Improvement of daratumumab- or elotuzumab-mediated NK cell activity by the bi-specific 4-1BB agonist, DARPin α-FAPx4-1BB: A preclinical study in multiple myeloma.

Multiple myeloma (MM) progression is closely dependent on cells in the bone marrow (BM) microenvironment, including fibroblasts (FBs) and immune cells. In their BM niche, MM cells adhere to FBs sustaining immune evasion, drug resistance and the undetectable endurance of tumor cells known as minimal residual disease (MRD). Here, we describe the novel bi-specific designed ankyrin repeat protein (DARPin) α-FAPx4-1BB (MP0310) with FAP-dependent 4-1BB agonistic activity. The α-FAPx4-1BB DARPin simultaneously binds to FAP and 4-1BB overexpressed by activated FBs and immune cells, respectively. Although flow cytometry analysis showed that T and NK cells from MM patients were not activated and did not express 4-1BB, stimulation with daratumumab or elotuzumab, monoclonal antibodies (mAbs) currently used for the treatment of MM, significantly upregulated 4-1BB both in vitro and in MM patients following mAb-based therapy. The mAb-induced 4-1BB overexpression allowed the engagement of α-FAPx4-1BB that acted as a bridge between FAP+FBs and 4-1BB+NK cells. Therefore, α-FAPx4-1BB enhanced both the adhesion of daratumumab-treated NK cells on FBs as well as their activation by improving release of CD107a and perforin, hence MM cell killing via antibody-mediated cell cytotoxicity (ADCC). Interestingly, α-FAPx4-1BB significantly potentiated daratumumab-mediated ADCC in the presence of FBs, suggesting that it may overcome the BM FBs' immunosuppressive effect. Overall, we speculate that treatment with α-FAPx4-1BB may represent a valuable strategy to improve mAb-induced NK cell activity fostering MRD negativity in MM patients through the eradication of latent MRD cells.

In vivo T1 mapping of neonatal brain tissue at 64 mT.

PURPOSE: Ultralow-field (ULF) point-of-care MRI systems allow image acquisition without interrupting medical provision, with neonatal clinical care being an important potential application. The ability to measure neonatal brain tissue T1 is a key enabling technology for subsequent structural image contrast optimization, as well as being a potential biomarker for brain development. Here we describe an optimized strategy for neonatal T1 mapping at ULF. METHODS: Examinations were performed on a 64-mT portable MRI system. A phantom validation experiment was performed, and a total of 33 in vivo exams were acquired from 28 neonates with postmenstrual age ranging from 31+4 to 49+0  weeks. Multiple inversion-recovery turbo spin-echo sequences were acquired with differing inversion and repetition times. An analysis pipeline incorporating inter-sequence motion correction generated proton density and T1 maps. Regions of interest were placed in the cerebral deep gray matter, frontal white matter, and cerebellum. Weighted linear regression was used to predict T1 as a function of postmenstrual age. RESULTS: Reduction of T1 with postmenstrual age is observed in all measured brain tissue; the change in T1 per week and 95% confidence intervals is given by dT1  = -21 ms/week [-25, -16] (cerebellum), dT1  = -14 ms/week [-18, -10] (deep gray matter), and dT1  = -35 ms/week [-45, -25] (white matter). CONCLUSION: Neonatal T1 values at ULF are shorter than those previously described at standard clinical field strengths, but longer than those of adults at ULF. T1 reduces with postmenstrual age and is therefore a candidate biomarker for perinatal brain development.

Creation of a regional hazardous drug handling task force.

