Anesthesia Capacity in Ghana: A Teaching Hospital's Resources, and the National Workforce and Education.

BACKGROUND: Quality anesthetic care is lacking in low- and middle-income countries (LMICs). Global health leaders call for perioperative capacity reports in limited-resource settings to guide improved health care initiatives. We describe a teaching hospital's resources and the national workforce and education in this LMIC capacity report. METHODS: A prospective observational study was conducted at Komfo Anokye Teaching Hospital (KATH) in Kumasi, Ghana, during 4 weeks in August 2016. Teaching hospital data were generated from observations of hospital facilities and patient care, review of archival records, and interviews with KATH personnel. National data were obtained from interviews with KATH personnel, correspondence with Ghana's anesthesia society, and review of public records. RESULTS: The practice of anesthesia at KATH incorporated preanesthesia clinics, intraoperative management, and critical care. However, there were not enough physicians to consistently supervise care, especially in postanesthesia care units (PACUs) and the critical care unit (CCU). Clean water and electricity were usually reliable in all 16 operating rooms (ORs) and throughout the hospital. Equipment and drugs were inventoried in detail. While much basic infrastructure, equipment, and medications were present in ORs, patient safety was hindered by hospital-wide oxygen supply failures and shortage of vital signs monitors and working ventilators in PACUs and the CCU. In 2015, there were 10,319 anesthetics administered, with obstetric and gynecologic, general, and orthopedic procedures comprising 62% of surgeries. From 2011 to 2015, all-cause perioperative mortality rate in ORs and PACUs was 0.65% or 1 death per 154 anesthetics, with 99% of deaths occurring in PACUs. Workforce and education data at KATH revealed 10 anesthesia attending physicians, 61 nurse anesthetists (NAs), and 7 anesthesia resident physicians in training. At the national level, 70 anesthesia attending physicians and 565 NAs cared for Ghana's population of 27 million. Providers were heavily concentrated in urban areas, and NAs frequently practiced independently. Two teaching hospitals provided accredited postgraduate training modeled after European curricula to 22 anesthesia resident physicians. CONCLUSIONS: While important limitations to capacity exist in Ghana, the overall situation is good compared to other LMICs. Many of the challenges encountered resulted from insufficient PACU and CCU provisions and few providers. Inadequate outcomes reporting made analysis and resolution of problem areas difficult. While many shortcomings stemmed from limited funding, strengthening physician commitment to overseeing care, ensuring oxygen supplies are uninterrupted, keeping ventilators in working order, and making vital signs monitors ubiquitously available are feasible ways to increase patient safety with the tools currently in place.

Determinants of activity at human Toll-like receptors 7 and 8: quantitative structure-activity relationship (QSAR) of diverse heterocyclic scaffolds.

Toll-like receptor (TLR) 7 and 8 agonists are potential vaccine adjuvants, since they directly activate APCs and enhance Th1-driven immune responses. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence of the selectivity for TLR7 vis-à-vis TLR8 on the electronic configurations of the heterocyclic systems, which we sought to examine quantitatively with the goal of developing "heuristics" to define structural requisites governing activity at TLR7 and/or TLR8. We undertook a scaffold-hopping approach, entailing the syntheses and biological evaluations of 13 different chemotypes. Crystal structures of TLR8 in complex with the two most active compounds confirmed important binding interactions playing a key role in ligand occupancy and biological activity. Density functional theory based quantum chemical calculations on these compounds followed by linear discriminant analyses permitted the classification of inactive, TLR8-active, and TLR7/8 dual-active compounds, confirming the critical role of partial charges in determining biological activity.

Exquisite selectivity for human toll-like receptor 8 in substituted furo[2,3-c]quinolines.

Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds may be promising candidate adjuvants. We synthesized and evaluated hitherto unexplored furo[2,3-c]quinolines and regioisomeric furo[3,2-c]quinolines derived via a tandem, one-pot Sonogashira coupling and intramolecular 5-endo-dig cyclization strategy in a panel of primary screens. We observed a pure TLR8-agonistic activity profile in select furo[2,3-c]quinolines, with maximal potency conferred by a C2-butyl group (EC50 = 1.6 µM); shorter, longer, or substituted homologues as well as compounds bearing C1 substitutions were inactive, which was rationalized by docking studies using the recently described crystal structure of human TLR8. The best-in-class compound displayed prominent proinflammatory cytokine induction (including interleukin-12 and interleukin-18), but was bereft of interferon-α inducing properties, confirming its high selectivity for human TLR8.

Structure-activity relationships in Toll-like receptor 7 agonistic 1H-imidazo[4,5-c]pyridines.

Engagement of TLR7 in plasmacytoid dendritic cells leads to the induction of IFN-α/ß which plays essential functions in the control of adaptive immunity. We had previously examined structure-activity relationships (SAR) in TLR7/8-agonistic imidazoquinolines with a focus on substituents at the N(1), C(2), N(3) and N(4) positions, and we now report SAR on 1H-imidazo[4,5-c]pyridines. 1-Benzyl-2-butyl-1H-imidazo[4,5-c]pyridin-4-amine was found to be a pure TLR7-agonist with negligible activity on TLR8. Increase in potency was observed in N(6)-substituted analogues, especially in those compounds with electron-rich substituents. Direct aryl-aryl connections at C6 abrogated activity, but TLR7 agonism was reinstated in 6-benzyl and 6-phenethyl analogues. Consistent with the pure TLR7-agonistic behavior, prominent IFN-α induction in human PBMCs was observed with minimal proinflammatory cytokine induction. A benzologue of imidazoquinoline was also synthesized which showed substantial improvements in potency over the parent imidazopyridine. Distinct differences in N(6)-substituted analogues were observed with respect to IFN-α induction in human PBMCs on the one hand, and CD69 upregulation in lymphocytic subsets, on the other.

Design and development of stable, water-soluble, human Toll-like receptor 2 specific monoacyl lipopeptides as candidate vaccine adjuvants.

Antigens in modern subunit vaccines are largely soluble and poorly immunogenic proteins inducing relatively short-lived immune responses. Appropriate adjuvants initiate early innate immune responses, amplifying subsequent adaptive immune responses. Agonists of Toll-like receptor 2 (TLR2) are devoid of significant proinflammatory activity in ex vivo human blood models and yet are potently adjuvantic, suggesting that this chemotype may be a safe and effective adjuvant. Our earlier work on the monoacyl lipopeptide class of TLR2 agonists led to the design of a highly potent lead but with negligible aqueous solubility, necessitating the reintroduction of aqueous solubility. We explored several strategies of introducing ionizable groups on the lipopeptide, as well as the systematic evaluation of chemically stable bioisosteres of the ester-linked palmitoyl group. These studies have led to a fully optimized, chemically stable, and highly water-soluble human TLR2-specific agonist, which was found to have an excellent safety profile and displayed prominent adjuvantic activities in rabbit models.