Innovations for Communication: Innovations for Improving Honors Faculty-Student Communication

Prepare to embark on a journey of discovery in the realm of the Frederik Meijer Honors College (FMHC) and the student psyche that drives its operations. Over the course of the Winter 2019 semester, the Honors Course: Design Thinking to Meet Real World Needs addressed a problem as proposed by the Honors College Director, Roger Gilles. Using the Stanford method of Design Thinking, our team of four innovators empathized with our problem stakeholders, properly defined our problem, and innovated in order to create potential solutions which will later be prototyped and tested for efficacy. The following report outlines the entirety of this process, and the results obtained throughout the research. We hope our findings serve as a resource to the evolution of the FMHC as well as a resource to other Honors Colleges

Ascospore release and survival in Sclerotinia sclerotiorum

The release and survival of ascospores of a UK Sclerotinia sclerotiorum isolate were studied. Apothecia placed in a spore clock apparatus with different lighting regimes at 15 °C released ascospores continuously with an increasing rate for the duration of experiments (72–84 h). Spore release was not confined to light or dark periods in alternating regimes and occurred in continuous dark or light. Ascospores were released in both saturated air (90–95% rh) and at 65–75% rh. High temperature and rh were detrimental to ascospore survival but spore viability was maintained for longer periods than previously reported. The significance of these results in relation to disease control is discussed

Native amine dehydrogenases can catalyze the direct reduction of carbonyl compounds to alcohols in the absence of ammonia

Native amine dehydrogenases (nat-AmDHs) catalyze the (S)-stereoselective reductive amination of various ketones and aldehydes in the presence of high concentrations of ammonia. Based on the structure of CfusAmDH from Cystobacter fuscus complexed with NADP+ and cyclohexylamine, we previously hypothesized a mechanism involving the attack at the electrophilic carbon of the carbonyl by ammonia followed by delivery of the hydride from the reduced nicotinamide cofactor on the re-face of the prochiral ketone. The direct reduction of carbonyl substrates into the corresponding alcohols requires a similar active site architecture and was previously reported as a minor side reaction of some nat-AmDHs and variants. Here we describe the ketoreductase (KRED) activity of a set of nat-AmDHs and variants, which proved to be significant in the absence of ammonia in the reaction medium but negligible in its presence. Conducting this study on a large set of substrates revealed the heterogeneity of this secondary KRED activity, which was dependent upon the enzyme/substrate pairs considered. In silico docking experiments permitted the identification of some relationships between KRED activity and the structural features of the enzymes. Kinetic studies of MsmeAmDH highlighted the superior performance of this nat-AmD

Native amine dehydrogenases can catalyze the direct reduction of carbonyl compounds to alcohols in the absence of ammonia

Native amine dehydrogenases (nat-AmDHs) catalyze the (S)-stereoselective reductive amination of various ketones and aldehydes in the presence of high concentrations of ammonia. Based on the structure of CfusAmDH from Cystobacter fuscus complexed with Nicotinamide adenine dinucleotide phosphate (NADP+) and cyclohexylamine, we previously hypothesized a mechanism involving the attack at the electrophilic carbon of the carbonyl by ammonia followed by delivery of the hydride from the reduced nicotinamide cofactor on the re-face of the prochiral ketone. The direct reduction of carbonyl substrates into the corresponding alcohols requires a similar active site architecture and was previously reported as a minor side reaction of some native amine dehydrogenases and variants. Here we describe the ketoreductase (KRED) activity of a set of native amine dehydrogenases and variants, which proved to be significant in the absence of ammonia in the reaction medium but negligible in its presence. Conducting this study on a large set of substrates revealed the heterogeneity of this secondary ketoreductase activity, which was dependent upon the enzyme/substrate pairs considered. In silico docking experiments permitted the identification of some relationships between ketoreductase activity and the structural features of the enzymes. Kinetic studies of MsmeAmDH highlighted the superior performance of this native amine dehydrogenases as a ketoreductase but also its very low activity towards the reverse reaction of alcohol oxidation

Eff ectiveness of 4% chlorhexidine umbilical cord care on neonatal mortality in Southern Province, Zambia (ZamCAT): a cluster-randomised controlled trial

