Nanobody-liposomes as novel cancer vaccine platform to efficiently stimulate T cell immunity.

Cancer vaccines can be utilized in combination with checkpoint inhibitors to optimally stimulate the anti-tumor immune response. Uptake of vaccine antigen by antigen presenting cells (APCs) is a prerequisite for T cell priming, but often relies on non-specific mechanisms. Here, we have developed a novel vaccination strategy consisting of cancer antigen-containing liposomes conjugated with CD169- or DC-SIGN-specific nanobodies (single domain antibodies) to achieve specific uptake by APCs. Our studies demonstrate efficient nanobody liposome uptake by human and murine CD169+ and DC-SIGN+ APCs in vitro and in vivo when compared to control liposomes or liposomes with natural ligands for CD169 and DC-SIGN. Uptake of CD169 nanobody liposomes resulted in increased T cell activation by human APCs and stimulated naive T cell priming in mouse models. In conclusion, while nanobody liposomes have previously been utilized to direct drugs to tumors, here we show that nanobody liposomes can be applied as vaccination strategy that can be extended to other receptors on APCs in order to elicit a potent immune response against tumor antigens.

Tailoring the wrap: intraoperative functional lumen imaging probe (FLIP) during hiatal hernia repair.

INTRODUCTION: The introduction of the functional lumen imaging probe (FLIP) has provided objective, real-time feedback on the geometric variations with each component of a hiatal hernia repair (HHR). The utility of this technology in altering intraoperative decision-making has been scarcely reported. Herein, we report a single-center series of intraoperative FLIP during HHR. METHODS: A retrospective review of electronic medical records between 2020 and 2022 was conducted and all patients undergoing non-recurrent HHR with FLIP were queried. Patient and hernia characteristics, intraoperative FLIP values and changes in decision-making, as well as early post-operative outcomes were reported. Both diameter and distensibility index (DI) were measured at 40 ml and 50 ml balloon inflation after hiatal dissection, after hiatal closure, and after fundoplication when indicated. RESULTS: Thirty-three patients met inclusion criteria. Mean age was 62 ± 14 years and mean BMI was 28 ± 6 kg/m2. The majority (53%) were type I hiatal hernias. The largest drop in DI occurred after hiatal closure, with minimal change seen after fundoplication (mean DI of 4.3 ± 2. after completion of HH dissection, vs 2.7 ± 1.2 after hiatal closure and 2.3 ± 1 after fundoplication when performed). In 13 (39%) of cases, FLIP values directly impacted intraoperative decision-making. Fundoplication was deferred in 4/13 (31%) patients, the wrap was loosened in 2/13 (15%); the type of fundoplication was altered to achieve adequate anti-reflux values in 2/13 (15%) patients, and in 1/13 (3%) the wrap was tightened. CONCLUSION: FLIP measurements can be used intraoperatively to guide decision-making and alter management plan based on objective values. Long-term outcomes and further prospective studies are required to better delineate the value of this technology.

Practices and perspectives on advanced diagnostic and interventional bronchoscopy among pediatric pulmonologists in the United States.

INTRODUCTION: Advanced diagnostic bronchoscopy includes endobronchial ultrasound (EBUS) guided transbronchial lung and lymph node biopsies, CT navigation and robotic bronchoscopy. Interventional bronchoscopy refers to procedures performed for therapeutic purposes such as balloon dilation of the airway, tissue debulking, cryotherapy, removal of foreign bodies and insertion of endobronchial valves [1]. For adult patients, these procedures are standard of care [2, 3]. Despite a lack of formalized training, there are numerous case reports and case series describing the use of advanced diagnostic and interventional bronchoscopy techniques in children. The safety and feasibility of EBUS-TBNA, cryotherapy techniques, endobronchial valves among other techniques have been demonstrated in these publications [1, 4-9]. METHODS: We sought to better understand the current practices and perspectives on interventional and advanced bronchoscopy among pediatric pulmonologists through surveys sent to pediatric teaching hospitals across the United States. RESULTS: We received 43 responses representing 28 programs from 25 states. The highest bronchoscopy procedure volume occurred in the 0-5 years age group. Among our respondents, 31% self-identified as a pediatric interventional/advanced bronchoscopist. 79% believe that advanced and interventional training is feasible in pediatric pulmonology and 77% believe it should be offered to pediatric pulmonary fellows. DISCUSSION: This is the first study to characterize current practices and perspectives regarding advanced diagnostic and interventional bronchoscopy procedures among pediatric pulmonologists in the United States. Pediatric interventional pulmonology (IP) is in its infancy and its beginnings echo those of the adult IP where only certain centers were performing these procedures.

