Seasonal Dynamics and Physiological Age of Ixodid Ticks Collected from Dogs.

In order to reproduce and complete life cycles, ticks have to feed on different hosts, thus participating as vectors and reservoirs in the maintenance and circulation of different pathogens. Since dogs can serve as suitable hosts for numerous tick species, the aims of this study were to determine tick species and their seasonal occurrence on pet dogs and to compare the accuracy of three indices frequently used to calculate engorged female physiological age. Ticks were collected from dogs brought to veterinary clinics. Three indices were analyzed: scutal index, alloscutal/scutal index ratio, and physiological age index. Four tick species were identified: Ixodes ricinus, Dermacentor marginatus, D. reticulatus, and Rhipicephalus sanguineus group, and the last was the most abundant. The highest number of collected ticks was in April, but two species were continuously active throughout the year. The statistical analyses distinguished the physiological age index as more precise because of lower variability. Dog owners usually ignore regular dog anti-tick treatments throughout the year, as they are not aware that ticks could be active during the winter months. Tick surveillance is unquestionably important in order to monitor and prevent the distribution of these vectors and also the diseases they transmit.

Alginate Gel-Based Carriers for Encapsulation of Carotenoids: On Challenges and Applications.

Sodium alginate is one of the most interesting and the most investigated and applied biopolymers due to its advantageous properties. Among them, easy, simple, mild, rapid, non-toxic gelation by divalent cations is the most important. In addition, it is abundant, low-cost, eco-friendly, bio-compatible, bio-adhesive, biodegradable, stable, etc. All those properties were systematically considered within this review. Carotenoids are functional components in the human diet with plenty of health benefits. However, their sensitivity to environmental and process stresses, chemical instability, easy oxidation, low water solubility, and bioavailability limit their food and pharmaceutical applications. Encapsulation may help in overcoming these limitations and within this review, the role of alginate-based encapsulation systems in improving the stability and bioavailability of carotenoids is explored. It may be concluded that all alginate-based systems increase carotenoid stability, but only those of micro- and nano-size, as well as emulsion-based, may improve their low bioaccessibility. In addition, the incorporation of other biopolymers may further improve encapsulation system properties. Furthermore, the main techniques for evaluating the encapsulation are briefly considered. This review critically and profoundly explains the role of alginates in improving the encapsulation process of carotenoids, suggesting the best alternatives for those systems. Moreover, it provides a comprehensive cover of recent advances in this field.

Factors Affecting the Consumption of Traditional Food in Tourism-Perceptions of the Management Sector of Catering Facilities.

The topic of this study is the factors that influence the consumption of traditional food products (TFPs) in tourism, as seen from the perspective of management-sector employees in food and beverage catering facilities. The paper aims to analyse the economic, environmental, social, and touristic factors that highly influence the consumption patterns of catering facilities which are significant providers of traditional gastronomic experiences in tourism, by using the specially designed TFPct scale. The study was conducted on a sample of 300 catering facilities in AP Vojvodina (the Republic of Serbia). An explanatory factor analysis was used to confirm the key factors that influence the consumption of traditional products used to prepare the meals that are a part of what catering facilities offer. Subsequently, a binary logistics regression model was used to establish which of the indicated factors has a statistically significant effect on the management's decision to purchase these products for their catering facility. The study showed that the TFPct scale is appropriate for this type of research, and that economic factors are key factors in the consumption of traditional products. Moreover, compared with other types of catering facilities, interest in the consumption of these products is clearly expressed by a la carte restaurants.

Clinical Outcomes in Fibrolamellar Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer primarily affecting children and young adults. Although considered a subset of hepatocellular carcinoma (HCC), FLC has unique molecular and pathologic characteristics, suggesting that it may require different treatment. Immune checkpoint inhibitors (ICIs) are used in the treatment of HCC, but efficacy and safety in FLC has not been characterized. METHODS: We performed a multicenter retrospective analysis of patients with FLC to determine responses to ICI therapy. Response rates were assessed based on RECIST 1.1 criteria, and Kaplan-Meier statistics were used for progression-free survival (PFS) and overall survival (OS). RESULTS: FLC tumors were characterized by low tumor mutational burden (TMB) and absent PD-L1 expression. We identified 19 patients who received ICIs, including 15 who received ICI therapy alone [programmed death receptor 1 (PD-1) inhibitor, +/- cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor]. Objective tumor responses were observed in 3/19 patients (15.8%), including 2/15 patients (13.3%) who received ICIs alone, all partial responses. Median PFS and OS were 5.5 and 26.0 months, respectively. Grade 3-4 immune related adverse events were observed in 4/19 (21.1%) patients. CONCLUSIONS: ICI therapy has modest clinical activity in FLC, and novel therapeutic combinations are needed.

