Tenofovir diphosphate in dried blood spots and HIV-1 resistance in South Africa.

BACKGROUND: Suboptimal antiretroviral (ART) adherence can lead to virologic failure with consequent HIV-1 resistance. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a powerful biomarker of cumulative adherence, predictive of future viremia. It has been associated with resistance in Persons With HIV (PWH) in South Africa and the US. We explored the relationship of TFV-DP concentrations with antiretroviral drug resistance at the time of treatment failure in SA. METHODS: Adult PWH from health clinics in Cape Town, South Africa on efavirenz-based first-line ART containing tenofovir disoproxil fumarate (TDF) with an undetectable (< 50 copies/mL) HIV-1 viral load (VL) were prospectively enrolled in an observational cohort for 12 months. Monthly study visits included blood collection for HIV-1 VL and DBS for TFV-DP. The first confirmed viral breakthrough (VB) > 400 copies/mL triggered HIV-1 genotyping at the subsequent visit. An electronic adherence (EA) device monitored ART adherence in real-time, estimated as a percent for the 30-days prior to VB. Wilcoxon rank sum test was used to compare median [IQR] TFV-DP by genotype outcome. RESULTS: Of 250 individuals, (n = 195, 78% women), 21 experienced VB, with a median of 5 [4;7] months on study, and a median EA of 33.3 [13.3;53.3]%. Demographic characteristics between those with and without VB were similar. Median VL at VB was 4.0 [3.2;4.5] log copies/mL. TFV-DP concentrations trended down towards the VB visit. Median TFV-DP concentrations were significantly higher in those HIV-1 genotype did not amplify due to being virally suppressed at the subsequent visit (n = 10; 380 [227-661] fmol/punch, p = 0.035; EA 45 [24.9; 59.2]%); than in those who were successfully genotyped with evidence of drug resistance (n = 5, 241 [150-247] fmol/punch, EA 20 [6.7;36.7]%) and in individuals who did not have resistance (n = 3, 39.9 [16.6; 93.9] fmol/punch; EA 33.3 [16-38]%). Three genotype collections were not done. Only non-nucleoside reverse transcriptase inhibitor-associated mutations were identified on resistance testing. (K103N, E138K, Y118H). CONCLUSION: TFV-DP in DBS showed a step-wise inverse relationship with VB and drug resistance, with evidence of low cumulative ART adherence in PWH who developed antiretroviral resistance. Monitoring TFV-DP concentrations could be a valuable tool for predicting future VB and future resistance.

Proteomic associations with forced expiratory volume - a Mendelian randomisation study.

A decline in forced expiratory volume (FEV1) is a hallmark of obstructive respiratory diseases, an important cause of morbidity among the elderly. While some data exist on biomarkers that are related to FEV1, we sought to do a systematic analysis of causal relations of biomarkers with FEV1. Data from the general population-based AGES-Reykjavik study were used. Proteomic measurements were done using 4,782 DNA aptamers (SOMAmers). Data from 1,648 participants with spirometric data were used to assess the association of SOMAmer measurements with FEV1 using linear regression. Bi-directional Mendelian randomisation (MR) analyses were done to assess causal relations of observationally associated SOMAmers with FEV1, using genotype and SOMAmer data from 5,368 AGES-Reykjavik participants and genetic associations with FEV1 from a publicly available GWAS (n = 400,102). In observational analyses, 473 SOMAmers were associated with FEV1 after multiple testing adjustment. The most significant were R-Spondin 4, Alkaline Phosphatase, Placental Like 2 and Retinoic Acid Receptor Responder 2. Of the 235 SOMAmers with genetic data, eight were associated with FEV1 in MR analyses. Three were directionally consistent with the observational estimate, Thrombospondin 2 (THBS2), Endoplasmic Reticulum Oxidoreductase 1 Beta and Apolipoprotein M. THBS2 was further supported by a colocalization analysis. Analyses in the reverse direction, testing whether changes in SOMAmer levels were caused by changes in FEV1, were performed but no significant associations were found after multiple testing adjustments. In summary, this large scale proteogenomic analyses of FEV1 reveals protein markers of FEV1, as well as several proteins with potential causality to lung function.