Semi-automatic artifact quantification in thermal ablation probe and algorithms for the evaluation of metal artifact reduction.

OBJECTIVES: To compare metal artifacts and evaluation of metal artifact reduction algorithms during probe positioning in computed tomography (CT)-guided microwave ablation (MWA), cryoablation (CRYO), and radiofrequency ablation (RFA). MATERIALS AND METHODS: Using CT guidance, individual MWA, CRYO, and RFA ablation probes were placed into the livers of 15 pigs. CT imaging was then performed to determine the probe's position within the test subject's liver. Filtered back projection (B30f) and iterative reconstructions (I30-1) were both used with and without dedicated iterative metal artifact reduction (iMAR) to generate images from the initial data sets. Semi-automatic segmentation-based quantitative evaluation was conducted to estimate artifact percentage within the liver, while qualitative evaluation of metal artifact extent and overall image quality was performed by two observers using a 5-point Likert scale: 1-none, 2-mild, 3-moderate, 4-severe, 5-non-diagnostic. RESULTS: Among MWA, RFA, and CRYO, compared with non-iMAR in B30f reconstruction, the largest extent of artifact volume percentages were observed for CRYO (11.5-17.9%), followed by MWA (4.7-6.6%) and lastly in RFA (5.5-6.2%). iMAR significantly reduces metal artifacts for CRYO and MWA quantitatively (p = 0.0020; p = 0.0036, respectively) and qualitatively (p = 0.0001, p = 0.0005), but not for RFA. No significant reduction in metal artifact percentage was seen after applying iterative reconstructions (p > 0.05). Noise, contrast-to-noise-ratio, or overall image quality did not differ between probe types, irrespective of the application of iterative reconstruction and iMAR. CONCLUSION: A dedicated metal artifact algorithm may decrease metal artifacts and improves image quality significantly for MWA and CRYO probes. Their application alongside with dedicated metal artifact algorithm should be considered during CT-guided positioning.

The treatment gap for mental disorders in adults enrolled in HIV treatment programmes in South Africa: a cohort study using linked electronic health records.

AIMS: Mental disorders are common in people living with HIV (PLWH) but often remain untreated. This study aimed to explore the treatment gap for mental disorders in adults followed-up in antiretroviral therapy (ART) programmes in South Africa and disparities between ART programmes regarding the provision of mental health services. METHODS: We conducted a cohort study using ART programme data and linked pharmacy and hospitalisation data to examine the 12-month prevalence of treatment for mental disorders and factors associated with the rate of treatment for mental disorders among adults, aged 15-49 years, followed-up from 1 January 2012 to 31 December 2017 at one private care, one public tertiary care and two pubic primary care ART programmes in South Africa. We calculated the treatment gap for mental disorders as the discrepancy between the 12-month prevalence of mental disorders in PLWH (aged 15-49 years) in South Africa (estimated based on data from the Global Burden of Disease study) and the 12-month prevalence of treatment for mental disorders in ART programmes. We calculated adjusted rate ratios (aRRs) for factors associated with the treatment rate of mental disorders using Poisson regression. RESULTS: In total, 182 285 ART patients were followed-up over 405 153 person-years. In 2017, the estimated treatment gap for mental disorders was 40.5% (95% confidence interval [CI] 19.5-52.9) for patients followed-up in private care, 96.5% (95% CI 95.0-97.5) for patients followed-up in public primary care and 65.0% (95% CI 36.5-85.1) for patients followed-up in public tertiary care ART programmes. Rates of treatment with antidepressants, anxiolytics and antipsychotics were 17 (aRR 0.06, 95% CI 0.06-0.07), 50 (aRR 0.02, 95% CI 0.01-0.03) and 2.6 (aRR 0.39, 95% CI 0.35-0.43) times lower in public primary care programmes than in the private sector programmes. CONCLUSIONS: There is a large treatment gap for mental disorders in PLWH in South Africa and substantial disparities in access to mental health services between patients receiving ART in the public vs the private sector. In the public sector and especially in public primary care, PLWH with common mental disorders remain mostly untreated.

[Perioperative pharmacological circulatory support in daily clinical routine]. / Perioperative medikamentöse Kreislaufunterstützung in der täglichen Routine.

Perioperative phases of hypotension are associated with an increase in postoperative complications and organ damage. Whereas some years ago hemodynamic stabilization was primarily carried out by volume supplementation, in recent years the use and dosing of cardiovascular-active substances has significantly increased. But like intravascular volume therapy, also substances with a cardiovascular effect have therapeutic margins, and thus, potential side effects. This review article discusses indications for each cardiovascular-active agent, weighing up advantages and disadvantages. Special attention is paid to the question how to administrate them: central venous catheter vs. peripheral indwelling venous cannula. The authors come to the conclusion that it is not a question of whether it is principally allowed to apply cardiovascular-active drugs via peripheral veins but more importantly, what should be taken into consideration if a peripheral venous access is used. This article provides concise recommendations.

Survival of composite restorations after selective or total caries removal in primary teeth and predictors of failures: A 36-months randomized controlled trial.

OBJECTIVES: The aim of this study was to assess the survival of composite restorations after selective (SCR) or total caries removal (TCR) and determine predictors of failures after 36 months. METHODS: 120 teeth with deep occlusal or occlusal-proximal carious lesions were randomly divided into control (TCR; n = 54; 69% Class II) and test (SCR; n = 66; 63% Class II) groups. Clinical evaluation was applied using the USPHS criteria, and the presence of Charlie or Delta scores at the marginal integrity were considered as a failure. RESULTS: The overall survival rate of restorations was 68% after 36 months, 81% for TCR and 57% for SCR (p = 0.004). The multivariable Cox Regression model demonstrated that restorations performed after SCR had 3.44 times greater probability of failure compared to TCR (p = 0.006). The other two predictors for failure of restorations were teeth with Class II cavities (hazard ratio = 3.3) and children with gingival bleeding over 20% (hazard ratio = 2.5). CONCLUSIONS: Performing composite restorations after SCR in primary teeth had success rate significantly lower than restorations performed after TCR. Complex cavities and worst patient´s oral hygiene were found to be predictors of failure of restorations. CLINICAL SIGNIFICANCE: Although SCR has been demonstrating high rates of pulp preservation, clinicians should consider that composite restorations fail in a higher frequency compared to TCR in primary teeth and, in some circumstances, may be preferable in terms of restoration longevity.

Periodontal status of individuals with Down syndrome: sociodemographic, behavioural and family perception influence.

BACKGROUND: The aim of the present study was to assess the periodontal condition of individuals with Down syndrome and the association with sociodemographic and behavioural characteristics and family perception of oral health. METHODS: This cross-sectional observational study was performed at a referral centre for dental assistance to disabled persons in Araçatuba, Brazil. Parents of the individuals were interviewed, and the visible plaque index, bleeding on probing, probing pocket depth and clinical attachment level were recorded by one periodontist in six sites per tooth of all teeth. The individual was the unit of analysis. The significance level was set at 5%. RESULTS: Sixty-four subjects (23.8 ± 8.3 years old) were included. Eighteen (28.1%) were diagnosed with gingivitis and 46 (71.9%) with periodontitis. In the multiple logistic regression final model, age and self-reported oral hygiene practices were associated with the occurrence of periodontitis. The chance of having periodontitis was 4.7 times higher among individuals older than 20 years and approximately 4 times higher in patients whose oral hygiene was performed by themselves and their parents, compared with those who performed oral hygiene alone. Sex, follow-up time in the centre, education, degree of participants' dependence, flossing and family history of periodontal disease were not associated with the occurrence of periodontitis. Higher levels of plaque and bleeding were observed for participants with parents reporting bad gingival health (76.2% and 46.9%) and deficient oral hygiene (79.5% and 47.3%). The perception of parents regarding gingival bleeding was correlated with higher bleeding detected clinically (P = 0.01; 50.1%). CONCLUSIONS: The prevalence of periodontitis in individuals with Down syndrome is high and increases with age, even in the face of the parents' perception about their children's oral condition.

