Prevalence and control of hypertension in a high HIV-prevalence setting, insights from a population based study in Botswana.

In a population-based representative sample of adults residing in 22 communities in Botswana, a southern African country with high HIV prevalence, 1 in 4 individuals had high blood pressure. High blood pressure was less prevalent in adults with HIV than without HIV. Sixty percent of persons with high blood pressure had not previously been diagnosed. Among individuals with a prior diagnosis of high blood pressure who reported being prescribed anti-hypertension medications, almost half had elevated blood pressure, irrespective of HIV-status. One-third of adults in this setting (mainly men) declined free non-invasive blood pressure assessments in their households. In conclusion, our study highlights alarmingly high hypertension rates in the community, with low levels of awareness and control, emphasizing the urgent need for community level BP screening and active management to reach recommended targets.

Semisolid Enteral Nutrients Alter the Pharmacokinetics of Orally Administered Levetiracetam in Rats.

Enteral nutrients (ENs) affect the plasma drug concentration of orally co-administered drugs, particularly those of antiepileptic drugs, such as phenytoin and carbamazepine. However, few studies have reported the interactions of levetiracetam (LEV), an upcoming antiepileptic drug, with ENs. In this study we aimed to investigate the pharmacokinetics of LEV in 55 rats after oral co-administration of LEV with liquid or semisolid ENs. Compared with the control group, co-administration with Terumeal ® Soft significantly decreased the plasma LEV concentration at 0.5, 1, and 2 h and area under the plasma concentration-time curve from 0 to 3 h (AUC0→3h) (P < 0.01). However, the AUC0→3h of LEV remained unchanged following the administration of Terumeal ® Soft 2 h after the initial LEV administration. Moreover, co-administration with semisolid Racol® NF delayed the absorption of LEV without decreasing the AUC0→3h, whereas liquid Racol ® NF did not alter LEV pharmacokinetics. Thus, co-administration of LEV with Terumeal® Soft reduced the absorption of LEV from the gastrointestinal tract, which was prevented by administering Terumeal ® Soft 2 h after LEV administration. Semisolid Racol ® NF altered LEV pharmacokinetics without decreasing its gastrointestinal absorption. Our findings suggested that careful monitoring of the plasma LEV levels is necessary when co-administering LEV with Terumeal ® Soft, semisolid Racol ® NF, or any other semisolid ENs, to prevent the inadvertent effects of the interaction between LEV and ENs.

Hypertension, a dementia polygenic risk score, APOE genotype, and incident dementia.

INTRODUCTION: There is inconsistent evidence on whether genetic risk for dementia modifies the association between hypertension and dementia. METHODS: In 198,965 dementia-free participants aged ≥60 years, Cox proportional-hazards models were used to investigate the association between hypertension and incident dementia. A polygenic risk score (PRS) based on 38 non-apolipoprotein E (APOE) single nucleotide polymorphisms and APOE ε4 status were used to determine genetic risk for dementia. RESULTS: Over 15 years follow-up, 6270 participants developed dementia. Hypertension was associated with a 19% increased risk of dementia (hazard ratio = 1.19, 95% confidence interval 1.11-1.27). The associations remained similar when stratifying by genetic risk, with no evidence for multiplicative interaction by dementia PRS (P = 0.20) or APOE ε4 status (P = 0.16). However, the risk difference between those with and without hypertension was larger among those at higher genetic risk. DISCUSSION: Hypertension was associated with an increased risk of dementia regardless of genetic risk for dementia.

Improving identification of symptomatic cancer at primary care clinics: A predictive modeling analysis in Botswana.