Understanding the differences in wear testing method standards for total knee replacement.

Preclinical evaluation of the wear of total knee replacements (TKR) is usually undertaken using International Standards Organization (ISO) test methods. Two international standards for the preclinical wear simulation of TKRs have been developed; using either force or displacement control. In addition, based on previously published measured kinematics of healthy subjects, a gait cycle (displacement control) was also developed at the University of Leeds, which pre-dates the ISO displacement control standard. Furthermore, different test methods have adopted different approaches to defining the centres of rotation and polarity (direction of application) of motions. However, the effects of using these different control regimes and input conditions on the kinematics, contact mechanics, and wear of any one TKR have not been fully investigated previously. The current study investigated the kinematics, contact mechanics, and wear performance of a TKR when running under ISO force and displacement control test methods as well as the Leeds gait cycle inputs using experimental and computational simulation methods, with the aim of understanding the mechanical and tribological outcomes predicted by the different test method standard conditions. Three ISO wear testing standards were investigated using a mid-size Sigma curved TKR (DePuy, UK), with moderately cross-linked UHMWPE curved inserts; ISO-14243-3-2004, ISO-14243-3-2014 and ISO-14243-1-2009. In addition, the Leeds displacement control gait cycle was also investigated. According to the computational simulation predictions, reversing the anterior-posterior (AP) displacement and tibial rotation polarities in the displacement control ISO-2014 standard compared to the ISO-2004 standard resulted in high stress, of more than 65 MPa, at the posterior edge of the inserts with more than 10% increase in wear rate for this TKR design. Although Leeds gait input kinematics produced femoral rollback, it did not result in high stress edge loading on the posterior lip of the insert. This was attributed to different test input kinematics and different centres of rotation of the femoral component adopted in the displacement control standard ISO-2014 and Leeds gait test methods. The predicted AP displacement and tibial rotation from the force control ISO-2009 had different polarities and magnitudes to the corresponding displacement control profiles. In addition, the predicted wear rate, from the computational model, under the force control ISO-2009 standard was more than double that predicted under displacement control ISO standards due to the increased AP displacement and tibial rotation motions predicted under the force control standard. These major differences, in the mechanics and wear, between different test methods imply that each standard must therefore be used with its own predicate control results from a device with proven clinical history and results across different standards should never be compared, as the choice of test method standard may well be dependent on the design solution for the knee. Clinically, the kinematics in the population are extremely variable, which results in highly variable wear rates. While a standard method is necessary, on its own it is not adequate and needs to be supported by tests under a portfolio of representative conditions with different kinematic conditions, different soft tissue constraints, as well as with different alignments, so that the variability and range of wear rates expected clinically might be determined. This study enables further progress towards the definition of such a portfolio of representative conditions, by deepening the understanding of the relationships between currently used input conditions and the resulting mechanical and wear outputs.

Considerations for understanding protein measurements: Identification of formation, degradation and more pathological relevant epitopes.

OBJECTIVES: There is a need for precision medicine and an unspoken promise of an optimal approach for identification of the right patients for value-based medicine based on big data. However, there may be a misconception that measurement of proteins is more valuable than measurement of fewer selected biomarkers. In population-based research, variation may be somewhat eliminated by quantity. However, this fascination of numbers may limit the attention to and understanding of the single. This review highlights that protein measurements (with collagens as examples) may mean different things depending on the targeted epitope - formation or degradation of tissues, and even signaling potential of proteins. DESIGN AND METHODS: PubMed was searched for collagen, neo-epitope, biomarkers. RESULTS: Ample examples of assays with specific epitopes, either pathological such as HbA1c, or domain specific such as pro-peptides, which total protein arrays would not have identified were evident. CONCLUSIONS: We suggest that big data may be considered as the funnel of data points, in which most important parameters will be selected. If the technical precision is low or the biological accuracy is limited, and we include suboptimal quality of biomarkers, disguised as big data, we may not be able to fulfill the promise of helping patients searching for the optimal treatment. Alternatively, if the technical precision of the total protein quantification is high, but we miss the functional domains with the most considerable biological meaning, we miss the most important and valuable information of a given protein. This review highlights that measurements of the same protein in different ways may provide completely different meanings. We need to understand the pathological importance of each epitope quantified to maximize protein measurements.