Actitud de odontólogos acerca de la atención de pacientes con necesidades especiales

Objetivo: Evaluar la actitud de los cirujanos dentistas acerca de la atención odontológica de pacientes con necesidades especiales (PNE). Métodos: Estudio transversal que utilizó el método cuantitativo a través de un cuestionario que fue contestado por 60 cirujanos dentistas (CDs) asistentes a una Jornada Odontológica del estado de Río Grande do Sul, Brasil. Resultados: El 73% de los CDs no atienden este tipo de pacientes, de los cuales: 62,1% por no saber atenderlos; 91,4% por no haber recibido un Curso de Pacientes Especiales durante su formación académica; 25,9% porque requiere mucho tiempo y paciencia y 69% por no poseer las condiciones emocionales. Por otro lado, el 4% de los encuestados respondieron si atenderlos; bajo alguna forma de contención, sedación o de ser el caso referirlos a un especialista. El 23% restante de CDs indicó prestar atención solamente si eran pacientes colaboradores. Conclusiones: La odontología para pacientes con necesidades especiales en el estado de Rio Grande do Sul-Brasil parece no cubrir los requerimientos de estos pacientes, no solo por las dificultades inherentes a los servicios y las especificidades de dichos pacientes, sino debido a los impedimentos relacionados con los propios dentistas, problemas con las técnicas odontológicas y por toda la complejidad que envuelve la atención a personas con deficiencia.

Objective: Evaluate the attitude of dental surgeons (DS) in relation to dental care for patients with special needs (PSN). Methods : Transversal study that used the quantitative method through a questionnaire which was answered by 60 DS attending at Dental Conference in the state of Rio Grande do Sul, Brazil. Results : 73% of the DS do not attend this type of patients, among these: 62.1% because they do not know how to treat them; 91.4% because they did not have a Special Patients Course during their academic education; 25.9% because it requires a lot of time and patience and 69% because it needs certain emotional conditions. On the other hand, 4% of the respondents answered that they atended PSN; under some form of containment, sedation or if it was the case, refer them to a specialist. The remaining 23% of DS indicated paying attention only if they were collaborating patients. Conclusions : Dentistry for PSN in the state of Rio Grande do Sul-Brazil does not seem to satisfy the requirements of these patients, not only due to the difficulties inherent to the services and the specificities of these patients, but also of the impediments related with the dentists themselves, problems with dental techniques and all the complexity involved in caring for people with disabilities.

Prevalence and characterization of azole-resistant Aspergillus fumigatus in patients with cystic fibrosis: a prospective multicentre study in Germany.

Objectives: Aspergillus fumigatus is the most prevalent filamentous fungus in the respiratory tract of patients with cystic fibrosis (CF). The aim of this prospective multicentre study was to investigate the prevalence of azole-resistant A. fumigatus (ARAF) in respiratory secretions from CF patients across Germany and to characterize ARAF isolates by phenotypic and molecular methods. Methods: Twelve tertiary care centres from Germany participated in the study. In total, 2888 A. fumigatus isolates from 961 CF patients were screened for ARAF by using azole-containing agar plates. Antifungal susceptibility testing of isolates was performed by broth microdilution according to EUCAST guidelines. Analysis of mutations mediating resistance was performed using PCR and sequencing of the cyp51A gene. Furthermore, genotyping by microsatellite PCR was performed. Results: Of a total of 2888 A. fumigatus isolates, 101 isolates from 51 CF patients were found to be azole resistant (prevalence per patient 5.3%). The Essen centre had the highest prevalence (9.1%) followed by Munich (7.8%), Münster (6.0%) and Hannover (5.2%). Most ARAF isolates (n = 89) carried the TR34/L98H mutation followed by eight G54E/R, one TR46/Y121F/T289A and one F219S mutation. In two isolates no mutation was found. Genotyping results showed no major clustering. Forty-five percent of CF patients with ARAF had previously received azole therapy. Conclusions: This is the first multicentre study analysing the prevalence of ARAF isolates in German CF patients. Because of a resistance rate of up to 9%, susceptibility testing of A. fumigatus isolates from CF patients receiving antifungal treatment should be part of standard diagnostic work-up.