PURPOSE: A regional task force of health-system pharmacy leaders was created to assist with successful adoption of United States Pharmacopeia (USP) general chapter <800>. SUMMARY: A group of pharmacy leaders in the Kansas City region identified potential benefits to healthcare personnel and patients if hazardous drug handling procedures were standardized. A task force was created, a preimplementation survey was distributed, and meetings were held monthly to discuss sections of USP <800> identified as the most challenging to implement. The task force focused on an assessment of risk tool, hot topics, cleanroom design, and a detailed analysis of controversial medications. After the first year of meetings, a postimplementation survey was distributed, and the results were analyzed. The task force created significant value for the participants and achieved the goal of facilitating efficient USP <800> implementation resulting in greater compliance and consistency across the multiple health systems represented. Over 5,100 beds and 200 clinic sites were affected by this task force's efforts. Nearly three-fourths (73%) of respondents reported that the task force was "extremely helpful," and the majority (64%) of respondents adopted most or all (81%-100%) of the task force's assessment of risk choices. Prioritization of tasks, information sharing, and decision-making were areas where the individual leaders were most supported. CONCLUSION: Creating a structure to eliminate barriers and facilitate collaboration among regional pharmacy leaders provided a framework for successful implementation of USP <800> requirements. This interdependent leadership model produced innovative and standardized solutions and should be considered when addressing complicated initiatives that impact the profession.

Using the critical path method to rollout and optimise new PMTCT guidelines to eliminate mother-to-child transmission of HIV in Zimbabwe: a descriptive analysis.

BACKGROUND: Achievement of the elimination target for mother-to-child transmission (MTCT) of HIV in selected countries has increased hope to end the HIV epidemic in children across the world. However, MTCT rates remain well above the 5% elimination target in most sub-Saharan Africa countries. These countries require innovative strategies to scale-up their interventions to end paediatric HIV. We describe how the Elizabeth Glaser Paediatric AIDS Foundation (EGPAF) consortium and the Children's Investment Fund Foundation (CIFF) used the critical path method to facilitate rapid expansion and optimization of 2010 and 2013 WHO PMTCT guidelines to reduce Zimbabwe's MTCT rate from 22% in 2010 to 6.4% in 2015. METHODS: We analysed activities implemented and PMTCT programme data for the period before and during the EGPAF-CIFF project. The critical path method involved a cycle of collecting and analysing quarterly PMTCT indicator data and planning and implementing targeted activities to improve the PMTCT indicators. We performed a graphical trend analysis of data that measured availability of PMTCT services. Using Pearson's Chi2 test, we compared results of PMTCT uptake indicators at the start and end of the EGPAF-CIFF project and used regression discontinuity analysis to assess effectiveness of activities implemented to improve the PMTCT service uptake indicators. RESULTS: Zimbabwe rolled out WHO 2010 and 2013 PMTCT guidelines in less than 1 year during the EGPAF-CIFF project, yet it took more than 4 years to roll-out previous guidelines. All PMTCT indicators increased significantly (p < 0.001) comparing the five-year periods before and during the EGPAF-CIFF project. Critical path activities implemented increased five of the seven PMTCT uptake indicators. CONCLUSION: Zimbabwe rapidly rolled-out and optimised new WHO PMTCT guidelines and drastically reduced its MTCT rate using the critical path method. We recommend wider use of the critical path method in public health programmes.

Effectiveness of a peer-led adolescent mental health intervention on HIV virological suppression and mental health in Zimbabwe: protocol of a cluster-randomised trial.