The influence of a calcium sulphate bone void filler on the third-body damage and polyethylene wear of total knee arthroplasty.

OBJECTIVES: Bone void fillers are increasingly being used for dead space management in arthroplasty revision surgery. The aim of this study was to investigate the influence of calcium sulphate bone void filler (CS-BVF) on the damage and wear of total knee arthroplasty using experimental wear simulation. METHODS: A total of 18 fixed-bearing U2 total knee arthroplasty system implants (United Orthopedic Corp., Hsinchu, Taiwan) were used. Implants challenged with CS-BVF were compared with new implants (negative controls) and those intentionally scratched with a diamond stylus (positive controls) representative of severe surface damage (n = 6 for each experimental group). Three million cycles (MC) of experimental simulation were carried out to simulate a walking gait cycle. Wear of the ultra-high-molecular-weight polyethylene (UHMWPE) tibial inserts was measured gravimetrically, and damage to articulating surfaces was assessed using profilometry. RESULTS: There was no significant difference (p > 0.05) between the wear rate of implants challenged with CS-BVF (3.3 mm3/MC (95% confidence interval (CI) 1.8 to 4.8)) and the wear rate of those not challenged (2.8 mm3/MC (95% CI 1.3 to 4.3)). However, scratching the cobalt-chrome (CoCr) significantly (p < 0.001) increased the wear rate (20.6 mm3/MC (95% CI 15.5 to 25.7)). The mean surface roughness of implants challenged with CS-BVF was equivalent to negative controls both after damage simulation (p = 0.98) and at the conclusion of the study (p = 0.28). CONCLUSION: When used close to articulating surfaces, a low-hardness, high-purity CS-BVF had no influence on wear. When trapped between the articulating surfaces of a total knee arthroplasty, CS-BVF did not scratch the surface of CoCr femoral components, nor did it increase the wear of UHMWPE tibial inserts compared with undamaged negative controls.Cite this article: R. M. Cowie, S. S. Aiken, J. J. Cooper, L. M. Jennings. The influence of a calcium sulphate bone void filler on the third-body damage and polyethylene wear of total knee arthroplasty. Bone Joint Res 2019;8:65-72. DOI: 10.1302/2046-3758.82.BJR-2018-0146.R1.

Development of a preclinical natural porcine knee simulation model for the tribological assessment of osteochondral grafts in vitro.

In order to pre-clinically evaluate the performance and efficacy of novel osteochondral interventions, physiological and clinically relevant whole joint simulation models, capable of reproducing the complex loading and motions experienced in the natural knee environment are required. The aim of this study was to develop a method for the assessment of tribological performance of osteochondral grafts within an in vitro whole natural joint simulation model. The study assessed the effects of osteochondral allograft implantation (existing surgical intervention for the repair of osteochondral defects) on the wear, deformation and damage of the opposing articular surfaces. Tribological performance of osteochondral grafts was compared to the natural joint (negative control), an injury model (focal cartilage defects) and stainless steel pins (positive controls). A recently developed method using an optical profiler (Alicona Infinite Focus G5, Alicona Imaging GmbH, Austria) was used to quantify and characterise the wear, deformation and damage occurring on the opposing articular surfaces. Allografts inserted flush with the cartilage surface had the lowest levels of wear, deformation and damage following the 2 h test; increased levels of wear, deformation and damage were observed when allografts and stainless steel pins were inserted proud of the articular surface. The method developed will be applied in future studies to assess the tribological performance of novel early stage osteochondral interventions prior to in vivo studies, investigate variation in surgical precision and aid in the development of stratified interventions for the patient population.

An in vitro simulation model to assess the severity of edge loading and wear, due to variations in component positioning in hip joint replacements.

The aim of this study was to develop a preclinical in vitro method to predict the occurrence and severity of edge loading condition associated with the dynamic separation of the centres of the head and cup (in the absence of impingement) for variations in surgical positioning of the cup. Specifically, this study investigated the effect of both the variations in the medial-lateral translational mismatch between the centres of the femoral head and acetabular cup and the variations in the cup inclination angles on the occurrence and magnitude of the dynamic separation, the severity of edge loading, and the wear rate of ceramic-on-ceramic hip replacement bearings in a multi-station hip joint simulator during a walking gait cycle. An increased mismatch between the centres of rotation of the femoral head and acetabular cup resulted in an increased level of dynamic separation and an increase in the severity of edge loading condition which led to increased wear rate in ceramic-on-ceramic bearings. Additionally for a given translational mismatch, an increase in the cup inclination angle gave rise to increased dynamic separation, worst edge loading conditions, and increased wear. To reduce the occurrence and severity of edge loading, the relative positions (the mismatch) of the centres of rotation of the head and the cup should be considered alongside the rotational position of the acetabular cup. This study has considered the combination of mechanical and tribological factors for the first time in the medial-lateral axis only, involving one rotational angle (inclination) and one translational mismatch. © 2017 The Authors Journal of Biomedical Materials Research Part B: Applied Biomaterials Published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1897-1906, 2018.

Development and characterisation of a large diameter decellularised vascular allograft.

The aims of this study were to develop a biological large diameter vascular graft by decellularisation of native human aorta to remove the immunogenic cells whilst retaining the essential biomechanical, and biochemical properties for the ultimate benefit of patients with infected synthetic grafts. Donor aortas (n = 6) were subjected to an adaptation of a propriety decellularisation process to remove the cells and acellularity assessed by histological analysis and extraction and quantification of total DNA. The biocompatibility of the acellular aortas was determined using standard contact cytotoxicity tests. Collagen and denatured collagen content of aortas was determined and immunohistochemistry was used to determine the presence of specific extracellular matrix proteins. Donor aortas (n = 6) were divided into two, with one half subject to decellularisation and the other half retained as native tissue. The native and decellularised aorta sections were then subject to uniaxial tensile testing to failure [axial and circumferential directions] and suture retention testing. The data was compared using a paired t-test. Histological evaluation showed an absence of cells in the treated aortas and retention of histoarchitecture including elastin content. The decellularised aortas had less than 15 ng mg-1 total DNA per dry weight (mean 94% reduction) and were biocompatible as determined by in vitro contact cytotoxicity tests. There were no gross changes in the histoarchitecture [elastin and collagen matrix] of the acellular aortas compared to native controls. The decellularisation process also reduced calcium deposits within the tissue. The uniaxial tensile and suture retention testing revealed no significant differences in the material properties (p > 0.05) of decellularised aorta. The decellularisation procedure resulted in minimal changes to the biological and biomechanical properties of the donor aortas. Acellular donor aorta has excellent potential for use as a large diameter vascular graft.

In vitro biomechanical and hydrodynamic characterisation of decellularised human pulmonary and aortic roots.

BACKGROUND AND PURPOSE OF THE STUDY: The use of decellularised biological heart valves in the replacement of damaged heart valves offers a promising solution to reduce the degradation issues associated with existing cryopreserved allografts. The purpose of this study was to assess the effect of low concentration sodium dodecyl sulphate decellularisation on the in vitro biomechanical and hydrodynamic properties of cryopreserved human aortic and pulmonary roots. METHOD: The biomechanical and hydrodynamic properties of cryopreserved decellularised human aortic and pulmonary roots were fully characterised and compared to cellular human aortic and pulmonary roots in an unpaired study. Following review of these results, a further study was performed to investigate the influence of a specific processing step during the decellularisation protocol ('scraping') in a paired comparison, and to improve the method of the closed valve competency test by incorporating a more physiological boundary condition. RESULTS: The majority of the biomechanical and hydrodynamic characteristics of the decellularised aortic and pulmonary roots were similar compared to their cellular counterparts. However, several differences were noted, particularly in the functional biomechanical parameters of the pulmonary roots. However, in the subsequent paired comparison of pulmonary roots with and without decellularisation, and when a more appropriate physiological test model was used, the functional biomechanical parameters for the decellularised pulmonary roots were similar to the cellular roots. CONCLUSION: Overall, the results demonstrated that the decellularised roots would be a potential choice for clinical application in heart valve replacement.

A comprehensive combined experimental and computational framework for pre-clinical wear simulation of total knee replacements.

A more robust pre-clinical wear simulation framework is required in order to simulate wider and higher ranges of activities, observed in different patient populations such as younger more active patients. Such a framework will help to understand and address the reported higher failure rates for younger and more active patients (National_Joint_Registry, 2016). The current study has developed and validated a comprehensive combined experimental and computational framework for pre-clinical wear simulation of total knee replacements (TKR). The input mechanical (elastic modulus and Poisson's ratio) and wear parameters of the moderately cross-linked ultra-high molecular weight polyethylene (UHMWPE) bearing material were independently measured from experimental studies under realistic test conditions, similar to the loading conditions found in the total knee replacements. The wear predictions from the computational wear simulation were validated against the direct experimental wear measurements for size 3 Sigma curved total knee replacements (DePuy, UK) in an independent experimental wear simulation study under three different daily activities; walking, deep squat, and stairs ascending kinematic conditions. The measured compressive mechanical properties of the moderately cross-linked UHMWPE material were more than 20% lower than that reported in the literature under tensile test conditions. The pin-on-plate wear coefficient of moderately cross-linked UHMWPE was significantly dependant of the contact stress and the degree of cross-shear at the articulating surfaces. The computational wear predictions for the TKR from the current framework were consistent and in a good agreement with the independent full TKR experimental wear simulation measurements, with 0.94 coefficient of determination of the framework. In addition, the comprehensive combined experimental and computational framework was able to explain the complex experimental wear trends from the three different daily activities investigated. Therefore, such a framework can be adopted as a pre-clinical simulation approach to optimise different designs, materials, as well as patient's specific total knee replacements for a range of activities.

The treatment of hidradenitis suppurativa with the glucagon-like peptide-1 agonist liraglutide.

Hidradenitis suppurativa (HS) is a cutaneous disease associated with systemic inflammation, obesity and metabolic syndrome. Effective treatment options are limited. The antidiabetic agents, incretins, have been used successfully to treat psoriasis - a disease also associated with metabolic syndrome. We report the use of liraglutide, a glucagon-like peptide-1 agonist, in a patient with HS, leading to subsequent weight loss and improvement in disease control. To our knowledge, this is the first report of liraglutide used in the treatment of HS.

The role of confinement and corona crystallinity on the bending modulus of copolymer micelles measured directly by AFM flexural tests.

We present an approach which makes it possible to directly determine the bending modulus of single elongated block copolymer micelles. This is done by forming arrays of suspended micelles onto microfabricated substrates and by performing three-point bending flexural tests, using an atomic force microscope, on their suspended portions. By coupling the direct atomic force microscopy measurements with differential scanning calorimetry data, we show that the presence of a crystalline corona strongly increases the modulus of the copolymer elongated micelles. This large increase suggests that crystallites in the corona are larger and more uniformly oriented due to confinement effects. Our findings together with this hypothesis open new interesting avenues for the preparation of core-templated polymer fibres with enhanced mechanical properties.

In vivo biodistribution of stable spherical and filamentous micelles probed by high-sensitivity SPECT.

Understanding how nanoparticle properties such as size, morphology and rigidity influence their circulation time and biodistribution is essential for the development of nanomedicine therapies. Herein we assess the influence of morphology on cellular internalization, in vivo biodistribution and circulation time of nanocarriers using polystyrene-b-poly(ethylene oxide) micelles of spherical or elongated morphology. The glassy nature of polystyrene guarantees the morphological stability of the carriers in vivo and by encapsulating Indium-111 in their core, an assessment of the longitudinal in vivo biodistribution of the particles in healthy mice is performed with single photon emission computed tomography imaging. Our results show prolonged blood circulation, longer than 24 hours, for all micelle morphologies studied. Dynamics of micelle accumulation in the liver and other organs of the reticuloendothelial system show a size-dependent nature and late stage liver clearance is observed for the elongated morphology. Apparent contradictions between recent similar studies can be resolved by considering the effects of flexibility and degradation of the elongated micelles on their circulation time and biodistribution.

Influence of contact pressure, cross-shear and counterface material on the wear of PEEK and CFR-PEEK for orthopaedic applications.

Total joint replacement is a successful surgical intervention for the treatment of the degeneration of many joints, particularly the hip and knee. As the demand for joint replacement grows, and the life expectancy of the population increases, the performance requirements of these implants also changes. New materials, to improve longevity and enhance performance have been explored including PEEK and CFR-PEEK. This study investigated whether CFR-PEEK and PEEK were appropriate materials for total joint replacement by examining wear performance in simple configuration studies articulating against cobalt chrome under a range of cross-shear and contact pressure conditions. Simple geometry pin on plate studies were conducted for one million cycles for each test condition, with the contact pressure and cross-shear conditions representing a range in which the material may need to operate in-vivo. The wear factor for PEEK was significantly higher than CFR-PEEK and conventional polyethylene under all test conditions. Both PEEK and CFR-PEEK wear were influenced by contact pressure, with the highest wear factors for both materials measured at the highest pressure conditions. PEEK appeared to have a cross-shear dependent wear response, but this was not observed for the CFR-PEEK material. This study has further characterised the wear performance of two materials that are gaining interest for total joint replacement. The wear performance of the PEEK material showed poorer wear performance compared to polyethylene when articulating with a metal counterface, but the performance of the CFR-PEEK material suggested it may provide a suitable alternative to polyethylene in some applications. The wear performance of CFR-PEEK was poorer than polyethylene when it was used as the plate, when there was translation of the contact zone over the surface of the CFR-PEEK plate. This has implications for applications in low conforming contacts, such as lower conformity knee replacement.

Proposed Diagnostic Criteria for Chronic Antibody-Mediated Rejection in Liver Allografts.

Donor-specific alloantibodies (DSA) can cause acute antibody-mediated rejection (AMR) in all solid organ allografts. However, long-term outcome in patients with posttransplant DSA needs further study. We retrospectively evaluated prospectively collected paired serum, tissue, and data on 45 matched DSA- positive [DSA+; mean florescence intensity (MFI) ≥10,000] and -negative (DSA-) recipients of a primary liver-only allograft from January 2000 to April 2009. Blinded histopathologic evaluation demonstrated that DSA+ versus DSA- patients were more likely to have subtle inflammation and unique patterns of fibrosis, despite normal or near-normal liver function tests. Stepwise multivariable modeling developed a score (putatively named the chronic AMR [cAMR] score) that included interface activity, lobular inflammation, portal tract collagenization, portal venopathy, sinusoidal fibrosis, and hepatitis C virus status. The score was developed (c = 0.811) and cross-validated (c = 0.704) to predict allograft failure. Two cutoffs were employed to optimize sensitivity and specificity (80% each); a value >27.5 predicted 50% 10-year allograft failure. We propose chronic AMR as a potential new entity defined by (1) a high cAMR score, (2) DSA, and (3) elimination of other potential causes of a similar injury pattern. In conclusion, cAMR score calculation identified liver allograft recipients with DSA at highest risk for allograft loss, although independent validation is needed.

Impact of IgG3 subclass and C1q-fixing donor-specific HLA alloantibodies on rejection and survival in liver transplantation.

