Assessing the quality of record keeping for cesarean deliveries: results from a multicenter retrospective record review in five low-income countries

BACKGROUND: Reliable, timely information is the foundation of decision making for functioning health systems; the quality of decision making rests on quality data. Routine monitoring, reporting, and review of cesarean section (CS) indications, decision-to-delivery intervals, and partograph use are important elements of quality improvement for maternity services. METHODS: In 2009 and 2010, a sample of CS records from calendar year 2008 was reviewed at nine facilities in Bangladesh, Guinea, Mali, Niger, and Uganda. Data from patient records and hospital registers were collected on key aspects of care such as timing of key events, indications, partograph use, maternal and fetal outcomes. Qualitative interviews were conducted with key informants at all study sites to provide contextual background about CS services and record keeping practices. RESULTS: A total of 2,941 records were reviewed and 57 key informant interviews were conducted. Patient record-keeping systems were of varying quality across study sites: at five sites, more than 20% of records could not be located. Across all sites, patient files were missing key aspects of CS care: timing of key events (e.g., examination, decision to perform CS), administration of prophylactic antibiotics, maternal complications, and maternal and fetal outcomes. Rates of partograph use were low at six sites: 0 to 23.9% of patient files at these sites had a completed partograph on file, and among those found, 2.1% to 65.1% were completed correctly. Information on fetal outcomes was missing in up to 40% of patient files. CONCLUSIONS: Deficits in the quality of CS patient records across a broad range of health facilities in low-resource settings in four sub-Saharan Africa countries and Bangladesh indicate an urgent need to improve record keeping

Oral Administration of the Pimelic Diphenylamide HDAC Inhibitor HDACi 4b Is Unsuitable for Chronic Inhibition of HDAC Activity in the CNS In Vivo

<div><p>Histone deacetylase (HDAC) inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich’s ataxia and Huntington’s disease, based on efficacy in cell and mouse models. These studies’ authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME) properties, as well as the central pharmacodynamic profile of one such compound, HDACi <b>4b</b>, previously described to show efficacy <em>in vivo</em> in the R6/2 mouse model of Huntington’s disease. Based on our data reported here, we conclude that while the <em>in vitro</em> selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp) substrate liability of HDACi <b>4b</b> render this compound suboptimal to investigate central Class I HDAC inhibition <em>in vivo</em> in mouse per oral administration. A drug administration regimen using HDACi <b>4b</b> dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington’s disease. We highlight physicochemical stability and metabolic issues with <b>4b</b> that are likely intrinsic liabilities of the benzamide chemotype in general.</p> </div

4b treatment does not affect histone acetylation in mouse brain.

<p>(A) Representative immunoblot showing histone acetylation in mouse brain in response to <b>4b</b> treatment. Mice treated with SAHA were used as a positive control (B). Acetylation at specific lysine residues on histone 3 (H3K4, H3K9, H3K14) and Histone 4 (H4K5) as well as global acetylation of H3 (Ac-H3) and H4 (Ac-H4) were studied using specific antibodies. Acetylation level was normalized to H3 and H4 expression level. (C) and (D) Quantification of (A) and (B) respectively. **P<0.01, *P<0.05 versus vehicle (veh). n = four per treatment. Error bars indicate SEM.</p

Biochemical and Cellular HDAC inhibition by 4b.

<p>(A) % inhibition of human recombinant Class I enzymes HDAC1 (red), HDAC2 (green), HDAC3 (black) and HDAC8 (blue) by <b>4b</b>. (B) No inhibition of ClassIIa/b enzymes by <b>4b</b>; HDAC 4(green), HDAC5 (red), HDAC7 (purple), HDAC9 (orange), HDAC6 (brown). (C) Time-dependence of human recombinant HDAC3 inhibition by varying preincubation time of <b>4b</b> with enzyme (as shown). (D) Cellular inhibition of endogenous Class I HDACs/HDAC6 using Boc_Lys_Ac (black traces) or Class IIa/HDAC8 HDACs using Boc_Lys_TFA substrate (red traces) by <b>4b</b> (closed circles) or reference compounds SAHA and Compound 26. (E) Time- dependence of cellular Class I HDAC inhibition by varying preincubation of <b>4b</b> with cells (as shown). (F) Plot of IC₅₀ values versus compound-cell preincubation time for SAHA (green) and <b>4b</b> (black).</p

Brain-to-plasma concentration ratio (B:P) following a single SC or PO administration to mice.

<p>NC = not calculated since concentrations were below the lower limit of assay quantitation (3 nM).</p>(a)<p>Values represent mean (standard deviation); N = 3.</p

Instability of 4b and C1 in mouse plasma and hepatic microsomes.

<p>(A) Time course of metabolism of <b>4b</b> (5 µM), and generation of metabolites <b>M1</b> and <b>M2</b> in mouse plasma. (B) Time course of metabolism of <b>C1</b> (3 µM), and generation of metabolites <b>M3</b> in mouse plasma. (C and D) Time course of metabolism of <b>4b</b> (1 µM), and generation of metabolites <b>M1</b>, <b>M2</b> and <b>M4</b> in mouse hepatic microsomes, in presence (C) and absence (D) of NADPH. The dashed black line indicates the sum of <b>4b</b> and metabolites measured at each time point.</p