In resource-limited settings, augmenting primary care provider (PCP)-based referrals with data-derived algorithms could direct scarce resources towards those patients most likely to have a cancer diagnosis and benefit from early treatment. Using data from Botswana, we compared accuracy of predictions of probable cancer using different approaches for identifying symptomatic cancer at primary clinics. We followed cancer suspects until they entered specialized care for cancer treatment (following pathologically confirmed diagnosis), exited from the study following noncancer diagnosis, or died. Routine symptom and demographic data included baseline cancer probability assessed by the primary care provider (low, intermediate, high), age, sex, performance status, baseline cancer probability by study physician, predominant symptom (lump, bleeding, pain or other) and HIV status. Logistic regression with 10-fold cross-validation was used to evaluate classification by different sets of predictors: (1) PCPs, (2) Algorithm-only, (3) External specialist physician review and (4) Primary clinician augmented by algorithm. Classification accuracy was assessed using c-statistics, sensitivity and specificity. Six hundred and twenty-three adult cancer suspects with complete data were retained, of whom 166 (27%) were diagnosed with cancer. Models using PCP augmented by algorithm (c-statistic: 77.2%, 95% CI: 73.4%, 81.0%) and external study physician assessment (77.6%, 95% CI: 73.6%, 81.7%) performed better than algorithm-only (74.9%, 95% CI: 71.0%, 78.9%) and PCP initial assessment (62.8%, 95% CI: 57.9%, 67.7%) in correctly classifying suspected cancer patients. Sensitivity and specificity statistics from models combining PCP classifications and routine data were comparable to physicians, suggesting that incorporating data-driven algorithms into referral systems could improve efficiency.

Are polygenic risk scores for systolic blood pressure and LDL-cholesterol associated with treatment effectiveness, and clinical outcomes among those on treatment?

AIMS: Many studies have investigated associations between polygenic risk scores (PRS) and the incidence of cardiovascular disease (CVD); few have examined whether risk factor-related PRS predict CVD outcomes among adults treated with risk-modifying therapies. We assessed whether PRS for systolic blood pressure (PRSSBP) and for low-density lipoprotein cholesterol (PRSLDL-C) were associated with achieving SBP and LDL-C-related targets, and with major adverse cardiovascular events (MACE: non-fatal stroke or myocardial infarction, CVD death, and revascularization procedures). METHODS AND RESULTS: Using observational data from the UK Biobank (UKB), we calculated PRSSBP and PRSLDL-C and constructed two sub-cohorts of unrelated adults of White British ancestry aged 40-69 years and with no history of CVD, who reported taking medications used in the treatment of hypertension or hypercholesterolaemia. Treatment effectiveness in achieving adequate risk factor control was ascertained using on-treatment blood pressure (BP) or LDL-C levels measured at enrolment (uncontrolled hypertension: BP ≥ 140/90 mmHg; uncontrolled hypercholesterolaemia: LDL-C ≥ 3 mmol/L). We conducted multivariable logistic and Cox regression modelling for incident events, adjusting for socioeconomic characteristics, and CVD risk factors. There were 55 439 participants using BP lowering therapies (51.0% male, mean age 61.0 years, median follow-up 11.5 years) and 33 787 using LDL-C lowering therapies (58.5% male, mean age 61.7 years, median follow-up 11.4 years). PRSSBP was associated with uncontrolled hypertension (odds ratio 1.70; 95% confidence interval: 1.60-1.80) top vs. bottom quintile, equivalent to a 5.4 mmHg difference in SBP, and with MACE [hazard ratio (HR) 1.13; 1.04-1.23]. PRSLDL-C was associated with uncontrolled hypercholesterolaemia (HR 2.78; 2.58-3.00) but was not associated with subsequent MACE. CONCLUSION: We extend previous findings in the UKB cohort to examine PRSSBP and PRSLDL-C with treatment effectiveness. Our results indicate that both PRSSBP and PRSLDL-C can help identify individuals who, despite being on treatment, have inadequately controlled SBP and LDL-C, and for SBP are at higher risk for CVD events. This extends the potential role of PRS in clinical practice from identifying patients who may need these interventions to identifying patients who may need more intensive intervention.

Taking a mass-balance approach to assess marine plastics in the South China Sea.

The South China Sea (SCS) is recognised as a global hotspot for plastic pollution. We review available field studies and identify a significant lack of data needed to construct a simple mass balance box model for plastic pollution in the SCS. Fundamental information on plastic mass input, transfer and sink terms are simply not available. Also unknown are the rates of accumulation in different environments, the dispersal pathways of plastic particles of different density, the residence times of plastic in the water column and the rate at which macroplastics are transformed into microplastics in different environments. Filling these information gaps is critical for states to determine adequate response measures, including developing and tracking impact of policies to deal with the problem of plastic pollution in the SCS.