Background Chlorhexidine umbilical cord washes reduce neonatal mortality in south Asian populations with high neonatal mortality rates and predominantly home-based deliveries. No data exist for sub-Saharan African populations with lower neonatal mortality rates or mostly facility-based deliveries. We compared the eff ect of chlorhexidine with dry cord care on neonatal mortality rates in Zambia. Methods We undertook a cluster-randomised controlled trial in Southern Province, Zambia, with 90 health facilitybased clusters. We enrolled women who were in their second or third trimester of pregnancy, aged at least 15 years, and who would remain in the catchment area for follow-up of 28 days post-partum. Newborn babies received clean dry cord care (control) or topical application of 10 mL of a 4% chlorhexidine solution once per day until 3 days after cord drop (intervention), according to cluster assignment. We used stratifi ed, restricted randomisation to divide clusters into urban or two rural groups (located <40 km or ≥40 km to referral facility), and randomly assigned clusters (1:1) to use intervention (n=45) or control treatment (n=45). Sites, participants, and fi eld monitors were aware of their study assignment. The primary outcomes were all-cause neonatal mortality within 28 days post-partum and all-cause neonatal mortality within 28 days post-partum among babies who survived the fi rst 24 h of life. Analysis was by intention to treat. Neonatal mortality rate was compared with generalised estimating equations. This study is registered at ClinicalTrials.gov (NCT01241318). Findings From Feb 15, 2011, to Jan 30, 2013, we screened 42 356 pregnant women and enrolled 39 679 women (mean 436·2 per cluster [SD 65·3]), who had 37 856 livebirths and 723 stillbirths; 63·8% of deliveries were facility-based. Of livebirths, 18 450 (99·7%) newborn babies in the chlorhexidine group and 19 308 (99·8%) newborn babies in the dry cord care group were followed up to day 28 or death. 16 660 (90·0%) infants in the chlorhexidine group had chlorhexidine applied within 24 h of birth. We found no signifi cant diff erence in neonatal mortality rate between the chlorhexidine group (15·2 deaths per 1000 livebirths) and the dry cord care group (13·6 deaths per 1000 livebirths; risk ratio [RR] 1·12, 95% CI 0·88–1·44). Eliminating day 0 deaths yielded similar fi ndings (RR 1·12, 95% CI 0·86–1·47). Interpretation Despite substantial reductions previously reported in south Asia, chlorhexidine cord applications did not signifi cantly reduce neonatal mortality rates in Zambia. Chlorhexidine cord applications do not seem to provide clear benefi ts for newborn babies in settings with predominantly facility-based deliveries and lower (<30 deaths per 1000 livebirths) neonatal mortality rates

Neonatal mortality within 24 hours of birth in six low- and lower-middle-income countries.

OBJECTIVE: To estimate neonatal mortality, particularly within 24 hours of birth, in six low- and lower-middle-income countries. METHODS: We analysed epidemiological data on a total of 149 570 live births collected between 2007 and 2013 in six prospective randomized trials and a cohort study from predominantly rural areas of Bangladesh, Ghana, India, Pakistan, the United Republic of Tanzania and Zambia. The neonatal mortality rate and mortality within 24 hours of birth were estimated for all countries and mortality within 6 hours was estimated for four countries with available data. The findings were compared with published model-based estimates of neonatal mortality. FINDINGS: Overall, the neonatal mortality rate observed at study sites in the six countries was 30.5 per 1000 live births (range: 13.6 in Zambia to 47.4 in Pakistan). Mortality within 24 hours was 14.1 per 1000 live births overall (range: 5.1 in Zambia to 20.1 in India) and 46.3% of all neonatal deaths occurred within 24 hours (range: 36.2% in Pakistan to 65.5% in the United Republic of Tanzania). Mortality in the first 6 hours was 8.3 per 1000 live births, i.e. 31.9% of neonatal mortality. CONCLUSION: Neonatal mortality within 24 hours of birth in predominantly rural areas of six low- and lower-middle-income countries was higher than model-based estimates for these countries. A little under half of all neonatal deaths occurred within 24 hours of birth and around one third occurred within 6 hours. Implementation of high-quality, effective obstetric and early newborn care should be a priority in these settings

LEARN: A multi-centre, cross-sectional evaluation of Urology teaching in UK medical schools

OBJECTIVE: To evaluate the status of UK undergraduate urology teaching against the British Association of Urological Surgeons (BAUS) Undergraduate Syllabus for Urology. Secondary objectives included evaluating the type and quantity of teaching provided, the reported performance rate of General Medical Council (GMC)-mandated urological procedures, and the proportion of undergraduates considering urology as a career. MATERIALS AND METHODS: LEARN was a national multicentre cross-sectional study. Year 2 to Year 5 medical students and FY1 doctors were invited to complete a survey between 3rd October and 20th December 2020, retrospectively assessing the urology teaching received to date. Results are reported according to the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). RESULTS: 7,063/8,346 (84.6%) responses from all 39 UK medical schools were included; 1,127/7,063 (16.0%) were from Foundation Year (FY) 1 doctors, who reported that the most frequently taught topics in undergraduate training were on urinary tract infection (96.5%), acute kidney injury (95.9%) and haematuria (94.4%). The most infrequently taught topics were male urinary incontinence (59.4%), male infertility (52.4%) and erectile dysfunction (43.8%). Male and female catheterisation on patients as undergraduates was performed by 92.1% and 73.0% of FY1 doctors respectively, and 16.9% had considered a career in urology. Theory based teaching was mainly prevalent in the early years of medical school, with clinical skills teaching, and clinical placements in the later years of medical school. 20.1% of FY1 doctors reported no undergraduate clinical attachment in urology. CONCLUSION: LEARN is the largest ever evaluation of undergraduate urology teaching. In the UK, teaching seemed satisfactory as evaluated by the BAUS undergraduate syllabus. However, many students report having no clinical attachments in Urology and some newly qualified doctors report never having inserted a catheter, which is a GMC mandated requirement. We recommend a greater emphasis on undergraduate clinical exposure to urology and stricter adherence to GMC mandated procedures

Development and validation of a simplified algorithm for neonatal gestational age assessment - protocol for the Alliance for Maternal Newborn Health Improvement (AMANHI) prospective cohort study.

