Campus Vol VIII N 2

Shaw, Ted. Cover. Picture. 0. Mckenny, Sam. Fiction and Fact From Sports Almanac . Prose. 2. LeFever, Joe. The Fourth Ring . Prose. 3. Lugar, Dick. The Meaning of Campus Government . Prose. 4. Huntington, Ann. Campus Calender Girls: January . Picture. 6. Lashar, Sally. Campus Calender Girls: Febuary . Picture. 6. Omundson, Marilyn. Campus Calender Girls: March . Picture. 6. Nuzum, Gret. Campus Calender Girls: April . Picture. 7. Nussbaum, Nancy. Campus Calender Girls: May . Picture. 7. Morrow, Bobbie. Campus Calender Girls: June . Picture. 7. Walker, Nancy. Campus Calender Girls: July . Picture. 8. Gregory, Mary Lou. Campus Calender Girls: August . Picture. 8. Dutro, Jacquie. Campus Calender Girls: September . Picture. 8. Woodward, Lee. Campus Calender Girls: October . Picture. 9. Thuma, Jane. Campus Calender Girls: November . Picture. 9. Drake, Mary. Campus Calender Girls: December . Picture. 9. Aabye, Nancy. The Dividing Line . Prose. 10. Anonymous. Untitled. Prose. 11. Miller, Bud. Denison\u27s Two new Varsity Sports---Lacrosse and Soccer . Prose. 12. Anonymous. Untitled. Prose. 13. H and S. From Here to Bexley . Prose. 14. Shaw, Ted. Vote Here . Cartoon. 15. Mackimm, Brad. Untitled. Cartoon. 16. Howard Studio. Ricky Helmerichs, Sophomore . Picture. 17

The cost-effectiveness of scaling-up rapid point-of-care testing for early infant diagnosis of HIV in southern Zambia.

IntroductionEarly infant diagnosis (EID) and treatment can prevent much of the HIV-related morbidity and mortality experienced by children but is challenging to implement in sub-Saharan Africa. Point-of-care (PoC) testing would decentralize testing and increase access to rapid diagnosis. The objective of this study was to determine the cost-effectiveness of PoC testing in Southern Province, Zambia.MethodsA decision tree model was developed to compare health outcomes and costs between the standard of care (SoC) and PoC testing using GeneXpert and m-PIMA platforms. The primary health outcome was antiretroviral treatment (ART) initiation within 60 days of sample collection. Additional outcomes included ART initiation by 12 months of age and death prior to ART initiation. Costs included both capital and recurrent costs. Health outcomes and costs were combined to create incremental cost effectiveness ratios (ICERs).ResultsThe proportion of children initiating ART within 60 days increased from 27.8% with SoC to 79.8-82.8% with PoC testing depending on the algorithm and platform. The proportion of children initiating ART by 12 months of age increased from 50.9% with SoC to 84.0-86.5% with PoC testing. The proportion of HIV-infected children dying prior to ART initiation decreased from 18.1% with SoC to 3.8-4.6% with PoC testing. Total program costs were similar for the SoC and GeneXpert but higher for m-PIMA. ICERs for PoC testing were favorable, ranging from $23-1,609 for ART initiation within 60 days,$37-2,491 for ART initiation by 12 months of age, and $90-6,188 for deaths prior to ART initiation. Factors impacting the costs of PoC testing, including the lifespan of the testing instruments and integrated utilization of PoC platforms, had the biggest impact on the ICERs. Integrating utilization across programs decreased costs for the EID program, such that PoC testing was cost-saving in some situations.ConclusionPoC testing has the potential to improve linkage to care and ART initiation for HIV-infected infants and should be considered for implementation within EID programs to achieve equity in access to HIV services and reduce HIV-related pediatric morbidity and mortality

Long-term survival outcomes of HIV infected children receiving antiretroviral therapy: an observational study from Zambia (2003–2015)