Prevalence and Determinants of Hypertension Awareness, Treatment, and Control in Botswana: A Nationally Representative Population-Based Survey.

INTRODUCTION: Hypertension is a leading risk factor for cardiovascular mortality and an emerging public health concern in sub-Saharan Africa. Few studies have examined performance on the management of hypertension in this region, where the context may be distinct from other developing regions. OBJECTIVES: We aimed to determine the prevalence and correlates of hypertension, awareness, treatment, and control among adults in Botswana, a middle-income African country undergoing rapid demographic transition and with high HIV burden. METHODS: In this 2014 cross-sectional survey of adults aged 15-69 years, information on sociodemographic characteristics, lifestyle behavior, and medical history was collected through in-person interviews and physical measurements (body mass index and triplicate blood pressure (BP)). Hypertension was defined as self-report of use of antihypertensives in the previous two weeks and/or having elevated BP (≥140/90 mmHg). Multivariable logistic regression was employed to explore factors associated with hypertension, awareness (report of previous diagnosis), treatment (antihypertensives), and control (BP < 140/90). RESULTS: Our analysis (N = 4,007) yielded an age-standardized hypertension prevalence of 30% (95% CI: 28%-32%, N = 1,393). Among hypertensives, 54% (50-58%) were unaware of their condition, 45% (40-50%) of those aware were untreated, and 63% (55-70%) of those on medications were suboptimally treated (BP ≥ 140/90 mmHg). A fifth of hypertensives who were diagnosed but not on medications had BP ≥ 180/110 mmHg. Diabetes was the strongest correlate of hypertension and awareness (aOR 4.00, 1.86-8.59; aOR 3.30, 1.44-7.55, respectively). Males were less likely to be aware (aOR 0.62, 0.41-0.94) or controlled (aOR 0.36, 0.16-0.83). Obese individuals were more likely to be treated (aOR 2.17, 1.12-4.22), yet less likely to be controlled (aOR 0.32, 0.15-0.66). CONCLUSIONS: We report the first nationally representative estimates of the hypertension care cascade performance in Botswana, which will support planning and future policy evaluations. Findings contribute to the relatively sparse evidence on this subject and may inform development of innovations that improve quality of hypertension management and adherence support in similar settings.

Integrating noncommunicable disease services into primary health care, Botswana.

Despite the rising burden of noncommunicable diseases, access to quality decentralized noncommunicable disease services remain limited in many low- and middle-income countries. Here we describe the strategies we employed to drive the process from adaptation to national endorsement and implementation of the 2016 Botswana primary healthcare guidelines for adults. The strategies included detailed multilevel assessment with broad stakeholder inputs and in-depth analysis of local data; leveraging academic partnerships; facilitating development of supporting policy instruments; and embedding noncommunicable disease guidelines within broader primary health-care guidelines in keeping with the health ministry strategic direction. At facility level, strategies included developing a multimethod training programme for health-care providers, leveraging on the experience of provision of human immunodeficiency virus care and engaging health-care implementers early in the process. Through the strategies employed, the country's first national primary health-care guidelines were endorsed in 2016 and a phased three-year implementation started in August 2017. In addition, provision of primary health-care delivery of noncommunicable disease services was included in the country's 11th national development plan (2017-2023). During the guideline development process, we learnt that strong interdisciplinary skills in communication, organization, coalition building and systems thinking, and technical grasp of best-practices in low- and middle-income countries were important. Furthermore, misaligned agendas of stakeholders, exaggerated by a siloed approach to guideline development, underestimation of the importance of having policy instruments in place and coordination of the processes initially being led outside the health ministry caused delays. Our experience is relevant to other countries interested in developing and implementing guidelines for evidence-based noncommunicable disease services.