Diazepam diminishes temozolomide efficacy in the treatment of U87 glioblastoma cell line.

AIMS: Many patients with glioblastoma (GBM) suffer from comorbid neurological/psychiatric disorders and, therefore, are treated with psychopharmacological agents. Diazepam (DIA) is widely adopted to treat status epilepticus, alleviate anxiety, and inhibit chemotherapy-associated delayed emesis in GBM patients. Even though temozolomide (TMZ) and DIA could be found as possible combination therapy in clinical practice, there are no reports of their combined effects in GBM. Hence, it may be of interest to investigate whether DIA enhances the antitumor efficacy of TMZ in GBM cells. METHODS: U87 human GBM was used to examine the effects of combined TMZ and DIA on cell viability, and the oxygen consumption within the cells, in order to evaluate mitochondrial bioenergetic response upon the treatment. RESULTS: The cooperative index showed the presence of antagonism between TMZ and DIA, which was confirmed on long-term observation. Moreover, the level of apoptosis after the TMZ treatment was significantly decreased when administered with DIA (p < 0.001). Concomitant use of TMZ and DIA increased the basal cell respiration rate, the oxidative phosphorylation rate, and maximal capacity of mitochondrial electron transport chain, as well as the activities of complexes I and II, vs. TMZ alone (p < 0.001). CONCLUSION: Comparing our results with data reported that DIA elicits cell cycle arrest in the G0/G1 phase and favors senescence reveals that DIA diminishes TMZ efficacy in concomitant use in the treatment of GBM. However, due to its great potency to hinder GBM proliferation and metabolism, it could be considered using DIA as maintenance therapy after TMZ cycles.

Ecology and prevalence of Borrelia burgdorferi s.l. in Ixodes ricinus (Acari: Ixodidae) ticks.

Weather conditions greatly affect tick population densities and activity, on which depends the occurrence of tick-borne diseases (TBDs). During the spring months from 2017 to 2019, 1,357 specimens of Ixodes ricinus ticks were collected at 9 localities in the vicinity of Novi Sad (Serbia). The number of collected ticks varied considerably among the different sampling sites and years. Also, a statistically significant difference was found between months and observed number of ticks for each stadium. By statistical analysis of tick activity depending on microclimatic conditions, a positive and statistically significant relationship between temperature and the number of ticks for each life stage was established, but not for humidity. Dew had a statistically significant impact only on nymphs but not on adults. The infection rate of Borrelia burgdorferi s.l. was the highest in March (46.5-51.2%) and the lowest in May (32.9-34.8%). The highest prevalence was detected in males and the lowest in nymphs. Since there is a positive and statistically significant correlation between tick number and prevalence, the ability to provide weather-based predictions of the seasonal patterns of current tick activity is important for the risk assessment of TBDs such as Lyme borreliosis.

Mitochondrial energy metabolism in baby hamster kidney (BHK-21/C13) cells treated with karnozin extra® / Metabolismo energético mitocondrial en células de riñón de hámster bebé (BHK-21 / C13) tratadas con karnozin extra®

SUMMARY: Carnosine is known as a natural dipeptide, which inhibits the proliferation of tumor cells throughout its action on mitochondrial respiration and cell glycolysis. However, not much is known about its effects on the metabolism of healthy cells. We explored the effects of Karnozin EXTRA® capsule with different concentrations of L-carnosine, on the cell viability and the expressions of intermediate filament vimentin (VIM) and superoxide dismutase (SOD2) in normal fibroblasts BHK-21/C13. Furthermore, we investigated its action on the energy production of these cells. Cell viability was quantified by the MTT assay. The Clark oxygen electrode (Oxygraph, Hansatech Instruments, England) was used to measure the "intact cell respiration rate", state 3 of ADP-stimulated oxidation, maximum oxidation capacity and the activities of complexes I, II and IV. Results showed that Karnozin EXTRA® capsule in concentrations of 2 and 5 mM of L-carnosine did not induce toxic effects and morphological changes in treated cells. Our data revealed a dose-dependent immunofluorescent signal amplification of VIM and SOD2 in the BHK-21/C13 cell line. This supplement substantially increased the recorded mitochondrial respiration rates in the examined cell line. Due to the stimulation of mitochondrial energy production in normal fibroblasts, our results suggested that Karnozin EXTRA® is a potentially protective dietary supplement in the prevention of diseases with altered mitochondrial function.