BACKGROUND: Adolescents living with HIV (ALHIV) experience a high burden of mental health disorder which is a barrier to antiretroviral therapy adherence. In Zimbabwe, trained, mentored peer supporters living with HIV (Community Adolescent Treatment Supporters - CATS) have been found to improve adherence, viral suppression and psychosocial well-being among ALHIV. The Friendship Bench is the largest integrated mental health programme in Africa. We hypothesise that combining the CATS programme and Friendship Bench will improve mental health and virological suppression among ALHIV compared with the CATS programme alone. METHODS: We will conduct a cluster-randomised controlled trial in 60 clinics randomised 1:1 in five provinces. ALHIV attending the control arm clinics will receive standard CATS support and clinic support following the Ministry of Health guidelines. Those attending the intervention arm clinics will receive Friendship Bench problem-solving therapy, delivered by trained CATS. Participants with the signs of psychological distress will be referred to the clinic for further assessment and management. The primary outcome is HIV virological failure (≥1000 copies/ml) or death at 48 weeks. Secondary outcomes include the proportion of adolescents with common mental disorder symptoms (defined as Shona Symptom Questionnaire (SSQ-14) score ≥8), proportion with depression symptoms (defined as Patient Health Questionnaire (PHQ-9) score ≥11), symptom severity (mean SSQ-14 and PHQ-9 scores) and EQ-5D score for health-related quality of life. CONCLUSIONS: This trial evaluates the effectiveness of peer-delivery of mental health care on mental health and HIV viral load among ALHIV. If effective this intervention has the potential to be scaled-up to improve these outcomes.Trial registration: PACTR201810756862405. 08 October 2018.

ACTing in Partnership to Accelerate Impact.

Partnership between funders plays a vital role in tackling the AIDS epidemic and can help partners deliver "more than the sum of their parts." But how do partnerships form? How is value leveraged and maximized? How can partnerships achieve policy change? This article addresses these questions through the example of the Accelerating Children's HIV/AIDS Treatment Initiative, an ambitious $200 million public private partnership with a goal of doubling the number of children living with HIV on treatment in 9 priority African countries over a 2-year period. It describes how the partnership formed between the US President's Emergency Plan for AIDS Relief (PEPFAR) and the Children's Investment Fund Foundation (CIFF), and the differing styles, vision, and resources each organization contributed. It also gives examples of policy influence at global level and policy change at national level. Finally, the article considers whether working in partnership was more or less effective than independent funding, with reflections on the value and challenges of collaboration.

When you see it, let it be: Urgency, mindfulness and adolescent substance use.

The emotion-based domains of impulsivity, positive and negative urgency, are facets that have garnered attention due to their associations with substance use, and mindfulness based strategies have shown promise in reducing substance use in adults. The aim of the current study was to examine relations among urgency, mindfulness, and substance use in adolescence. Cross-sectional data were collected from students (N=1,051) at a large, private high school in the Pacific Northwest. Both positive and negative urgency were uniquely associated with greater likelihood of lifetime and current alcohol use; only positive urgency predicted lifetime marijuana use. Mindfulness was associated with a lower likelihood of lifetime alcohol or marijuana use. Interactions between urgency and mindfulness were not supported. Our findings highlight the need to explore relations among baseline mindfulness, skills based mindfulness, and personality in adolescent alcohol and other drug use.

Five-year trends in epidemiology and prevention of mother-to-child HIV transmission, St. Petersburg, Russia: results from perinatal HIV surveillance.

BACKGROUND: The HIV epidemic in Russia has increasingly involved reproductive-aged women, which may increase perinatal HIV transmission. METHODS: Standard HIV case-reporting and enhanced perinatal HIV surveillance systems were used for prospective assessment of HIV-infected women giving birth in St. Petersburg, Russia, during 2004-2008. Trends in social, perinatal, and clinical factors influencing mother-to-child HIV transmission stratified by history of injection drug use, and rates of perinatal HIV transmission were assessed using two-sided χ2 or Cochran-Armitage tests. RESULTS: Among HIV-infected women who gave birth, the proportion of women who self-reported ever using injection drugs (IDUs) decreased from 62% in 2004 to 41% in 2008 (P<0.0001). Programmatic improvements led to increased uptake of the following clinical services from 2004 to 2008 (all P<0.01): initiation of antiretroviral prophylaxis at ≤28 weeks gestation (IDUs 44%-54%, non-IDUs 45%-72%), monitoring of immunologic (IDUs 48%-64%, non-IDUs 58%-80%) and virologic status (IDUs 8%-58%, non-IDUs 10%-75%), dual/triple antiretroviral prophylaxis (IDUs 9%-44%, non-IDUs 14%-59%). After initial increase from 5.3% (95% confidence interval [CI] 3.5%-7.8%) in 2004 to 8.5% (CI 6.1%-11.7%) in 2005 (P<0.05), perinatal HIV transmission decreased to 5.3% (CI 3.4%-8.3%) in 2006, and 3.2% (CI 1.7%-5.8%) in 2007 (P for trend<0.05). However, the proportion of women without prenatal care and without HIV testing before labor and delivery remained unchanged. CONCLUSIONS: Reduced proportion of IDUs and improved clinical services among HIV-infected women giving birth were accompanied by decreased perinatal HIV transmission, which can be further reduced by increasing outreach and HIV testing of women before and during pregnancy.

Are toxicological responses in laboratory (inbred) zebrafish representative of those in outbred (wild) populations? - A case study with an endocrine disrupting chemical.

Laboratory animals tend to be more inbred and less genetically diverse than wild populations, and thus may differ in their susceptibility to chemical stressors. We tested this hypothesis by comparing the responses of related inbred (theoretical inbreeding F(IT) = n + 0.25) and outbred (F(IT) = n) zebrafish (Danio rerio) WIK/Wild family lines to an endocrine disrupting chemical, clotrimazole. Exposure of inbred and outbred zebrafish to 2.9 µg clotrimazole/L had no effect on survival, growth, or gonadal development. Exposure of both lines to 43.7 µg clotrimazole/L led to male-biased sex ratios compared with controls (87% versus 55% and 92% vs 64%, for inbred and outbred males, respectively), advanced germ cell development, and reduced plasma 11-ketotestosterone concentrations in males. However, outbred males (but not inbred males) developed testis that were more than twice the weight of controls, which corresponded with a proliferation of Leydig cells and maintenance of the expression (rather than down-regulation occurring in inbreds) of gonadal aromatase (cyp19a1a) and insulin-like growth factor (igf1). Our results illustrate that the effects of an endocrine disrupting chemical (clotrimazole) on some end points (here testis development) can differ between inbred and outbred zebrafish. This highlights the need for reporting pedigree/genetic information and consistency in the responses of laboratory animals (e.g., by using model compounds as positive controls).

Friends or foes: social anxiety, peer affiliation, and drinking in middle school.

OBJECTIVE: The relation between social anxiety and alcohol consumption suggests aspects of both risk and protection, but most research has focused on late adolescents and emerging adults. METHOD: We investigated the synergistic impact of social anxiety, a need for affiliation with others, and perceived peer alcohol use on drinking in a sample of more than 1,500 early adolescents from southern California (48% girls). Via school-wide surveys, middle school students completed the Social Anxiety Scale for Children-Revised, a modified version of the Interpersonal Orientation Scale, as well as measures of perceived peer drinking and self-reported lifetime and current drinking. RESULTS: For socially anxious youths, high levels of perceived peer use in conjunction with high levels of affiliation need was associated with greater alcohol use on average and more frequent episodic drinking. Specific to heavy episodic drinking, the interaction of social anxiety and perceived peer drinking seemed to affect girls and boys differentially. Sex differences emerged for the moderation of social anxiety's influence on drinking initiation by perceived peer influence. CONCLUSIONS: These findings suggest that alcohol-related risks associated with social anxiety might be gender specific and more important in earlier stages of alcohol use than previously believed.

Antiretroviral prophylaxis to prevent perinatal HIV transmission in St. Petersburg, Russia: too little, too late.

BACKGROUND: We evaluated the influence of type and timing of prophylaxis on perinatal HIV transmission in St. Petersburg, Russia. METHODS: We linked surveillance data for 1498 HIV-infected mothers delivering from 2004 to 2007 with polymerase chain reaction data for 1159 infants to determine predictors of transmission. RESULTS: The overall perinatal transmission rate was 6.3% [73 of 1159, 95% confidence interval (CI) 4.9% to 7.7%]. Among the 12.8% (n = 149) of mother-infant pairs receiving full course (antenatal, intrapartum, postnatal) dual/triple antiretroviral prophylaxis, the transmission rate was 2.7%. Among the 1010 receiving less complete regimens (full course zidovudine, single-dose nevirapine, or incomplete), transmission ranged from 4.1% to 12.2%. Among the 28.9% (330) of mothers initiating antiretroviral drugs or=29 weeks (or not at all) had increased transmission odds (adjusted odds ratio: 4.9, 95% CI: 1.8 to 12.9; odds ratio: 5.1, 95% CI: 2.0 to 13.1, respectively). CONCLUSIONS: In St. Petersburg, the potential for further reductions in perinatal transmission is evident, given low transmission among women receiving early combination prophylaxis.

Relative importance of different spectral bands to consonant identification: relevance for frequency transposition in hearing aids.

Listeners with high-frequency dead regions (DRs) benefit from amplification of frequencies up to 1.7 times the edge frequency, f(e), of the DR. Better consonant identification might be achieved by replacing the band from f(e) to 1.7f(e) with a higher spectral band. We aimed to identify the optimal band, using simulations with normal-hearing listeners. In experiment 1, nonsense syllables were lowpass filtered to simulate DRs with f(e) of 0.5, 0.75, and 1.0 kHz. Identification was measured for each of these base bands alone and with a bandpass-filtered band added (but not transposed). The added band either extended from f(e) to 1.7f(e) or its center frequency was increased, keeping bandwidth fixed in ERB(N)-number. Performance improved with increasing center frequency and then reached an asymptote or declined. Experiment 2 used a mid-frequency base band, and a lower-frequency added band. The results also showed a beneficial effect of frequency separation of the added and base bands. Experiment 3 resembled experiment 1, but with bandwidth fixed in Hertz. For higher-frequency added bands, the benefit was lower than for experiment 1.

Evaluation of a frequency transposition algorithm using wearable hearing aids.

Transposition of acoustic information from higher to lower frequencies may help people with severe or profound high-frequency hearing loss, especially when a 'dead region' is present. Previously, we (Robinson et al, 2007 ) evaluated the benefit of an FFT-based transposition algorithm in a laboratory study. Although results were promising, we hypothesized that further training and exposure would be needed to gain the full benefit. This was tested here by implementing the algorithm in wearable digital hearing aids. Five subjects with high-frequency dead regions used the aids for five weeks. Performance on the transposing and control conditions was compared objectively using speech tests (vowel-consonant-vowel, 's' detection, and speech in noise) and subjectively using questionnaires. Overall, the results showed no benefit with the transposition even after experience. Subjective preference was generally for the control condition.

Preventing mother-to-child transmission of HIV in resource-limited settings: the Elizabeth Glaser Pediatric AIDS Foundation experience.

OBJECTIVES: In September 1999, the Elizabeth Glaser Pediatric AIDS Foundation initiated a multicountry, service-based programmatic effort in the developing world to reduce perinatally acquired HIV infection. We review 6(1/2) years of one of the world's largest programs for the prevention of mother-to-child transmission (PMTCT) of HIV. METHODS: Each PMTCT facility records patient data in antenatal clinics and labor and delivery settings about counseling, testing, HIV status, and antiretroviral prophylaxis and submits the data to foundation staff. RESULTS: More than 2.6 million women have accessed foundation-affiliated services through June 2006. Overall, 92.9% of women who received antenatal care or were eligible for PMTCT services in labor and delivery have been counseled, and 82.8% of those counseled accepted testing. Among women identified as HIV positive, 75.0% received antiretroviral prophylaxis (most a single dose of nevirapine), as did 45.6% of their infants. CONCLUSIONS: The foundation's experience has demonstrated that opt-out testing, supplying mothers with medication at time of diagnosis, and providing the infant dose early have measurably improved program efficiency. PMTCT should be viewed as an achievable paradigm and an essential part of the continuum of care.