Abstract Background In 2017, 64% of children living with HIV in Zambia accessed Antiretroviral Therapy (ART). Despite expanded ART coverage, there is paucity of information on effectiveness of pediatric ART in reducing mortality. The aim of this research is to describe treatment outcomes, measure mortality rates and assess predictors of mortality among children receiving ART. Methods Using a retrospective cohort study design, we abstracted routinely collected clinical data from medical records of children from birth to 15 years old, who had received ART for at least 6 months at Livingstone Central Hospital in Southern Province Zambia, between January 2003 and June 2015. The primary outcome was death. Cause of death was ascertained from medical records and death certificates. Distribution of survival times according to baseline covariates were estimated using Kaplan Meier and Cox Proportional Hazards methods. Results Overall, 1039 children were commenced on ART during the study period. The median age at treatment initiation was 3.6 years (IQR: 1.3–8.6) and 520 (50%) children were female. Of these, 71 (7%) died, 164 (16%) were lost to follow-up, 210 (20%) transferred and 594 (56%) were actively on treatment. After 4450 person years, mortality rate was 1.6/100 (95% CI: 1.4–1.8). Mortality was highest during the first 3 months of treatment (11.7/100 (95% CI: 7.6–16.3). In multivariable proportional hazards regression, the adjusted hazards of death were highest among children aged < 1 year (aHR = 3.1 (95% CI: 1.3–6.4), compared to those aged 6–15 years, WHO stage 4 (aHR =4.8 (95% CI: 2.3–10), compared to WHO stage 1 and 2. In the sensitivity analysis to address bias due to loss to follow-up, mortality increased 5 times when we assumed that all the children who were lost to follow up died within 90 days of their last visit. Conclusion We observed low attrition due to mortality among children on ART. Loss to follow-up was high (16%). Mortality was highest during the first 3 months of treatment. Children aged less than one year and those with advanced WHO disease stage had higher mortality. We recommend effective interventions to improve retention in care and early diagnosis of HIV in children

Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5′-Adenosine Monophosphate-Activated Protein Kinase (AMPK)

Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic acid clinical candidate (<b>1</b>) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds <b>10</b> (PF-06679142) and <b>14</b> (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3

Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5′-Adenosine Monophosphate-Activated Protein Kinase (AMPK)

Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic acid clinical candidate (<b>1</b>) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds <b>10</b> (PF-06679142) and <b>14</b> (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3

Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577

Indole acids <b>1</b>, <b>2</b>, and <b>3</b> are potent 5′-adenosine monophosphate-activated protein kinase (AMPK) activators for the potential treatment of diabetic nephropathy. Compounds <b>1</b>–<b>3</b> were scaled to supply material for preclinical studies, and indole <b>3</b> was selected for advancement to first-in-human clinical trials and scaled to kilogram quantities. The progression of the synthesis strategy for these AMPK activators is described, as routes were selected for efficient structure–activity relationship generation and then improved for larger scales. The developed sequences employed practical isolations of intermediates and APIs, reproducible cross-coupling, hydrolysis, and other transformations, and enhanced safety and purity profiles and led to the production of 40–50 g of <b>1</b> and <b>2</b> and 2.4 kg of <b>3</b>. Multiple polymorphs of <b>3</b> were observed, and conditions for the reproducible formation of crystalline material suitable for clinical development were identified

Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577

Indole acids <b>1</b>, <b>2</b>, and <b>3</b> are potent 5′-adenosine monophosphate-activated protein kinase (AMPK) activators for the potential treatment of diabetic nephropathy. Compounds <b>1</b>–<b>3</b> were scaled to supply material for preclinical studies, and indole <b>3</b> was selected for advancement to first-in-human clinical trials and scaled to kilogram quantities. The progression of the synthesis strategy for these AMPK activators is described, as routes were selected for efficient structure–activity relationship generation and then improved for larger scales. The developed sequences employed practical isolations of intermediates and APIs, reproducible cross-coupling, hydrolysis, and other transformations, and enhanced safety and purity profiles and led to the production of 40–50 g of <b>1</b> and <b>2</b> and 2.4 kg of <b>3</b>. Multiple polymorphs of <b>3</b> were observed, and conditions for the reproducible formation of crystalline material suitable for clinical development were identified

Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)

Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of <b>12</b>, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine <b>12</b>