Malgré la charge de morbidité croissante des maladies non transmissibles, l'accès à des services décentralisés de qualité pour lutter contre ces maladies reste limité dans de nombreux pays à revenu faible ou intermédiaire. Dans cet article, nous décrivons les stratégies qui ont été employées pour mener les étapes d'adaptation, de validation et de mise en œuvre à l'échelle nationale des Lignes directrices 2016 du Botswana sur les soins de santé primaires pour l'adulte. Ces stratégies ont inclus: une évaluation multiniveau détaillée avec une large implication des parties prenantes et une analyse approfondie des données locales; le recours à des partenariats universitaires; la promotion de l'élaboration d'instruments politiques propices; l'intégration de lignes directrices portant spécifiquement sur les maladies non transmissibles dans les lignes directrices générales sur les soins primaires, en écho à l'orientation stratégique du ministère de la Santé. Au niveau des établissements de santé, les stratégies ont inclus: la création d'un programme de formation multiméthode à destination des prestataires de soins; l'exploitation de l'expérience acquise dans la prise en charge du virus de l'immunodéficience humaine et l'implication des prestataires de soins très tôt dans le processus. Grâce aux stratégies employées, les premières lignes directrices nationales sur les soins de santé primaires ont été validées en 2016, et une étape de mise en œuvre graduelle, sur trois ans, a commencé en août 2017. De plus, la prestation de soins de santé primaires contre les maladies non transmissibles a été incluse dans le 11e plan national de développement du pays (2017-2023). Pendant la phase d'élaboration des lignes directrices, nous avons constaté toute l'importance, dans les pays à revenu faible et intermédiaire, de pouvoir compter sur de solides compétences interdisciplinaires en matière de communication, d'organisation, de création de coalitions et de réflexion systémique et d'obtenir une bonne compréhension technique des meilleures pratiques. Nous avons par ailleurs observé des retards provoqués par des problèmes d'incompatibilité d'agendas entre les différentes parties prenantes, exagérés par des approches cloisonnées lors de la phase d'élaboration des lignes directrices, par la sous-estimation de l'importance d'avoir des outils politiques déjà en place et par des difficultés de coordination des processus initialement pilotés hors du ministère de la Santé. Notre expérience peut être utile pour d'autres pays qui souhaiteraient élaborer et mettre en œuvre des lignes directrices pour des services de soins contre les maladies non transmissibles fondés sur des données probantes.

A pesar de la creciente carga de las enfermedades no transmisibles, el acceso a servicios de calidad descentralizados para estas enfermedades sigue siendo limitado en muchos países de bajos y medianos ingresos. A continuación, describimos las estrategias que empleamos para impulsar el proceso desde la adaptación a la aprobación nacional y la implementación de las directrices de atención primaria de la salud para adultos de Botswana de 2016. Las estrategias incluían una evaluación detallada a varios niveles con amplias aportaciones de las partes interesadas y un análisis a fondo de los datos locales; el aprovechamiento de las asociaciones académicas; la facilidad para elaborar instrumentos normativos de apoyo; la incorporación de directrices sobre las enfermedades no transmisibles en las directrices más amplias sobre la atención primaria de la salud, de conformidad con la dirección estratégica del Ministerio de Salud. A nivel de los centros de salud, las estrategias incluían la elaboración de un programa de capacitación multimétodo para los proveedores de servicios de salud, el aprovechamiento de la experiencia en la prestación de servicios de atención del virus de la inmunodeficiencia humana y la participación de los encargados de la ejecución de los servicios de salud en las primeras etapas del proceso. Gracias a las estrategias empleadas, en 2016 se aprobaron las primeras directrices nacionales de atención primaria de la salud del país y en agosto de 2017 se inició una aplicación por etapas de tres años. Además, la prestación de servicios de atención primaria de la salud para las enfermedades no transmisibles se incluyó en el 11º plan nacional de desarrollo del país (2017-2023). Durante el proceso de desarrollo de las directrices, aprendimos que eran importantes las buenas habilidades interdisciplinarias en comunicación, organización, formación de coaliciones y pensamiento sistémico, así como la comprensión técnica de las mejores prácticas en los países de ingresos bajos y medios. Por otra parte, las agendas desalineadas de las partes interesadas, exageradas por el enfoque aislado del desarrollo de las directrices, la subestimación de la importancia de contar con instrumentos de política y la coordinación de los procesos que inicialmente se llevaban a cabo fuera del ministerio de salud causaron retrasos. Nuestra experiencia es relevante para otros países interesados en desarrollar e implementar directrices para servicios de enfermedades no transmisibles basados en la evidencia.

A Step Toward Timely Referral and Early Diagnosis of Cancer: Implementation and Impact on Knowledge of a Primary Care-Based Training Program in Botswana.

INTRODUCTION: Health system delays in diagnosis of cancer contribute to the glaring disparities in cancer mortality between high-income countries and low- and middle-income countries. In Botswana, approximately 70% of cancers are diagnosed at late stage and median time from first health facility visit for cancer-related symptoms to specialty cancer care was 160 days (IQR 59-653). We describe the implementation and early outcomes of training targeting primary care providers, which is a part of a multi-component implementation study in Kweneng-East district aiming to enhance timely diagnosis of cancers. METHODS: Health-care providers from all public facilities within the district were invited to participate in an 8-h intensive short-course program developed by a multidisciplinary team and adapted to the Botswana health system context. Participants' performance was assessed using a 25-multiple choice question tool, with pre- and post-assessments paired by anonymous identifier. Statistical analysis with Wilcoxon signed-rank test to compare performance at the two time points across eight sub-domains (pathophysiology, epidemiology, social context, symptoms, evaluation, treatment, documentation, follow-up). Linear regression and negative binomial modeling were used to determine change in performance. Participants' satisfaction with the program was measured on a separate survey using a 5-point Likert scale. RESULTS: 176 participants attended the training over 5 days in April 2016. Pooled linear regression controlling for test version showed an overall performance increase of 16.8% after participation (95% CI 15.2-18.4). Statistically significant improvement was observed for seven out of eight subdomains on test A and all eight subdomains on test B. Overall, 71 (40.3%) trainees achieved a score greater than 70% on the pretest, and 161 (91.5%) did so on the posttest. Participants reported a high degree of satisfaction with the training program's content and its relevance to their daily work. CONCLUSION: We describe a successfully implemented primary health care provider-focused training component of an innovative intervention aiming to reduce health systems delays in cancer diagnosis in sub-Saharan Africa. The training achieved district-wide participation, and improvement in the knowledge of primary health-care providers in this setting. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT02752061.

Patellofemoral reconstruction for patellar instability with patella alta in middle-aged patients: Clinical outcomes.

INTRODUCTION: Although several surgical treatments for patellar instability with patella alta have been reported, the clinical outcomes and optimal surgical procedures for patellar instability with patella alta in middle-aged patients are still controversial. We hypothesized that optimal surgical procedures for patellar instability with patella alta in middle-aged patients may induce good clinical outcomes with better patellofemoral geometry. MATERIALS AND METHODS: Twelve middle-aged patients with a mean age of 44 years (range: 40-55 years), who presented with patellar instability and patella alta, were treated with a combination of several surgeries, such as medial patellofemoral ligament (MPFL) reconstruction, trochleoplasty, lateral release, and three-dimensional transfer of the tibial tuberosity, based on a surgical algorithm. Patellar position and clinical outcomes were evaluated postoperatively. The mean follow-up time was 41.5 months (range: 24-72 months). RESULTS: Patellar position altered from 1.31 (1.21-1.53) preoperatively to 0.88 (0.69-1.06) postoperatively on the Caton-Deschamps Index (p<0.01). The tibial tuberosity-trochlear groove (TT-TG) distance altered from 21.8mm (20.1-25.8mm) to 10.3mm (5.1-14.7mm), and patellar tilt ranged from 28.1° (21-40°) to 14.6° (5-28°), respectively (p<0.01). Clinical outcomes on the Lysholm and Kujala scales improved from 43.1 and 38.4 to 86.7 and 78.3, respectively, at final follow-up (p<0.01). Surgical treatment that included trochleoplasty resulted in better outcomes than other surgical combinations without trochleoplasty (p<0.05). Sulcus angle and postoperative patellar tilt improved more in those who underwent trochleoplasty than in those who did not (p<0.05). DISCUSSION: Surgical treatment for patellar instability with patella alta in middle-aged patients resulted in improved clinical outcomes. In particular, a combination surgery including trochleoplasty resulted in the greatest improvement in case of severe trochlear dysplasia. LEVEL OF EVIDENCE: IV. Retrospective case series study.

Pursuing equity in cancer care: implementation, challenges and preliminary findings of a public cancer referral center in rural Rwanda.

BACKGROUND: Cancer services are inaccessible in many low-income countries, and few published examples describe oncology programs within the public sector. In 2011, the Rwanda Ministry of Health (RMOH) established Butaro Cancer Center of Excellence (BCCOE) to expand cancer services nationally. In hopes of informing cancer care delivery in similar settings, we describe program-level experience implementing BCCOE, patient characteristics, and challenges encountered. METHODS: Butaro Cancer Center of Excellence was founded on diverse partnerships that emphasize capacity building. Services available include pathology-based diagnosis, basic imaging, chemotherapy, surgery, referral for radiotherapy, palliative care and socioeconomic access supports. Retrospective review of electronic medical records (EMR) of patients enrolled between July 1, 2012 and June 30, 2014 was conducted, supplemented by manual review of paper charts and programmatic records. RESULTS: In the program's first 2 years, 2326 patients presented for cancer-related care. Of these, 70.5% were female, 4.3% children, and 74.3% on public health insurance. In the first year, 66.3% (n = 1144) were diagnosed with cancer. Leading adult diagnoses were breast, cervical, and skin cancer. Among children, nephroblastoma, acute lymphoblastic leukemia, and Hodgkin lymphoma were predominant. As of June 30, 2013, 95 cancer patients had died. Challenges encountered include documentation gaps and staff shortages. CONCLUSION: Butaro Cancer Center of Excellence demonstrates that complex cancer care can be delivered in the most resource-constrained settings, accessible to vulnerable patients. Key attributes that have made BCCOE possible are: meaningful North-south partnerships, innovative task- and infrastructure-shifting, RMOH leadership, and an equity-driven agenda. Going forward, we will apply our experiences and lessons learned to further strengthen BCCOE, and employ the developed EMR system as a valuable platform to assess long-term clinical outcomes and improve care.

Implementation Science for Global Oncology: The Imperative to Evaluate the Safety and Efficacy of Cancer Care Delivery.

PURPOSE: The development of cancer care treatment facilities in resource-constrained settings represents a challenge for many reasons. Implementation science-the assessment of how services are set up and delivered; contextual factors that affect delivery, treatment safety, toxicity, and efficacy; and where adaptations are needed-is essential if we are to understand the performance of a treatment program, know where the gaps in care exist, and design interventions in care delivery models to improve outcomes for patients. METHODS: The field of implementation science in relation to cancer care delivery is reviewed, and the experiences of the integrated implementation science program at the Butaro Cancer Center of Excellence in Rwanda are described as a practical application. Implementation science of HIV and tuberculosis care delivery in similar challenging settings offers some relevant lessons. RESULTS: Integrating effective implementation science into cancer care in resource-constrained settings presents many challenges, which are discussed. However, with carefully designed programs, it is possible to perform this type of research, on regular and ongoing bases, and to use the results to develop interventions to improve quality of care and patient outcomes and provide evidence for effective replication and scale-up. CONCLUSION: Implementation science is both critical and feasible in evaluating, improving, and supporting effective expansion of cancer care in resource-limited settings. In ideal circumstances, it should be a prospective program, established early in the lifecycle of a new cancer treatment program and should be an integrated and continual process.

Capacity building for oncology programmes in sub-Saharan Africa: the Rwanda experience.

Despite an estimated 456,000 deaths caused by cancer in sub-Saharan Africa in 2012 and a cancer burden that is predicted to double by 2030, the region accounts for only 0·3% of worldwide medical expenditure for cancer. Challenges to cancer care in sub-Saharan Africa include a shortage of clinicians and training programmes, weak healthcare infrastructure, and inadequate supplies. Since 2011, Rwanda has developed a national cancer programme by designing comprehensive, integrated frameworks of care, building local human resource capacity through partnerships, and delivering equitable, rights-based care. In the 2 years since the inauguration of Rwanda's first cancer centre, more than 2500 patients have been enrolled, including patients from every district in Rwanda. Based on Rwanda's national cancer programme development, we suggest principles that could guide other nations in the development of similar cancer programmes.

Rwanda 20 years on: investing in life.

Two decades ago, the genocide against the Tutsis in Rwanda led to the deaths of 1 million people, and the displacement of millions more. Injury and trauma were followed by the effects of a devastated health system and economy. In the years that followed, a new course set by a new government set into motion equity-oriented national policies focusing on social cohesion and people-centred development. Premature mortality rates have fallen precipitously in recent years, and life expectancy has doubled since the mid-1990s. Here we reflect on the lessons learned in rebuilding Rwanda's health sector during the past two decades, as the country now prepares itself to take on new challenges in health-care delivery.

Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE-cadherin.

The use of nanomaterials has raised safety concerns, as their small size facilitates accumulation in and interaction with biological tissues. Here we show that exposure of endothelial cells to TiO2 nanomaterials causes endothelial cell leakiness. This effect is caused by the physical interaction between TiO2 nanomaterials and endothelial cells' adherens junction protein VE-cadherin. As a result, VE-cadherin is phosphorylated at intracellular residues (Y658 and Y731), and the interaction between VE-cadherin and p120 as well as ß-catenin is lost. The resulting signalling cascade promotes actin remodelling, as well as internalization and degradation of VE-cadherin. We show that injections of TiO2 nanomaterials cause leakiness of subcutaneous blood vessels in mice and, in a melanoma-lung metastasis mouse model, increase the number of pulmonary metastases. Our findings uncover a novel non-receptor-mediated mechanism by which nanomaterials trigger intracellular signalling cascades via specific interaction with VE-cadherin, resulting in nanomaterial-induced endothelial cell leakiness.

Bone bonding ability and handling properties of a titania-polymethylmethacrylate (PMMA) composite bioactive bone cement modified with a unique PMMA powder.

One of the challenges of using bioactive bone cements is adjusting their handling properties for clinical application. To resolve the poorer handling properties of bioactive bone cements we developed a novel bioactive bone cement containing a unique polymethylmethacrylate (PMMA) powder, termed SPD-PMMA (40 µm in diameter), composed of cohered minute particles of PMMA (0.5 µm). The present study aimed to examine the mechanical and handling properties and the in vivo bone bonding strength of this cement. The titania content of the cement varied from 10 to 30 wt.% (Ts10, Ts20, and Ts30). The mechanical and thermal properties of Ts10 and Ts20 exceeded those of commercially available PMMA cements (PMMAc). The setting properties of Ts20, including a shorter dough time and a working time that was comparable with that of PMMAc, were adequate for clinical application. Hardened cylindrical cement specimens were inserted into rabbit femurs and the interfacial shear strengths were measured by a push-out test at 6, 12, and 26 weeks after the operation. The interfacial shear strength values (in Newtons per square millimeter) of Ts10, Ts20, and Ts30 at 12 weeks and those of Ts20 and Ts30 at 26 weeks were significantly higher than that of PMMAc (P<0.05). These results show that a bioactive titania-PMMA composite bone cement modified by SPD-PMMA particles possesses adequate mechanical and handling properties, as well as osteoconductivity and in vivo bone bonding ability, and can be used for prosthesis fixation.

Osteoinduction of porous Ti implants with a channel structure fabricated by selective laser melting.

Many studies have shown that certain biomaterials with specific porous structures can induce bone formation in non-osseous sites without the need for osteoinductive biomolecules, however, the mechanisms responsible for this phenomenon (intrinsic osteoinduction of biomaterials) remain unclear. In particular, to our knowledge the type of pore structure suitable for osteoinduction has not been reported in detail. In the present study we investigated the effects of interconnective pore size on osteoinductivity and the bone formation processes during osteoinduction. Selective laser melting was employed to fabricate porous Ti implants (diameter 3.3mm, length 15 mm) with a channel structure comprising four longitudinal square channels, representing pores, of different diagonal widths, 500, 600, 900, and 1200 µm (termed p500, p600, p900, and p1200, respectively). These were then subjected to chemical and heat treatments to induce bioactivity. Significant osteoinduction was observed in p500 and p600, with the highest observed osteoinduction occurring at 5mm from the end of the implants. A distance of 5mm probably provides a favorable balance between blood circulation and fluid movement. Thus, the simple architecture of the implants allowed effective investigation of the influence of the interconnective pore size on osteoinduction, as well as the relationship between bone quantity and its location for different pore sizes.

Bone bonding bioactivity of Ti metal and Ti-Zr-Nb-Ta alloys with Ca ions incorporated on their surfaces by simple chemical and heat treatments.

Ti15Zr4Nb4Ta and Ti29Nb13Ta4.6Zr, which do not contain the potentially cytotoxic elements V and Al, represent a new generation of alloys with improved corrosion resistance, mechanical properties, and cytocompatibility. Recently it has become possible for the apatite forming ability of these alloys to be ascertained by treatment with alkali, CaCl2, heat, and water (ACaHW). In order to confirm the actual in vivo bioactivity of commercially pure titanium (cp-Ti) and these alloys after subjecting them to ACaHW treatment at different temperatures, the bone bonding strength of implants made from these materials was evaluated. The failure load between implant and bone was measured for treated and untreated plates at 4, 8, 16, and 26 weeks after implantation in rabbit tibia. The untreated implants showed almost no bonding, whereas all treated implants showed successful bonding by 4 weeks, and the failure load subsequently increased with time. This suggests that a simple and economical ACaHW treatment could successfully be used to impart bone bonding bioactivity to Ti metal and Ti-Zr-Nb-Ta alloys in vivo. In particular, implants heat treated at 700 °C exhibited significantly greater bone bonding strength, as well as augmented in vitro apatite formation, in comparison with those treated at 600 °C. Thus, with this improved bioactive treatment process these advantageous Ti-Zr-Nb-Ta alloys can serve as useful candidates for orthopedic devices.

Efficacy of computer-assisted pedicle screw insertion for cervical instability in RA patients.

We evaluated the efficacy of the computer-assisted cervical pedicle screw insertion, compared with those inserted without the help of the system on the cervix of rheumatoid arthritis (RA) patients. Eighty-six cervical pedicle screws were inserted without the help of the system. Of the 86, 59 screws were in non-RA patients with degenerative spine, and 27 were in RA patients. The accuracy of the screw insertions was evaluated by a CT-based method. Then, 25 screws were inserted with the system into the cervical spines between C2 and C6 in RA patients (Navigation group). The efficacy of the system was assessed by the CT-based method, compared with 27 screws inserted without the system (Conventional group). The screws in RA patients tended to be more deviated than those in non-RA patients. In Conventional group, four screws (15%) were placed far laterally, and two (7%), far medially. In contrast, no screw was placed far laterally or medially in Navigation group (P < 0.05).

Bone-bonding ability of a hydroxyapatite coated zirconia-alumina nanocomposite with a microporous surface.

Using a combination of hydroxyapatite (HA) coating and microporous surface treatment, bone-bonding ability was given to composites of ceria-stabilized tetragonal zirconia and alumina (CZA), which possesses excellent mechanical and wear properties and phase stability. Four types of CZA plates (2 x 10 x 15 mm3) were prepared for this study, which were CZA with a polished surface (group 1), a microporous surface prepared by hydrofluoric acid and heat treatment (group 2), a microporous surface with a submicron HA coating prepared by alternately soaking the plate from group 2 in aqueous CaCl2/HCl and Na2HPO4 solutions (group 3), and a microporous surface with a 4-microm HA coating prepared by the biomimetic method, where the plates from group 3 were soaked in simulated body fluid (group 4). Plates were implanted into rabbit tibia, and after 4, 8, and 16 weeks, tensile testing and histological examination of the bone-implant interface were conducted. At 4 weeks, group 4 had superior bone-bonding ability compared with other implants, which was maintained at the later postimplantation times. This HA-coated CZA with a microporous surface has the possibility of clinical use as a bearing material in cementless joint prostheses or as a load-bearing bone substitute.