Uptake of an HIV voluntary counseling and testing program for pregnant women in Georgia.

From 2002 to 2005 the Elizabeth Glaser Pediatric AIDS Foundation prevention of mother-to-child transmission of HIV project operated in Georgia and was managed by the Maternal and Child Care Union. The project covered Tbilisi, the capital, and included 34 clinics that provide women's healthcare. Out of 35,385 pregnant women starting prenatal care in clinics involved in the project, 91% (32,262) had received HIV counseling and, among those counseled, 94% (30,330) were tested for HIV antibodies; 14 pregnant women (<0.001%) were found to be HIV-infected.

Rapid HIV testing and prevention of perinatal HIV transmission in high-risk maternity hospitals in St. Petersburg, Russia.

OBJECTIVE: The purpose of this study was to evaluate the effectiveness of a human immunodeficiency virus (HIV) rapid testing (RT) program. STUDY DESIGN: From April 13, 2004, to April 13, 2005, pregnant women at 2 high-risk maternity hospitals with no or incomplete HIV testing results (negative tests at <34 weeks, none thereafter) were offered point-of-care RT, with antiretroviral prophylaxis for RT-positive women and their infants. RESULTS: Overall, 89.2% of eligible women (3671/4117) underwent RT, of whom 90.4% received results before delivery. HIV seroprevalence among all women who underwent RT was 2.7% (100/3671 women); among previously untested women, seroprevalence was 6.5% (90/1375 women); the incidence of HIV seroconversion among women with previous negative tests during pregnancy was 0.4% (10/2296 women). After adjustment, the main predictor of receiving RT results after delivery was late admission. Among HIV-exposed infants, 97.9% (92/94) received prophylaxis; 61.7% (58/94) had available follow-up data, and 8.6% (5/58) met criteria for definitive or presumptive HIV infection. CONCLUSION: The RT program achieved timely detection of HIV-infected women in labor with unknown HIV status and effectively prevented perinatal HIV transmission.

Using transposition to improve consonant discrimination and detection for listeners with severe high-frequency hearing loss.

Transposition of high-frequency information to lower frequencies may help people with high-frequency hearing loss associated with a 'dead region' (DR) to detect and identify certain consonants, such as 's'. Conventional high-frequency amplification is often not beneficial in such cases. We designed and evaluated a new transposition algorithm which was adapted to each subject's high-frequency DR. Frequency components from well within the DR were transposed to just within the DR without applying frequency compression. Low-frequency components were amplified, but unaffected by transposition. Transposition only occurred if there was significant high-frequency energy, preventing high-frequency background noise of moderate level from being transposed. Consonant discrimination was tested using vowel-consonant-vowel (VCV) stimuli, and the detection of word-final 's' and 'z' was assessed using word pairs. Seven subjects with high-frequency DRs were tested in quiet using a transposed and a control condition. Following transposition, two subjects improved significantly and none performed significantly worse on the VCV-test overall. The perception of affricates was consistently improved. Averaged across subjects, the detection of word-final 's' and 'z' was significantly improved, with five subjects improving significantly individually.

Rapid HIV testing, pregnancy, antiretroviral prophylaxis and infant abandonment in St Petersburg.

In St Petersburg, Russia, a rapid HIV-testing programme was implemented in April 2004 for high-risk women giving birth. Among 670 women without prenatal care who received rapid HIV testing, 6.4% (43) had positive results. Among HIV-positive mothers, receipt of intrapartum antiretroviral prophylaxis increased significantly compared to pre-programme levels (76 versus 41%). Additionally, infant abandonment increased significantly (50% versus 26%), and was 10 times greater in women with unintended versus intended pregnancies (73% versus 7%).