction. Analyses consisted of descriptive statistics, t tests, and path analysis, exploring R&S satisfaction in online- and offline-initiated relationships. RESULTS: R&S satisfaction scores were moderate for adolescents who reported meeting partners online and in person but were statistically higher in offline-initiated relationships. There was an inverse relationship between having an online partner and both relationship and sexual satisfaction. Additionally, knowing partners for a longer period of time and feeling more knowledgeable about partners before having sex were statistically significantly related to higher R&S satisfaction. CONCLUSIONS: Teens in this study reported more satisfying relationships with partners met offline compared with online. Results suggest that encouraging teens to wait longer and to get to know their partner(s) better before engaging in sex may improve satisfaction with, and quality of, those relationships. These findings provide an important contribution to sexual health promotion among young people, with whom technology use is ubiquitous.

GYT: Get Yourself Tested Campaign Awareness: Associations With Sexually Transmitted Disease/HIV Testing and Communication Behaviors Among Youth.

BACKGROUND: The GYT: Get Yourself Tested campaign promotes sexually transmitted disease (STD) and HIV testing and communication with partners and providers among youth. We evaluated these behaviors in relation to campaign awareness among youth through a national survey. METHODS: We collected data from 4017 respondents aged 15 to 25 years through an online panel survey designed to be representative of the US population. The GYT campaign targeted 4 key behaviors: STD testing, HIV testing, talking to partners about testing, and talking to providers about testing. RESULTS: Respondents who were aware of the GYT campaign (24.4%) were more likely to report engaging in each of the 4 target behaviors. Associations remained significant when stratified by race and sex and when taking into account sexuality, sexual activity, age, insurance status, and use of campaign partner-provided services. CONCLUSIONS: Awareness of the GYT campaign is related to the 4 target behaviors promoted by the campaign, suggesting that health promotions campaigns oriented toward youth can be successful in increasing STD-related, health-seeking behavior, including among populations disproportionately affected by STD.

Development of Immunoassays for the Quantitative Assessment of Amyloid-ß in the Presence of Therapeutic Antibody: Application to Pre-Clinical Studies.

Utilizing decision making biomarkers in drug development requires thorough assay validation. Special considerations need to be taken into account when monitoring biomarkers using immunoassays in the presence of therapeutic antibodies. We have developed robust and sensitive assays to assess target engagement and proof of mechanism to support the clinical progression of a human monoclonal antibody against the neurotoxic amyloid-ß (Aß)42 peptide. Here we present the introduction of novel pre-treatment steps to ensure drug-tolerant immunoassays and describe the validation of the complete experimental procedures to measure total Aß42 concentration (bound and unbound) in cerebrospinal fluid (CSF) and plasma, free Aß42 concentration (unbound) in CSF, and Aß40 concentration in CSF. The difference in composition of the matrices (CSF and plasma) and antigen levels therein, in combination with the hydrophobic properties of Aß protein, adds to the complexity of validation. Monitoring pharmacodynamics of an Aß42 specific monoclonal antibody in a non-human primate toxicology study using these assays, we demonstrated a 1500-fold and a 3000-fold increase in total Aß42 in plasma, a 4-fold and 8-fold increase in total Aß42 in CSF together with a 95% and 96% reduction of free Aß42 in CSF following weekly intravenous injections of 10 mg/kg and 100 mg/kg, respectively. Levels of Aß40 were unchanged. The accuracy of these data is supported by previous pre-clinical studies as well as predictive pharmacokinetic/pharmacodynamics modeling. In contrast, when analyzing the same non-human primate samples excluding the pre-treatment steps, we were not able to distinguish between free and total Aß42. Our data clearly demonstrate the importance of thorough evaluation of antibody interference and appropriate validation to monitor different types of biomarkers in the presence of a therapeutic antibody.

An assessment of the GYT: Get Yourself Tested campaign: an integrated approach to sexually transmitted disease prevention communication.

BACKGROUND: Youth in the United States bear a disproportionate burden of sexually transmitted diseases (STDs). Stigma, misconceptions, and access challenges keep many from getting tested or treated. The GYT: Get Yourself Tested campaign was launched in 2009 to reduce stigma and promote STD communication and testing. This evaluation sought to assess the first 2 years of campaign engagement and associations with STD testing among youth. METHODS: Campaign engagement with select GYT on-the-ground events, social media sites, and STD testing locator tools was measured through process/media tracking metrics. Sexually transmitted disease testing patterns were assessed using data from Planned Parenthood affiliates (2008-2010) and national trend data from clinics participating in national infertility prevention activities (2003-2010). RESULTS: On-the-ground events reached an estimated 20,000 youth in 2009 and 52,000 youth in 2010. Across 2009 to 2010, GYT's Facebook page gained 4477 fans, Twitter feed gained 1994 followers, and more than 140,000 referrals were made to the STD testing locator. From April 2008 to 2010, there was a 71% increase in STD testing and a 41% increase in chlamydia testing at reporting Planned Parenthood affiliates (representing ∼118 health centers). Chlamydia case positivity rates during this period were stable at 6.6% (2008) and 7.3% (2010). Trend data indicate that testing was higher in spring 2009 and 2010 compared with other periods during those years; this pattern is commensurate with STD Awareness Month/GYT activities. CONCLUSIONS: Data quality is limited in a manner similar to many STD prevention efforts. Within these limitations, evidence suggests that GYT reaches youth and is associated with increased STD testing.

Speech-language pathologist-led fiberoptic endoscopic evaluation of swallowing: functional outcomes for patients after stroke.

BACKGROUND: Dysphagia is a common complication after stroke and is associated with the development of pneumonia. Early detection of dysphagia and specifically aspiration is, therefore, critical in the prevention of pneumonia. Fiberoptic endoscopic evaluation of swallowing (FEES) is a safe bedside instrumental tool for detecting dysphagia and aspiration and, therefore, has the potential to inform dysphagia management. This study investigated the clinical utility of a speech-language pathologist-led FEES service on functional outcomes for patients after acute stroke. METHODS: A retrospective file audit was carried out on 220 patients before FEES was introduced and on 220 patients after the implementation of a speech-language pathologist-led FEES service. The primary outcome measure was incidence of pneumonia, and secondary outcome measures included mortality, diet on discharge, discharge destination, duration nil-by-mouth, incidence of nonoral feeding, and length of stay. RESULTS: There was a significant increase in instrumental assessment use in the group that had access to FEES (P < .001). There was a significant reduction of pneumonia rates in the group that had access to FEES (P = .037). Patients were also significantly more likely to leave hospital on standard diets (P = .004) but had longer periods of nonoral feeding (P = .013) and increased length of hospitalization (P < .001). CONCLUSION: When used selectively, FEES services have potential for improving functional outcomes for patients after stroke.

Evaluating the Internet as a sexually transmitted disease risk environment for teens: findings from the communication, health, and teens study.

BACKGROUND: Few studies have examined the association between sexual health risks and online sex-seeking among teenagers. The purpose of this study was to assess the associations between meeting sex partners online and a range of sexual risk behaviors and outcomes among adolescents. METHODS: Participants aged 13 to 19 years were recruited from a publicly funded teen clinic in Florida. After obtaining informed consent/assent, 273 participants completed an audio computer-assisted self-interview that included questions on demographics, sexual behavior, sexually transmitted disease (STD) history, and online sex-seeking behaviors and experiences. Participants also provided urine samples for chlamydia and gonorrhea testing. Data were analyzed using logistic regression to identify the association between having an online sex partner and sexual behaviors/outcomes. RESULTS: After adjusting for significant bivariate correlates, teens reporting online sex partners were more likely to be male, be multiracial, have a history of same-sex sexual activity, report a higher number of vaginal sex partners, and report a lower age at first vaginal sex. However, teens with online sex partners were no more likely to have ever had an STD or a current biological STD. CONCLUSIONS: This study is one of the first to correlate biological STD results to online sexual partnering data in a youth population. Although meeting a sex partner online was not associated with past or current STDs, it was associated with other sexual risk behaviors. Future research is needed to examine the complex nature of online sexual partnering among adolescents and to develop intervention approaches.

Assessing the role of prevention partnerships in STD prevention: a review of comprehensive STD prevention systems progress reports.

Systematic analysis of STD programme data contributes to a national portrait of sexually transmitted disease (STD) prevention activities, including research and evaluation specifically designed to optimise programme efficiency and impact. We analysed the narrative of the 2009 annual progress reports of the US Comprehensive STD Prevention Systems cooperative agreement for 58 STD programmes, concentrating on programme characteristics and partnerships. Programmes described 516 unique partnerships with a median of seven organisations cited per STD programme. Non-profit organisations (including service providers) were most frequently cited. Higher gonorrhoea morbidity was associated with reporting more partnerships; budget problems were associated with reporting fewer. Challenges to engaging in partnerships included budget constraints, staff turnover and low interest. Data provide a source of information for judging progress in programme collaboration and for informing a sustained programme-focused research and evaluation agenda.

Comparison of cough reflex test against instrumental assessment of aspiration.

BACKGROUND: Silent aspiration is associated with pneumonia and mortality, and is poorly identified by traditional clinical swallowing evaluation (CSE). The aim of this study was to validate cough reflex testing (CRT) for identification of silent aspiration against aspiration confirmed by instrumental assessment. METHODS: Cough reflex threshold testing was completed on all patients using inhaled, nebulised citric acid. Within an hour, 80 patients underwent videofluoroscopic study of swallowing (VFSS) and 101 patients underwent fibreoptic endoscopic evaluation of swallowing (FEES). All tests were recorded and analysed by two researchers blinded to the result of the alternate test. RESULTS: Significant associations between CRT result and cough response to aspiration on VFSS (X(2) (2)=11.046, p=.003) and FEES (X(2) (2)=34.079, p<.001) were identified. Sensitivity and specificity were optimised at 0.6mol/L in patients undergoing VFSS (71%, 60% respectively) and at 0.4mol/L in patients undergoing FEES (69%, 71% respectively). A concentration of 0.8mol/L had the highest odds ratio (OR) for detecting silent aspiration (8 based on VFSS; 7 based on FEES). CONCLUSION: CRT results are significantly associated with aspiration response on instrumental assessment. Lower concentrations of citric acid provide a better predictive measure of silent aspiration.

Monoclonal antibody therapeutics: history and future.

Over the last three decades, monoclonal antibodies have made a dramatic transformation from scientific tools to powerful human therapeutics. At present, approximately 30 therapeutic monoclonal antibodies are marketed in the United States and Europe in a variety of indications, with sales in the US alone reaching approximately $18.5 billion in 2010. This review describes how antibody engineering has revolutionized drug discovery and what are considered the key areas for future development in the monoclonal antibody therapy field.

High-risk behaviour in steady and in casual relationships among men who have sex with men in Israel.

OBJECTIVE: To explore the differences in sexual risk behaviour between men who have sex with men (MSM) with steady partners versus casual partner(s) in the gay community. METHODS: This online cross-sectional convenience-sampling study assessed MSM practices, their knowledge and their motivation regarding safe sex. Participants not knowing their HIV status or who performed insertive or receptive unprotected anal intercourse (UAI) or with a sex partner whose HIV status was unknown or discordant were considered 'at-risk'. RESULTS: Of all 2569 participants who completed the questionnaire, 907/2569 (35.3%) had a steady partner, and 896/2569 (34.9%) had a casual partner(s) in the past 6 months. 262/907 (28.9%) with steady partners and 248/896 (27.7%) with casual partners demonstrated at-risk sexual behaviour. Of all participants with steady partners, 108/907 (11.9%) performed UAI with their partner without undergoing mutual HIV testing. Of all participants with steady partners, 476/907 (52.5%) had a concurrent casual partner, and 144/476 (30.3%) performed UAI with both the steady and the casual partner. Of all participants with steady partners, 775/907 (85.4%) negotiated the possibility of sex outside their relationship with their main partner. The length of the steady relationship correlated with the number of concurrent casual partners. CONCLUSIONS: At-risk sexual behaviour was associated with insufficient negotiation skills, difficulties in condom use and a general risk-taking profile. Health educators should encourage MSM with steady partners to perform HIV testing before practising UAI, to improve their negotiation skills during the contact and to support open discussions with regard to sexual contact besides the steady relationship, as it may not be monogamous.