Recent literature confirms donor-specific HLA alloantibodies (DSA) impair 5-year survival in some but not all liver transplant recipients. In an effort to improve DSA testing's association with rejection and death, we retrospectively evaluated 1270 liver transplant recipients for the presence of IgG3 and C1q-fixing DSA. In patients with preformed DSA, 29 and 51% had IgG3 and C1q-fixing DSA, respectively. In patients with de novo DSA, 62% and 67% had IgG3 and C1q-fixing DSA, respectively. When different types of DSA positive patients were compared to DSA negative patients, multivariable analysis showed that IgG3 DSA positivity had the highest numerical hazard ratio for death (IgG3: HR = 2.4, p < 0.001; C1q: HR = 1.9, p < 0.001; standard DSA: HR = 1.6, p < 0.001). Similarly, multivariable analysis demonstrated de novo IgG3 DSA positivity compared to no DSA had the highest hazard ratio for death (IgG3: HR = 2.1, p = 0.004; C1q: HR = 1.9, p = 0.02; standard DSA: HR = 1.8, p = 0.007). Preformed C1q-fixing class II DSA showed the strongest correlation with early rejection. In conclusion, preformed and de novo IgG3 subclass DSA positive patients had the highest absolute HR for death in side-by-side comparison with C1q and standard DSA positive versus DSA negative patients; however, IgG3 negative DSA positive patients still had inferior outcomes compared to DSA negative patients.

Use of job aids to improve facility-based postnatal counseling and care in rural Benin.

This study examined the effect of a job aids-focused intervention on quality of facility-based postnatal counseling, and whether increased communication improved in-hospital newborn care and maternal knowledge of home practices and danger signs requiring urgent care. Ensuring mothers and newborns receive essential postnatal services, including health counseling, is integral to their survival. Yet, quality of clinic-based postnatal services is often low, and evidence on effective improvement strategies is scarce. Using a pre-post randomized design, data were drawn from direct observations and interviews with 411 mother-newborn pairs. Multi-level regression models with difference-in-differences analyses estimated the intervention's relative effect, adjusting for changes in the comparison arm. The mean percent of recommended messages provided to recently-delivered women significantly improved in the intervention arm as compared to the control (difference-in-differences [∆i - ∆c] +30.9, 95 % confidence interval (CI) 19.3, 42.5), and the proportion of newborns thermally protected within the first hour (∆i - ∆c +33.7, 95 % CI 19.0, 48.4) and delayed for bathing (∆i - ∆c +23.9, 95 % CI 9.4, 38.4) significantly increased. No significant changes were observed in early breastfeeding (∆i - ∆c +6.8, 95 % CI -2.8, 16.4) which was nearly universal. Omitting traditional umbilical cord substances rose slightly, but was insignificant (∆i - ∆c +8.5, 95 % CI -2.8, 19.9). The proportion of mothers with correct knowledge of maternal (∆i - ∆c +27.8, 95 % CI 11.0, 44.6) and newborn (∆i - ∆c +40.3, 95 % CI 22.2, 58.4) danger signs grew substantially, as did awareness of several home-care practices (∆i - ∆c +26.0, 95 % CI 7.7, 44.3). Counseling job aids can improve the quality of postnatal services. However, achieving reduction goals in maternal and neonatal mortality will likely require more comprehensive approaches to link enhanced facility services with community-based initiatives.

An analytical solution to patient prioritisation in radiotherapy based on utilitarian optimisation.

The detrimental impact of a radiotherapy waiting list can in part be compensated by patient prioritisation. Such prioritisation is phrased as an optimisation problem where the probability of local control for the overall population is the objective to be maximised and a simple analytical solution derived. This solution is compared with a simulation of a waiting list for the same population of patients. It is found that the analytical solution can provide an optimal ordering of patients though cannot explicitly constrain optimal waiting times. The simulation-based solution was undertaken using both the analytical solution and a numerical optimisation routine for daily patient ordering. Both solutions provided very similar results with the analytical approach reducing the calculation time of the numerical solution by several orders of magnitude. It is suggested that treatment delays due to resource limitations and resulting waiting lists be incorporated into treatment optimisation and that the derived analytical solution provides a mechanism for this to occur.