Vitamin D levels and risk for periodontal disease: A systematic review.

OBJECTIVE: To evaluate the existing evidence supporting or refuting the following questions: (i) Do patients with lower vitamin D levels have higher risk for periodontal disease? (ii) Are periodontal treatment outcomes improved by the adjuvant supplementation of vitamin D or by elevated serum vitamin D levels? MATERIAL AND METHODS: MEDLINE, SCOPUS, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched up to September 2017. Studies were included if they had measured serum vitamin D levels or vitamin D intake and any periodontal parameter. RESULTS: Overall, 27 studies were included (13 cross-sectional studies, 6 case-control studies, 5 cohort studies, 2 randomized clinical trials and 1 case series study). Sixty-five percent of the cross-sectional studies reported significant associations between low vitamin D levels and poor periodontal parameters. None of the observational longitudinal studies found that periodontal disease progression could be attributed to lower vitamin D levels. No interventional studies that evaluated the use of vitamin D supplementation as a solely adjuvant to periodontal treatment was found. No meta-analysis was performed due to high variability across studies. CONCLUSION: The data to support or refute the association between vitamin D levels and periodontal disease are inconclusive at the moment. More rigorously designed longitudinal studies with standardized definitions of periodontal disease and vitamin D are necessary.

[Anticancer therapy for symptom relief? : A systematic review of clinical trials in oncology]. / Symptomlinderung durch Tumortherapie? : Eine systematische Übersicht über onkologische Therapiestudien.

BACKGROUND: When patients suffer from incurable cancer, drug-based, systemic anticancer therapy is usually used with the aim of longer survival, while minimizing toxicity and ensuring a tolerable quality of life. It is unclear to what extent and with what degree of success systemic tumor therapy can be used to specifically improve pre-existing pain and an already compromised quality of life (QoL). METHODS: Therefore, a systematic review of oncological therapy studies (PubMed) was conducted. Only studies that identified the pain-relieving and QoL-enhancing effects of systemic anticancer therapy as the primary endpoint were selected and evaluated descriptively. RESULTS: Of the 2229 abstracts identified using a piloted search string, only 13 studies met the inclusion criteria. Of these, 10 studies showed an improvement in QoL-parameters through the use of systemic tumor therapies. DISCUSSION: Only a few studies focused primarily on the improvement of parameters related to quality of life-although this is the primary therapeutic goal for many patients suffering from incurable and advanced cancer. The study results encourage regular inclusion of symptom- and QoL-related data in clinical studies and to more explicitly address the potential of systemic anticancer therapy in relieving pain and other symptoms, thereby supporting the goals of palliative care.

Effects of 16-weeks of Pilates on health perception and sleep quality among elderly women.

The objective of this study was to determine the effect of 16 weeks of mat-based Pilates training on health perception and sleep quality among elderly women. A randomized and controlled trial was conducted in Caxias do Sul, Brazil, in 2015, in which 61 healthy older women were divided into two groups: experimental group (EG; n=31, average of 64.25 years old, SD 0.14) and control group (CG; n=30, average of 63.75 years old, SD 0.08). The EG participants performed mat-based Pilates exercises twice a week in 60-min sessions, whereas the CG did not train. All participants completed Brazilian-adapted and validated versions of the Pittsburgh Sleep Quality Index (PSQI-BR) and General Health Questionnaire (GHQ-12) at baseline and after 16 weeks. Significant time x group interaction effects were found for the GHQ-12 total score (p<0.001, η2=0.19), and the depression (p=0.002, η2=0.15) and social dysfunction subscales (p=0.001, η2=0.18), as well as the PSQI-BR total score (p=0.017, η2=0.09), and the sleep latency (p=0.023, η2=0.09) and use of sleeping medication subscales (p=0.019, η2=0.09), indicating better improvements (reductions) in these outcome variables for the Pilates EG when compared to the CG. All significant effects were classified as moderate to high. These results indicate that 16 weeks of mat-based Pilates training significantly improves the perceived health status and some sleep quality indices among elderly women. However, more studies are needed to assess the effectiveness of equipment-based Pilates exercises among this population.

Quantification of Phosphatidylinositol Phosphate Species in Purified Membranes.

Phosphoinositide lipids (PIPs) are required for various processes during macroautophagy, such as phagophore formation and autophagosome-lysosome fusion. Hence, quantification of the seven PIP species in autophagosome membranes is an important tool to understand how these lipids govern the transition of autophagosomes into autolysosomes. Here, we describe microscopic and mass spectrometry methods which, although designed to quantify the different PIP species on purified lysosomes, can also be applied to analyze autophagosomal PIPs.

The Perioperative Lung Transplant Virome: Torque Teno Viruses Are Elevated in Donor Lungs and Show Divergent Dynamics in Primary Graft Dysfunction.

Primary graft dysfunction (PGD) is a principal cause of early morbidity and mortality after lung transplantation, but its pathogenic mechanisms are not fully clarified. To date, studies using standard clinical assays have not linked microbial factors to PGD. We previously used comprehensive metagenomic methods to characterize viruses in lung allografts >1 mo after transplant and found that levels of Anellovirus, mainly torque teno viruses (TTVs), were significantly higher than in nontransplanted healthy controls. We used quantitative polymerase chain reaction to analyze TTV and shotgun metagenomics to characterize full viral communities in acellular bronchoalveolar lavage from donor organs and postreperfusion allografts in PGD and non-PGD lung transplant recipient pairs. Unexpectedly, TTV DNA levels were elevated 100-fold in donor lungs compared with healthy adults (p = 0.0026). Although absolute TTV levels did not differ by PGD status, PGD cases showed a smaller increase in TTV levels from before to after transplant than did control recipients (p = 0.041). Metagenomic sequencing revealed mainly TTV and bacteriophages of respiratory tract bacteria, but no viral taxa distinguished PGD cases from controls. These findings suggest that conditions associated with brain death promote TTV replication and that greater immune activation or tissue injury associated with PGD may restrict TTV abundance in the lung.

Association between chronic oral inflammatory burden and physical fitness in males: a cross-sectional observational study.

AIM: To evaluate the association between chronic oral inflammatory burden (OIB) - as the combination of periodontal and endodontic disease load - and physical fitness. METHODOLOGY: One hundred and twelve nonsmoker male police officers who performed a standardized physical fitness test (PFT) were analysed. Participants underwent oral clinical and periapical radiographic examinations. Periodontal disease was assessed by probing depth (PD) and clinical attachment loss (AL). For radiographic analysis, both apical periodontitis (AP) and root canal treatment (RCT) variables were analysed. Endodontic Burden (EB) was calculated merging the total number of teeth with AP and/or RCT per individual. OIB was calculated combining EB and AL. The outcome of physical fitness was dichotomized according to whether the highest PFT score was 'achieved' or 'not-achieved'. Multivariable logistic regression models were adjusted for age, body mass index and frequency of daily exercise. RESULTS: There was no significant association between AP, RCT and EB with physical fitness whereas PD, AL and OIB were significantly associated with low physical fitness (P < 0.05). Multivariate regression analysis revealed that individuals with OIB = EB ≥ 3 and AL ≥ 4 mm had a 81% lower chance of reaching the highest PFT score (OR = 0.19, 95%CI = 0.04-0.87, P = 0.03) compared to individuals with EB < 3 and and no AL ≥ 4 mm. Individuals with unfavourable periodontal parameters but with low EB (OIB = EB < 3 & AL ≥ 4 mm) showed no significant differences on the chance to reach the highest PFT score compared to participants with favourable periodontal status and low EB (OIB = EB < 3 & no AL ≥ 4 mm). CONCLUSIONS: The OIB - higher levels of EB in periodontal patients - was independently associated with poor physical fitness in males.