OBJECTIVE: The objective of the Alliance for Maternal and Newborn Health Improvement (AMANHI) gestational age study is to develop and validate a programmatically feasible and simple approach to accurately assess gestational age of babies after they are born. The study will provide accurate, population-based rates of preterm birth in different settings and quantify the risks of neonatal mortality and morbidity by gestational age and birth weight in five South Asian and sub-Saharan African sites. METHODS: This study used on-going population-based cohort studies to recruit pregnant women early in pregnancy (<20 weeks) for a dating ultrasound scan. Implementation is harmonised across sites in Ghana, Tanzania, Zambia, Bangladesh and Pakistan with uniform protocols and standard operating procedures. Women whose pregnancies are confirmed to be between 8 to 19 completed weeks of gestation are enrolled into the study. These women are followed up to collect socio-demographic and morbidity data during the pregnancy. When they deliver, trained research assistants visit women within 72 hours to assess the baby for gestational maturity. They assess for neuromuscular and physical characteristics selected from the Ballard and Dubowitz maturation assessment scales. They also measure newborn anthropometry and assess feeding maturity of the babies. Computer machine learning techniques will be used to identify the most parsimonious group of signs that correctly predict gestational age compared to the early ultrasound date (the gold standard). This gestational age will be used to categorize babies into term, late preterm and early preterm groups. Further, the ultrasound-based gestational age will be used to calculate population-based rates of preterm birth. IMPORTANCE OF THE STUDY: The AMANHI gestational age study will make substantial contribution to improve identification of preterm babies by frontline health workers in low- and middle- income countries using simple evaluations. The study will provide accurate preterm birth estimates. This new information will be crucial to planning and delivery of interventions for improving preterm birth outcomes, particularly in South Asia and sub-Saharan Africa

Population-based rates, timing and causes of maternal deaths, stillbirths, and neonatal deaths in south Asia and sub-Saharan Africa: a multi-country prospective cohort study

BackgroundModelled mortality estimates have been useful for health programmes in low-income and middle-income countries. However, these estimates are often based on sparse and low-quality data. We aimed to generate high quality data about the burden, timing, and causes of maternal deaths, stillbirths, and neonatal deaths in south Asia and sub-Saharan Africa.MethodsIn this prospective cohort study done in 11 community-based research sites in south Asia and sub-Saharan Africa, between July, 2012, and February, 2016, we conducted population-based surveillance of women of reproductive age (15–49 years) to identify pregnancies, which were followed up to birth and 42 days post partum. We used standard operating procedures, data collection instruments, training, and standardisation to harmonise study implementation across sites. Verbal autopsies were done for deaths of all women of reproductive age, neonatal deaths, and stillbirths. Physicians used standardised methods for cause of death assignment. Site-specific rates and proportions were pooled at the regional level using a meta-analysis approach.FindingsWe identified 278 186 pregnancies and 263 563 births across the study sites, with outcomes ascertained for 269 630 (96·9%) pregnancies, including 8761 (3·2%) that ended in miscarriage or abortion. Maternal mortality ratios in sub-Saharan Africa (351 per 100 000 livebirths, 95% CI 168–732) were similar to those in south Asia (336 per 100 000 livebirths, 247–458), with far greater variability within sites in sub-Saharan Africa. Stillbirth and neonatal mortality rates were approximately two times higher in sites in south Asia than in sub-Saharan Africa (stillbirths: 35·1 per 1000 births, 95% CI 28·5–43·1 vs 17·1 per 1000 births, 12·5–25·8; neonatal mortality: 43·0 per 1000 livebirths, 39·0–47·3 vs 20·1 per 1000 livebirths, 14·6–27·6). 40–45% of pregnancy-related deaths, stillbirths, and neonatal deaths occurred during labour, delivery, and the 24 h postpartum period in both regions. Obstetric haemorrhage, non-obstetric complications, hypertensive disorders of pregnancy, and pregnancy-related infections accounted for more than three-quarters of maternal deaths and stillbirths. The most common causes of neonatal deaths were perinatal asphyxia (40%, 95% CI 39–42, in south Asia; 34%, 32–36, in sub-Saharan Africa) and severe neonatal infections (35%, 34–36, in south Asia; 37%, 34–39 in sub-Saharan Africa), followed by complications of preterm birth (19%, 18–20, in south Asia; 24%, 22–26 in sub-Saharan Africa).InterpretationThese results will contribute to improved global estimates of rates, timing, and causes of maternal and newborn deaths and stillbirths. Our findings imply that programmes in sub-Saharan Africa and south Asia need to further intensify their efforts to reduce mortality rates, which continue to be high. The focus on improving the quality of maternal intrapartum care and immediate newborn care must be further enhanced. Efforts to address perinatal asphyxia and newborn infections, as well as preterm birth, are critical to achieving survival goals in the Sustainable Development Goals era

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival