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In this study, we present confocal Raman microscopy for chemically selective analysis of a human buccal epithelial cell layer with a focus on label-free visualization of particle uptake into the cells. We demonstrate the suitability and benefit of this analytical technique in comparison to confocal fluorescence microscopy for three dimensional imaging of in vitro cell models. [ABSTRACT FROM AUTHOR]

— Aims: The frequency of the Taq I A alleles (A1 and A2) of the D2 dopamine receptor (DRD2) gene was examined in Caucasian post-traumatic stress disorder (PTSD) patients and controls. Results: In 91 PTSD patients, the frequency of the A1 allele was higher (P = 6.12 × 10−3) than in the 51 controls. In the 38 PTSD harmful drinkers (≥60 g alcohol/day), A1 allelic frequency was higher (P = 3.91 × 10−2) than in the 53 non-harmful drinkers (<60 g alcohol/day), the former being also higher (P = 3.76 × 10−4) than in controls. However, there was no difference between non-harmful drinkers and controls. Based on DRD2 allelic association, the 35 PTSD patients with the A1+ (A1A1, A1A2) allele consumed more than twice the daily amount of alcohol than the 56 patients with the A1− (A2A2) allele (P = 1.94 × 10−3). When the hourly rate of alcohol consumed was compared, A1+ allelic patients consumed twice the rate of the A1− allelic patients (P < 10−7). Conclusion: The DRD2 A1 allele was associated with PTSD. However, this association was found only in the harmful drinkers. PTSD patients with the A1+ allele consumed more alcohol than patients with the A1− allele. The importance of determining alcohol consumption in DRD2 association studies with PTSD is suggested. [ABSTRACT FROM PUBLISHER]

Tuberculosis (TB) and depression is common and is associated with poor TB outcomes. The World Health Organization End TB Strategy explicitly calls for the integration of TB and mental health services. Interpersonal Counseling (IPC) is a brief evidence-based treatment for depression that can be delivered by non-mental health specialists with expert supervision. The goal of this study was to explore potential barriers and facilitators to training non-specialist providers to deliver IPC within the TB Control Program and primary care in Itaboraí, Rio de Janeiro state. Data collection consisted of six focus groups (n = 42) with health professionals (n = 29), program coordinators (n = 7), and persons with TB (n = 6). We used open coding to analyze the data, followed by deductive coding using the Chaudoir multi-level framework for implementation outcomes. The main structural barriers identified were poverty, limited access to treatment, political instability, violence, and social stigma. Organizational barriers included an overburdened and under-resourced health system with high staff turnover. Despite high levels of stress and burnout among health professionals, several provider-level facilitators emerged including a high receptivity to, and demand for, mental health training; strong community relationships through the community health workers; and overall acceptance of IPC delivered by any type of health provider. Patients were also receptive to IPC being delivered by any type of professional. No intervention-specific barriers or facilitators were identified. Despite many challenges, integrating depression treatment into primary care in Itaboraí using IPC was perceived as acceptable, feasible, and desirable.

Background: A central challenge to closing the mental health treatment gap in low- and middle-income countries (LMICs) is determining the most effective pathway for delivering evidence-based mental health services. We are conducting a cluster-randomized, Type 2 hybrid implementation-effectiveness trial across 20 districts of Mozambique called the Partnerships in Research to Implement and Disseminate Sustainable and Scalable EBPs (PRIDE) program. Following training of nonspecialized providers in facilitation of evidence-based treatments for mental health and informed by the Consolidated Framework for Implementation Research (CFIR), we identified how PRIDE compares to care as usual and the perceived barriers and facilitators of implementation and modifications needed for widescale service delivery and scale-up., Methods: We conducted rapid ethnographic assessment using freelisting among 34 providers, followed by four focus group discussions (n = 29 participants) with a subsample of psychiatric technicians and primary care providers from 14 districts in Nampula Province. We used Thematic Analysis to inductively apply open codes to transcripts and then deductively applied the CFIR domains and constructs to organize open codes., Results: The main Outer Setting constructs relevant to implementation were recognition that patient mental health needs were significant. Additionally, numerous community-level characteristics were identified as barriers, including distance between clinics; shortage of providers; and low awareness of mental health problems, stigma, and discrimination among community members towards those with mental health struggles. The PRIDE program was perceived to offer a relative advantage over usual care because of its use of task-sharing and treating mental illness in the community. PRIDE addressed Inner Setting barriers of having available resources and training and provider low self-efficacy and limited knowledge of mental illness. Providers recommended leadership engagement to give support for supervision of other task-shared professionals delivering mental healthcare., Conclusions: Primary care providers and psychiatric technicians in Mozambique perceived the relative advantage of the PRIDE program to address mental health treatment access barriers and offered recommendations for successful sustainment and scale up of integrated mental health care., (© 2024. The Author(s).)

Pediatric tumors of the central nervous system are the most common cause of cancer-related death in children. The five-year survival rate for high-grade gliomas in children is less than 20%. Due to their rarity, the diagnosis of these entities is often delayed, their treatment is mainly based on historic treatment concepts, and clinical trials require multi-institutional collaborations. The MICCAI Brain Tumor Segmentation (BraTS) Challenge is a landmark community benchmark event with a successful history of 12 years of resource creation for the segmentation and analysis of adult glioma. Here we present the CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs 2023 challenge, which represents the first BraTS challenge focused on pediatric brain tumors with data acquired across multiple international consortia dedicated to pediatric neuro-oncology and clinical trials. The BraTS-PEDs 2023 challenge focuses on benchmarking the development of volumentric segmentation algorithms for pediatric brain glioma through standardized quantitative performance evaluation metrics utilized across the BraTS 2023 cluster of challenges. Models gaining knowledge from the BraTS-PEDs multi-parametric structural MRI (mpMRI) training data will be evaluated on separate validation and unseen test mpMRI dataof high-grade pediatric glioma. The CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs 2023 challenge brings together clinicians and AI/imaging scientists to lead to faster development of automated segmentation techniques that could benefit clinical trials, and ultimately the care of children with brain tumors.

Malaria is endemic in Guinea; however, the extent and role in transmission of asymptomatic malaria are not well understood. In May 2023, we conducted a rapid community survey to determine Plasmodium falciparum ( P. falciparum ) prevalence among asymptomatic individuals in Middle Guinea (Prefecture Dalaba) and Forest Guinea (Prefecture Guéckédou). In Dalaba, 6 of 239 (2.1%, confidence interval (CI) 0.9-4.8%) individuals tested positive for P. falciparum by a rapid diagnostic test (RDT), while in Guéckédou, 147 of 235 (60.9%, CI 54.5-66.9%) participants tested positive. Asymptomatic malaria needs to be considered more strongly as a driver of transmission when designing control strategies, especially in Forest Guinea and potentially other hyper-endemic settings.

Exposure to intimate partner violence (IPV) incurs significant public health consequences. Understanding risk markers can accelerate prevention and response efforts, important in settings like Sub-Saharan Africa (SSA) where resources are scarce. In this study, four databases were searched to identify studies that examined risk markers for male-to-female physical IPV. With application of the socioecological model, we analyzed 11 risk markers for male physical IPV perpetration (with 71 effect sizes) and 16 risk markers for female physical IPV victimization (with 131 effect sizes) in SSA from 51 studies. For male IPV perpetration, we found medium-to-large effect sizes for six risk markers: perpetrating emotional abuse and sexual IPV, witnessing parental IPV, being abused as a child, cohabitating (not married), and exhibiting controlling behaviors. We found small effect sizes for substance use. Employment, age, marital status, and education were not significant risk markers. For female IPV victimization, a medium effect size was found for post-traumatic stress symptoms. Small effect sizes were found for reporting depressive symptoms, being abused as a child, witnessing parental IPV, and reporting drug and alcohol use. Rural residence, approval of violence, length of relationship, income, education, employment, age, marital status, and religiosity were not significant risk markers. Findings highlight opportunities for screening and intervention at the couple level, show the need to test and incorporate interventions for IPV in mental health treatment, and emphasize the importance of further research on sociodemographic risk markers and the interventions that target them., Competing Interests: Declarations of Conflicts of InterestThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The burden of depression and anxiety disorders is high in sub-Saharan Africa, especially for people with HIV (PWH). The Patient Health Questionnaire-4 (PHQ-4) and Electronic Mental Wellness Tool-3 (E-mwTool-3) are ultra-brief screening tools for these disorders. We compared the performance of PHQ-4 and E-mwTool-3 for screening MINI-International Neuropsychiatric Interview diagnoses of depression and anxiety among a sample of individuals with and without HIV in two primary care clinics and one general hospital in Maputo City, Mozambique. Areas-under-the-curve (AUC) were calculated along with sensitivities and specificities at a range of cutoffs. For PWH, at a sum score cutoff of ≥ 1, sensitivities were strong: PHQ-4:Depression = 0.843; PHQ-4:Anxiety = 0.786; E-mwTool-3:Depression = 0.843; E-mwTool-3:Anxiety = 0.929. E-mwTool-3 performance was comparable to PHQ-4 among people with and without HIV., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Alternative cancer therapy is associated with increased mortality, but little is known about those who pursue it., Objective: We aimed to describe individuals' motivations for using alternative cancer therapies and determine whether motivations differ based on individuals' timing of seeking alternative therapies., Methods: We used data from 649 campaigns posted on the website GoFundMe between 2011 and 2019 for beneficiaries with cancer pursuing alternative therapy. The data were analyzed using a mixed methods approach. Campaigns were categorized by timing of alternative therapy (either before or after experiencing conventional therapy). Qualitative analysis identified motivational themes. Chi-square tests of independence and Fisher tests (all 2-sided) determined significant differences in the presence of motivational themes between groups., Results: The expression of concerns about the efficacy of conventional therapy was significantly more likely in campaigns for individuals who used conventional therapy first than in campaigns for individuals who started with alternative therapy (63.3% vs 41.7%; P<.001). Moreover, on comparing those who started with alternative therapy and those who switched from conventional to alternative therapy, those who started with alternative therapy more often expressed natural and holistic values (49.3% vs 27.0%; P<.001), expressed an unorthodox understanding of cancer (25.5% vs 16.4%; P=.004), referenced religious or spiritual beliefs (15.1% vs 8.9%; P=.01), perceived alternative treatment as efficacious (19.1% vs 10.2%; P=.001), and distrusted pharmaceutical companies (3.2% vs 0.5%; P=.04)., Conclusions: Individuals sought treatments that reflected their values and beliefs, even if scientifically unfounded. Many individuals who reported prior conventional cancer therapy were motivated to pursue alternative treatments because they perceived the conventional treatments to be ineffective., (©John Peterson, Trevor Wilson, Joshua Gruhl, Sydney Davis, Jaxon Olsen, Matthew Parsons, Benjamin Kann, Angela Fagerlin, Melissa Watt, Skyler Johnson. Originally published in JMIR Cancer (https://cancer.jmir.org), 07.06.2022.)

Psychiatric disorders are the number one cause of disability in adolescents worldwide. Yet, in low- and middle-income countries (LMIC), where 90% of adolescents reside, mental health services are extremely limited, and the majority do not have access to treatment. Integration of mental health services within primary care of LMICs has been proposed as an efficient and sustainable way to close the adolescent mental health treatment gap. However, there is limited research on how to effectively implement integrated mental health care in LMIC. In the present study, we employed Implementation Mapping to develop a multilevel strategy for integrating adolescent depression services within primary care clinics of Maputo, Mozambique. Both in-person and virtual approaches for Implementation Mapping activities were used to support an international implementation planning partnership and promote the engagement of multilevel stakeholders. We identified determinants to implementation of mental health services for adolescents in LMIC across all levels of the Consolidated Framework for Implementation Research, of which of 25% were unique to adolescent-specific services. Through a series of stakeholder workshops focused on implementation strategy selection, prioritization, and specification, we then developed an implementation plan comprising 33 unique strategies that target determinants at the intervention, patient, provider, policy, and community levels. The implementation plan developed in this study will be evaluated for delivering adolescent depression services in Mozambican primary care and may serve as a model for other low-resource settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lovero, dos Santos, Adam, Bila, Fernandes, Kann, Rodrigues, Jumbe, Duarte, Beidas and Wainberg.)

Introduction: Unhealthy alcohol use (UAU) is a major public health challenge, particularly in low- and middle-income countries. Mozambique is the fourth poorest country in the world where half of the population lives below the poverty line. UAU is frequent among drinkers in Mozambique; however, resources and infrastructure to treat UAU are very limited. This paper examines how task-shifting and a provider-facing mobile health application are being used to improve access to care. In this paper, the feasibility, acceptability and appropriateness of a provider-facing mobile health application being used under a task-shifting model to identify UAU and provide a four-session brief motivational interviewing intervention are described., Method: The study used a sequential exploratory mixed-methods design with a QUAL → quan structure. First, 15 psychiatric technicians and primary care providers in Mozambique's Nampula Province participated in semi-structured interviews. These interviews were recorded and transcribed. Then, 45 providers completed a 12-item quantitative survey on tablets. Quantitative analysis used descriptive statistic calculation and qualitative analysis used thematic analysis., Results: Nonspecialized providers found the mobile health app to be acceptable, appropriate, and feasible when delivering a 4-session brief motivational intervention under a task-shifting model. Central benefits of the technology were enhanced standardization and efficiency of sessions as well as feelings of legitimacy when interacting with patients. Main concerns were feasibility of implementing the intervention due to time constraints of workload and internet connectivity issues., Conclusions: Provider-facing technology shows promise in supporting task-shifting models that can expand alcohol intervention services and increase access to care in low- and middle-income countries. Providers without specialized training in behavioral health interventions can provide critical services to patients with UAU and provider-facing mobile health applications may help bring such models to scale., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Armed conflict and the HIV pandemic are significant global health issues. Evidence of the association between armed conflict and HIV infection has been conflicting. Our objective was to examine the role of mediating risk factors, such as engagement in transactional sex work, to elucidate the relation between armed conflict and HIV infection., Methods: We used multistage sampling across three Northeastern Ugandan districts to randomly select 605 women aged 13 to 49 to answer cross-sectional surveys from January to May of 2016. We used multivariate logistic regression model with R 4.0.3 to examine if exposure to armed conflict has an indirect effect on reporting having an HIV-positive serostatus through engagement in transactional sex work. Age and district residence were included as covariates., Results: Exposure to armed conflict β = .16, SE = .04, p < .05, OR = 1.17, 95% [CI .08, .23] was significantly associated with reporting a HIV-positive serostatus. For each 1-unit increase in exposure to armed conflict (i.e., additional type of armed conflict exposure), there was a 17% increase in the odds of reporting a HIV-positive serostatus. Engagement in transactional sex work was not associated with reporting a HIV-positive serostatus β = .04, SE = .05, p = .37, 95% [CI - .051, .138]. We found district of residence, age, and interaction effects., Conclusions: Although exposure to armed was associated with reporting an HIV-positive serostatus, this relationship was not mediated by engagement in transactional sex. Further research is needed on risk factors that mediate this relationship. The likelihood of reporting a HIV-positive serostatus increased with each additional type of exposure to armed conflict. Thus, screening for exposure to multiple traumatic stressors should occur in HIV prevention settings. Healthcare services that are trauma-informed and consider mental distress would likely improve HIV outcomes., (© 2022. The Author(s).)

Clinical informatics is a young, diverse and rapidly growing field. We asked eight clinical informaticians from a variety of oncology specialties, training pathways and careers for personal narratives to illustrate the wide spectrum of clinical informatics careers. Primary clinical specialties included radiation oncology, medical/haematology oncology and palliative care. Training pathways included fellowship, non-fellowship formal training and informal training. Careers included clinical care, research, operations and industry. We summarised common themes and advice for trainees. We hope to raise awareness of clinical informatics among trainees and oncologists to reveal new career opportunities and to avoid inadvertently taking clinical informatics and informaticians for granted., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objective: To report the interim results from the training of providers inevidence-based psychotherapies (EBPs) and use of mobile applications., Design and Setting: The Partnerships in Research to Implement and Disseminate Sustainable and Scalable Evidence (PRIDE) study is a cluster-randomised hybrid effectiveness-implementation trial comparing three delivery pathways for integrating comprehensive mental healthcare into primary care in Mozambique. Innovations include the use of EBPs and scaling-up of task-shifted mental health services using mobile applications., Main Outcome Measures: We examined EBP training attendance, certification, knowledge and intentions to deliver each component. We collected qualitative data through rapid ethnography and focus groups. We tracked the use of the mobile applications to investigate early reach of a valid screening tool (Electronic Mental Wellness Tool) and the roll out of the EBPs PARTICIPANTS: Psychiatric technicians and primary care providers trained in the EBPs., Results: PRIDE has trained 110 EBP providers, supervisors and trainers and will train 279 community health workers in upcoming months. The trainings improved knowledge about the EBPs and trainees indicated strong intentions to deliver the EBP core components. Trained providers began using the mobile applications and appear to identify cases and provide appropriate treatment., Conclusions: The future of EBPs requires implementation within existing systems of care with fidelity to their core evidence-based components. To sustainably address the vast mental health treatment gap globally, EBP implementation demands: expanding the mental health workforce by training existing human resources; sequential use of EBPs to comprehensively treat mental disorders and their comorbid presentations and leveraging digital screening and treatment applications., Competing Interests: Competing interests: MAO receives royalties from the Research Foundation for Mental Hygiene for the commercial use of the Columbia Suicide Severity Rating Scale and owns shares in Mantra, Inc. She serves as an advisor to Alkermes and Fundacion Jimenez Diaz (Madrid). Her family owns stock in Bristol Myers Squibb.MMW receives royalties from Multi-Health Systems Inc. for use of the Social Adjustment Scale-Self-Report (SAS-SR) as well as book royalties from Perseus Press, Oxford Press, and APA Publishing. Additionally, MMW has received research funding from the Brain and Behavior Foundation, Templeton Foundation and the Sackler Foundation., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Artificial intelligence (AI) has the potential to fundamentally alter the way medicine is practised. AI platforms excel in recognizing complex patterns in medical data and provide a quantitative, rather than purely qualitative, assessment of clinical conditions. Accordingly, AI could have particularly transformative applications in radiation oncology given the multifaceted and highly technical nature of this field of medicine with a heavy reliance on digital data processing and computer software. Indeed, AI has the potential to improve the accuracy, precision, efficiency and overall quality of radiation therapy for patients with cancer. In this Perspective, we first provide a general description of AI methods, followed by a high-level overview of the radiation therapy workflow with discussion of the implications that AI is likely to have on each step of this process. Finally, we describe the challenges associated with the clinical development and implementation of AI platforms in radiation oncology and provide our perspective on how these platforms might change the roles of radiotherapy medical professionals.

Objective: To analyze potential benefits with regards to infectious complications with combined use of mechanical bowel preparation (MBP) and ABP in elective colorectal resections., Background: Despite recent literature suggesting that MBP does not reduce infection rate, it still is commonly used. The use of oral antibiotic bowel preparation (ABP) has been practiced for decades but its use is also controversial., Methods: Patients undergoing elective colorectal resection in the 2012 to 2015 American College of Surgeons National Surgical Quality Improvement Program cohorts were selected. Doubly robust propensity score-adjusted multivariable regression was conducted for infectious and other postoperative complications., Results: A total of 27,804 subjects were analyzed; 5471 (23.46%) received no preparation, 7617 (32.67%) received MBP only, 1374 (5.89%) received ABP only, and 8855 (37.98%) received both preparations. Compared to patients receiving no preparation, those receiving dual preparation had less surgical site infection (SSI) [odds ratio (OR) = 0.39, P < 0.001], organ space infection (OR = 0.56, P ≤ 0.001), wound dehiscence (OR = 0.43, P = 0.001), and anastomotic leak (OR = 0.53, P < 0.001). ABP alone compared to no prep resulted in significantly lower rates of surgical site infection (OR = 0.63, P = 0.001), organ space infection (OR = 0.59, P = 0.005), anastomotic leak (OR = 0.53, P = 0.002). MBP showed no significant benefit to infectious complications when used as monotherapy., Conclusions: Combined MBP/ABP results in significantly lower rates of SSI, organ space infection, wound dehiscence, and anastomotic leak than no preparation and a lower rate of SSI than ABP alone. Combined bowel preparation significantly reduces the rates of infectious complications in colon and rectal procedures without increased risk of Clostridium difficile infection. For patients undergoing elective colon or rectal resection we recommend bowel preparation with both mechanical agents and oral antibiotics whenever feasible.

Increased molecular understanding of multifactorial diseases paves the way for novel therapeutic approaches requiring sophisticated carriers for intracellular delivery of actives. We designed and characterized self-assembling lipid-core nanocapsules for coencapsulation of two poorly soluble natural polyphenols curcumin and resveratrol. The polyphenols were identified as high-potential therapeutic candidates intervening in the intracellular inflammation cascade of chondrocytes during the progress of osteoarthritis. To elucidate the interplay between chondrocytes and nanocapsules and their therapeutic effect, we pursued a complementary analytical approach combining label-free visualization with biological assays. Primary human chondrocytes did not show any adverse effects upon nanocapsule application and coherent anti-Stokes Raman scattering images visualized their intracellular uptake. Further, by systematically blocking different uptake mechanisms, an energy independent uptake into the cells could be identified. Additionally, we tested the therapeutic effect of the polyphenol-loaded carriers on inflamed chondrocytes. Treatment with nanocapsules resulted in a major reduction of nitric oxide levels, a well-known apoptosis trigger during the course of osteoarthritis. For a more profound examination of this protective effect on joint cells, we pursued studies with atomic force microscopy investigations. Significant changes in the cell cytoskeleton as well as prominent dents in the cell membrane upon induced apoptosis were revealed. Interestingly, these effects could not be detected for chondrocytes which were pretreated with the nanocapsules. Overall, besides presenting a sophisticated carrier system for joint application, these results highlight the necessity of establishing combinatorial analytical approaches to elucidate cellular uptake, the interplay of codelivered drugs and their therapeutic effect on the subcellular level.

Polyphenols, which are secondary plant metabolites, gain increasing research interest due to their therapeutic potential. Among them, resveratrol and curcumin are two agents showing antioxidant, anti-inflammatory, antimicrobial as well as anticarcinogenic effects. In addition to their individual therapeutic effect, increased activity was reported upon co-delivery of the two compounds. However, due to the poor water solubility of resveratrol and curcumin, their clinical application is currently limited. In this context, lipid-core nanocapsules (LNC) composed of an oily core surrounded by a polymeric shell were introduced as drug carrier systems with the potential to overcome this obstacle. Furthermore, the encapsulation of polyphenols into LNC can increase their photostability. As the attributes of the polyphenols make them excellent candidates for skin treatment, the aim of this study was to investigate the effect of co-delivery of resveratrol and curcumin by LNC upon topical application on excised human skin. In contrast to the formulation with one polyphenol, resveratrol penetrated into deeper skin layers when the co-formulation was applied. Based on vibrational spectroscopy analysis, these effects are most likely due to interactions of curcumin and the stratum corneum, facilitating the skin absorption of the co-administered resveratrol. Furthermore, the interaction of LNC with primary human skin cells was analyzed encountering a cellular uptake within 24h potentially leading to intracellular effects of the polyphenols. Thus, the simultaneous delivery of resveratrol and curcumin by LNC provides an intelligent way for immediate and sustained polyphenol delivery for skin disease treatment., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Progress in advanced therapeutic concepts requires the development of appropriate carrier systems for intracellular drug delivery. Consequently, analysis of interaction between carriers, drugs and cells as well as their uptake and intracellular fate is a current focus of research interest. In this context, Raman spectroscopy recently became an emerging analytical technique, due to its non-destructive, chemically selective and label-free working principle. In this review, we briefly present the state-of-the-art technologies for cell visualization and drug internalization. Against this background, Raman microscopy is introduced as a versatile analytical technique. An overview of various Raman spectroscopy investigations in this field is given including interactions of cells with drug molecules, carrier systems and other nanomaterials. Further, Raman instrumentations and sample preparation methods are discussed. Finally, as the analytical limit is not reached yet, a future perspective for Raman microscopy in pharmaceutical and biomedical research on the single cell level is given., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: Overall treatment package time (from surgery to radiotherapy [RT] completion) > 100 days can portend poor outcomes in head and neck cancer. Faster postoperative recovery seen with transoral robotic surgery may decrease treatment duration and toxicity for adjuvant RT and chemoradiation., Methods: We retrospectively reviewed all patients treated with transoral robotic surgery (n = 124) and adjuvant RT and chemoradiation (n = 33) at our institution for head and neck cancer from April 2007 to December 2011 to determine treatment duration, acute toxicity, and long-term percutaneous gastric tube rates., Results: The median overall treatment time was 86 days and from surgery to RT start was 41 days; median RT duration was 44 days. No wound breakdown or infection occurred during or after RT. Two-year actuarial locoregional control, distant metastasis-free survival, and overall survival rates were 93%, 96%, and 97%, respectively., Conclusions: Adjuvant RT after transoral robotic surgery for head and neck cancer can be completed safely and in a timely fashion. Longer follow-up and a larger cohort will be needed to determine if this regimen is more effective than traditional surgery followed by adjuvant RT., (© The Author(s) 2014.)

Aim of this study was to implement a modified phospholipid vesicle-based permeation assay (PVPA) barrier as alternative to Caco-2 cell monolayers in a combined dissolution and permeation system for testing of solid dosage forms. Commercially available Transwell® inserts were coated with egg phospholipids (Lipoid E 80) and characterized by confocal Raman microscopy. The modified PVPA barrier was then evaluated in permeation studies with solutions of different drugs as well as in combined dissolution and permeation studies utilizing an immediate and an extended release tablet formulation. Raman cross section images demonstrated complete filling of the membrane pores with lipids and the formation of a continuous lipid layer of increasing thickness on top of the membrane during the stepwise coating procedure. Furthermore, it could be shown that this lipid coating remains intact for at least 18h under dynamic flow conditions, significantly exceeding the viability of Caco-2 cell monolayers. Permeability data for both drug solutions as well as for a fast and slow release tablet formulation were in excellent correlation with those data obtained for Caco-2 cell monolayers. Especially under the dynamic flow conditions prevailing in such a setup, the modified PVPA barrier is more robust and easier to handle than epithelial cell monolayers and can be prepared rather easily at a fraction of costs and time. The modified PVPA barrier may therefore represent a valuable alternative to Caco-2 cell monolayers in such context., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Drying is a common pharmaceutical process, whose potential to alter the final drug properties-even at relatively low temperatures-is often neglected. The present study addresses the impact of drying at 20 and 50 °C on wet-extruded calcium stearate (CaSt) pellets. Drying at 20 °C caused the majority of ibuprofen to accumulate at the pellet surface due to a strong convective flow from the pellet's center to the surface. In contrast, pellets dried at 50 °C still contained ibuprofen in the pellet's interior due to the higher drying rate and the associated film breakage during drying. Moreover, the higher drying temperature caused CaSt to form a second lamellar phase and ibuprofen to convert (partly) into its amorphous state. Overall, the drying process affected the solid state and the spatial ibuprofen distribution within the pellet. Knowledge of these effects can aid in tailoring advanced multipellet formulations.

The development of an academic surgical career can be an overwhelming prospect, and one that is not intuitive. Establishing a structured plan and support structure is critical to success. Starting a successful academic surgical career begins with defining one's academic goals within several broad categories: personal goals, academic goals, research goals, educational goals, and financial goals. Learning the art of self-promotion is the means by which many of these goals are achieved. It is important to realize that achieving these goals requires a delicate personal balance between work and home life, and the key ways in which to achieve success require establishment of well thought-out goals, a reliable support structure, realistic and clear expectations, and frequent re-evaluation.

Embedding a poorly water-soluble drug as a solid dispersion in a hydrophilic carrier by cogrinding is a possible strategy for enhancing the drug dissolution rate. Although general interest in continuous processes for manufacturing drug formulations has increased, many publications still focus on batch processes. The jet mill used in this study is a promising tool for continuous cogrinding. Investigation of different drug-to-carrier ratios (griseofulvin/mannitol) demonstrated that a drug load of 10% is best suited to investigate the enhanced dissolution behavior. To gain deeper insight into the underlying mechanisms, the coground dispersion is compared with different physical mixtures in terms of physicochemical properties and dissolution behavior. Differential scanning calorimetry and X-ray powder diffraction were used to verify the crystalline structure of the coground formulation. On the basis of the Hixson-Crowell model, particle size reduction was ruled out as the main reason for dissolution enhancement. An increase of surface free energies because of grinding is shown with contact angle measurements. Confocal Raman microscopy investigations revealed the drug's bulk dispersity in the coground formulation as an additional factor for the increased dissolution rate. In conclusion, the continuous cogrinding approach is a promising technique to prepare the drug in a rapidly dissolving, yet crystalline, form., (© 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Drying is a common pharmaceutical process, whose potential to modify the final drug and/or dosage form properties is often underestimated. In the present study, pellets consisting of the matrix former calcium stearate (CaSt) incorporating the active pharmaceutical ingredient ibuprofen were prepared via wet extrusion and spheronization. Subsequent drying was performed by either desiccation, fluid-bed drying, or lyophilization, and the final pellets were compared with respect to their microstructure. To minimize the effect of solute ibuprofen molecules on the shrinking behavior of the CaSt, low ibuprofen loadings were used, as ibuprofen is soluble in the granulation liquid. Pellet porosity and specific surface area increased during desiccation, fluid-bed drying, and lyophilization. The inlet-air temperature during fluid-bed drying affected the specific surface area, which increased at lower inlet-air temperatures rather than the pellet porosity. The in vitro dissolution profiles were found to be a nonlinear function of the specific surface area. Overall, the microstructure, including porosity, pore size, and specific surface area, of CaSt pellets was a strong function of the drying conditions., (© 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Confocal Raman microscopy is an analytical technique with a steadily increasing impact in the field of pharmaceutics as the instrumental setup allows for nondestructive visualization of component distribution within drug delivery systems. Here, the attention is mainly focused on classic solid carrier systems like tablets, pellets, or extrudates. Due to the opacity of these systems, Raman analysis is restricted either to exterior surfaces or cross sections. As Raman spectra are only recorded from one focal plane at a time, the sample is usually altered to create a smooth and even surface. However, this manipulation can lead to misinterpretation of the analytical results. Here, we present a trendsetting approach to overcome these analytical pitfalls with a combination of confocal Raman microscopy and optical profilometry. By acquiring a topography profile of the sample area of interest prior to Raman spectroscopy, the profile height information allowed to level the focal plane to the sample surface for each spectrum acquisition. We first demonstrated the basic principle of this complementary approach in a case study using a tilted silica wafer. In a second step, we successfully adapted the two techniques to investigate an extrudate and a lyophilisate as two exemplary solid drug carrier systems. Component distribution analysis with the novel analytical approach was neither hampered by the curvature of the cylindrical extrudate nor the highly structured surface of the lyophilisate. Therefore, the combined analytical approach bears a great potential to be implemented in diversified fields of pharmaceutical sciences.

Introduction: Work rules have changed medical education. Knowledge previously acquired by experience must now be actively taught to avoid prolonging the training period. We report the feasibility of and clinical clerk opinions regarding a novel simulated floor management course to teach patient care concepts required on the surgical wards., Methods: We created a hospital ward with simulators exhibiting physical exam findings and active vital signs. Surgical clerks gathered data during "morning rounds," wrote notes, and provided care. An acute event allowed students to participate in active evaluation and treatment. Findings and plans were communicated to their "chief resident," a surgical attending. We distributed a survey to participants to determine attitudes and opinions about the course., Results: The course required five faculty, two medical educators, four surgical house staff, and 2.5 h to accommodate 40-50 students. Faculty and surgical house staff provided guidance and feedback on clinical skills. Fifty students completed the survey (56% response rate). Most clinical clerks thought that the simulated floor management course improved their understanding of medical management of surgical issues (66%) and their documentation skills (78%). Clinical clerks reported that attending involvement made the experience more valuable (89%) and was not intimidating (66%). Most expressed an interest in participating in more clinical scenarios (72%)., Conclusions: A simulation course for teaching patient care concepts is feasible and regarded positively by clinical clerk participants. Further development and use of such simulated patient care exercises may be an effective adjunct for training future house staff and hospital staff in patient care in a time of shifting work hour paradigms., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Nanoparticle applications in medicine have seen a tremendous growth in the past decade. In addition to their drug targeting application and their ability to improve bioavailability of drugs, nanoparticles can be designed to allow their detection with a variety of imaging methodologies. In the current study, we developed a multimodal nanoparticle platform to enable imaging guided therapy, which was evaluated in a colon cancer mouse model. This "theranostic" platform is based on oil-in-water nanoemulsions and carries iron oxide nanocrystals for MRI, the fluorescent dye Cy7 for NIRF imaging, and the hydrophobic glucocorticoid prednisolone acetate valerate (PAV) for therapeutic purposes. Angiogenesis-targeted nanoemulsions functionalized with αvβ(3)-specific RGD peptides were evaluated, as well. When subcutaneous tumors were palpable, the nanoemulsions were administered at a dose of 30 mg of FeO/kg and 10 mg of PAV/kg. MRI and NIRF imaging showed significant nanoparticle accumulation in the tumors, while tumor growth profiles revealed a potent inhibitory effect in all of the PAV nanoemulsion-treated animals as compared to the ones treated with control nanoemulsions, the free drug, or saline. This study demonstrated that our nanoemulsions, when loaded with PAV, iron oxide nanocrystals, and Cy7, represent a flexible and unique theranostic nanoparticle platform that can be applied for imaging guided therapy of cancer.

Various methods have been employed to reconstruct complex abdominal wall defects. Structural prosthetic materials such as polypropylene mesh and ePTFE (expanded polytetrafluoroethylene) have been widely used to close these large fascial defects, however, complications with infection and adhesions have led to the recent use of more biocompatible implants. Permacol (acellular porcine dermis) is used as a dermal scaffold, which eventually becomes vascularised and remodelled to reconstruct the abdominal wall in these complex patients. A retrospective review was performed of all patients who underwent consecutive abdominal wall reconstruction with Permacol at our institution in the year 2006. Twenty-eight patients were identified and included in our study. Factors evaluated were: body mass index, relevant co-morbidities, aetiology of hernia, hernia defect size based on CT scan and intraoperative measurement, size of Permacol implant, length of hospital stay, and postoperative complications. Surgical technique was standardised among six surgeons and involved a single layer of acellular porcine dermis as a subfascial 'underlay' graft under moderate tension upon maximal hernia reduction. Tissue expanders were not required for skin closure. Out of 28 patients, 12 were male and 16 were female. Mean intraoperative hernia size was 150 cm(2) (range of 10 cm(2) to 600 cm(2)). Mean age was 55 years with an average body mass index (BMI) of 34 (largest BMI of 61.4). Defects were attributed to either a previous laparotomy incision or open abdomen. Mean hospital stay was 9.67 days. At a mean follow-up of sixteen months, there were three recurrent hernias (10.7%) based on physical examination and postoperative CT scan evaluation. One patient developed a superficial wound dehiscence which was successfully treated with local wound care and one patient developed a cellulitis which was successfully treated with antibiotic therapy. Four patients (14.3%) developed a chronic, non-infected fluid collection lasting >one month all of which resolved. No patient required removal of the implant due to infection. Permacol can be successfully used in the reconstruction of both small and large ventral hernias. This biodegradable matrix serves as a safe and useful alternative to both synthetic mesh and AlloDerm., ((c) 2009 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Bevacizumab (Avastin, Genentech, Inc, San Francisco, CA), a humanized monoclonal antibody against vascular endothelial growth factor, was recently approved for the treatment of metastatic breast cancer.A PubMed and OVID search was performed using keywords: bevacizumab, Avastin, wound healing, VEGF, angiogenesis, and colorectal cancer. Our objective was to review the current literature in regard to bevacizumab and its adverse effects on surgical wound healing.Bevacizumab has been associated with multiple complications in regard to wound healing, such as dehiscence, ecchymosis, surgical site bleeding, and wound infection. Current literature suggests patients should wait at least 6 to 8 weeks (>40 days) after cessation to have surgery (half-life = 20 days). In addition, postoperative reinitiation of bevacizumab must wait > or =28 days to prevent an increased risk of wound healing complications, and the surgical incision should be fully healed.The adverse effects of bevacizumab in regard to wound healing must be considered in all surgical patients.

Background: Variations in genes related to the dopaminergic pathway have been implicated in neuropsychiatric disorders such as schizophrenia, substance misuse, Alzheimer's disease and Post Traumatic Stress Disorder (PTSD). A single nucleotide polymorphism (SNP) (957C>T) and a deletion polymorphism (-141delC) in the DRD2 gene and a SNP (Taq1A) in a gene directly downstream of DRD2 have all been implicated in dopamine functioning in the brain., Methods: To test the importance of these three polymorphisms in PTSD susceptibility, a genetic screen was performed in 127 war veterans diagnosed with PTSD and 228 control individuals without a history of PTSD., Results: No significant association was found between PTSD and the Taq1A or -141delC polymorphisms. However, a significant association was observed with PTSD and the 957C>T polymorphism. PTSD individuals were more likely to carry the C allele compared to the controls (P=0.021)., Conclusions: Our findings suggest that the 957C>T polymorphism in the DRD2 gene is one of the genetic factors for susceptibility to PTSD., ((c) 2008 Wiley-Liss, Inc.)

Endosonography enables detection and localization of small pancreatic neuroendocrine tumors (PETs) which cannot be detected by computed tomography, magnetic resonance imaging, or somatostatin receptor scintigraphy. Knowledge about the prognosis of very small PETs in MEN1 is limited, and if there are no clinical symptoms, endocrine activity or mechanical problems and thus no clear indication for surgical therapy, an appropriate decision for the management of such patients might be to control their follow-up by endosonographic imaging. Therefore, the reproducibility of the measurement of the diameter of very small PETs by endosonographic imaging was investigated in this prospective study. We included 33 PETs smaller than 15 mm in their largest diameter detected by endosonographic imaging (Pentax FG 32 UA) in ten patients with genetically confirmed MEN1-disease. Three repeated measurements of each tumor were performed. Reproducibility was expressed as mean coefficient of variation of intra-observer variability. Mean tumor diameter was 6.9 +/- 3.4 mm (range 2.8 - 14.2 mm). Mean coefficient of variation was 5.5 +/- 4.6 % (range 0.0 - 19.4 %): in tumors < 5 mm (n = 13) 7.1 +/- 6.3 %, in tumors > 5 mm (n = 20) 4.4 +/- 2.6 %. Least significant change (p < 0.05) was calculated as 15.4 % (tumors < 5 mm: 19.9 %; tumors > 5 mm: 12.3 %). In conclusion, endosonographic imaging enables the measurement of small PETs with an acceptable reproducibility. Changes of tumor diameter of more than 20 % have to be taken as statistically significant.

Objective: To identify clusters of patients with post-traumatic stress disorder (PTSD) according to symptom profile and to examine the association of the A1 allele of the D2 dopamine receptor (DRD2) gene with these clusters., Method: Fifty-seven untreated Caucasian Vietnam veterans with PTSD were administered the General Health Questionnaire-28 (GHQ) and the Mississippi Scale for combat-related PTSD. DRD2 allelic status was determined by PCR., Results: Subjects with the DRD2 Al allele compared to those without this allele had significantly higher scores on GHQ 2 (anxiety/insomnia), GHQ 3 (social dysfunction) and GHQ 4 (depression). Cluster analysis of the GHQ data identified two primary groups. A high psychopathology cluster (cluster 3), featured by high co-morbid levels of somatic concerns, anxiety/insomnia, social dysfunction and depression, and a low psychopathology cluster (cluster 1), manifested by the reverse pattern. Scores in each of the four GHQ groups were significantly higher in cluster 3 than cluster 1, as was Mississippi Scale PTSD score. DRD2 A1 allele veterans compared to those without this allele were significantly more likely to be found in the high than the low psychopathology cluster group., Conclusions: DRD2 variants are associated with severe co-morbid psychopathology in PTSD subjects.

This study examined whether allelic status of the D2 dopamine receptor (DRD2) gene was associated with response to a selective serotonin reuptake inhibitor, paroxetine, in the treatment of posttraumatic stress disorder (PTSD). Sixty-three Caucasian war veterans with combat-related PTSD were treated with paroxetine for 8 weeks. Patients were assessed at baseline and at follow-up using the General Health Questionnaire-28 (GHQ). TaqI A DRD2 alleles were determined by PCR. Before paroxetine treatment, patients with the DRD2 A1+ allele (A1A2 genotype) compared to those with the A1- allele (A2A2 genotype) had higher total GHQ psychopathological scores (P=0.040) and higher GHQ subscale scores for anxiety/insomnia (0.046), social dysfunction (P=0.033) and depression (P=0.011). In an intention-to-treat analysis, paroxetine was associated with significant improvement in total GHQ scores (P=0.014) and in the factor scores of social dysfunction (P=0.033), anxiety (P=0.009) and depression (P=0.026). Furthermore, there was a significant allele by time interaction on the social dysfunction scale, with A1+ allelic patients showing significant improvement in social functioning compared to A1- allelic patients (P=0.031), an effect independent of changes in depression or anxiety. This suggests changes in social functioning induced by paroxetine may be, in part, mediated via D2 dopamine receptors. The DRD2 A1 allele may prove to be a useful marker to assist clinicians in predicting which patients with PTSD are likely to obtain improvements in social functioning with paroxetine treatment.

Appendiceal diverticulitis as the etiology of right lower quadrant pain is an uncommon entity in younger populations. The incidence is <1 per cent among patients under 30 years of age undergoing appendectomy. Herein, we present a case of a 17-year-old male with perforated appendiceal diverticulitis. The history, physical findings, diagnosis, and treatment are outlined. Additionally the literature concerning appendiceal diverticulitis is reviewed.