RESUMEN: La carnosina se conoce como dipéptido natural, que inhibe la proliferación de células tumorales a través de su acción sobre la respiración mitocondrial y la glucólisis celular. Sin embargo, no se sabe mucho de sus efectos sobre el metabolismo de las células sanas. Exploramos los efectos de la cápsula Karnozin EXTRA® con diferentes concentraciones de L-carnosina, sobre la viabilidad celular y las expresiones de vimentina de filamento intermedio (VIM) y superóxido dismutasa (SOD2) en fibroblastos normales BHK-21 / C13. Además, estudiamos su acción sobre la producción de energía de estas células. La viabilidad celular se cuantificó mediante el ensayo MTT. Se utilizó el electrodo de oxígeno Clark (Oxygraph, Hansatech Instruments, Inglaterra) para medir la "tasa de respiración de células intactas", el estado 3 de oxidación estimulada por ADP, la capacidad máxima de oxidación y las actividades de los complejos I, II y IV. Los resultados mostraron que la cápsula de Karnozin EXTRA® en concentraciones de 2 y 5 mM de L- carnosina no indujo efectos tóxicos ni cambios morfológicos en las células tratadas. Nuestros datos revelaron una amplificación de señal inmunofluorescente dependiente de la dosis de VIM y SOD2 en la línea celular BHK-21 / C13. Este suplemento aumentó sustancialmente las tasas de respiración mitocondrial registradas en la línea celular examinada. Debido a la estimulación de la producción de energía mitocondrial en fibroblastos normales, nuestros resultados sugirieron que Karnozin EXTRA® es un suplemento dietético potencialmente protector en la prevención de enfermedades con función mitocondrial alterada.

Reporting of Infectious Diseases in the United States During the Coronavirus Disease 2019 (COVID-19) Pandemic.

Reporting of infectious diseases other than COVID-19 has been greatly decreased throughout the COVID-19 pandemic. We find this decrease varies by routes of transmission, reporting state, and COVID-19 incidence at the time of reporting. These results underscore the need for continual investment in routine surveillance efforts despite pandemic conditions.

An unusual finding of tumorlet carcinoid and endobronchial hamartoma in the lobar bronchus / Hallazgo inusual de tumorlet carcinoide y hamartoma endobronquial en el bronquio lobar

SUMMARY: Neuroendocrine lung tumours are a group of different tumours that have similar morphological, immunohistochemical and molecular characteristics, and represents 1-2 % of all malignant lung tumours. Tumorlet carcinoids represent the nodular proliferation of hyperplastic neuroendocrine cells that is smaller than 5 mm in size. In this study, we reported the unusual finding of tumour carcinoid and endobronchial hamartoma in the same bronchus. A 49-year-old male patient with symptoms of prolonged severe cough and fever, and was treated for pneumonia. Since he did not adequately respond to antibiotic therapy lung CT scan was performed which showed middle lobe bronchus obstruction. Bronchoscopy revealed a lobulated whitish tumour which was biopsied and histopathological diagnosis was hamartoma. Tumour could not be completely removed during bronchoscopy, it was decided to surgically remove it. On serial section, during gross examination in the same bronchus, an oval yellowish area with a diameter of 3 mm was found along the bronchial wall. According to gross and histomorphological characteristics and immunophenotype of tumour cells, the diagnosis of tumour carcinoid was set. Diagnosis of carcinoids of the tumorlet type is usually an accidental finding and it can be seen on CT in the form of subcentimeter, single or multiple, nodular changes. Considering that the clinical picture is nonspecific, they should always be kept in mind as a possible differential diagnosis.

RESUMEN: Los tumores neuroendocrinos de pulmón son un grupo de tumores de diferentes características morfológicas, inmunohistoquímicas y moleculares similares, y representan el 1- 2 % de todos los tumores malignos de pulmón. Los carcinoides tumorales representan la proliferación nodular de células neuroendocrinas hiperplásicas de tamaño inferior a 5 mm. En este estudio reportamos el hallazgo inusual de tumor carcinoide y hamartoma endobronquial en el mismo bronquio. Un paciente varón de 49 años con síntomas de tos severa prolongada y fiebre fue tratado por neumonía. Al no responder adecuadamente a la terapia con antibióticos, se realizó una tomografía computarizada de pulmón que mostró obstrucción del bronquio del lóbulo medio. La broncoscopia reveló una tumoración blanquecina lobulada de la cual se tomó biopsia y el diagnóstico histopatológico fue hamartoma. No fue posible extirpar el tumor por completo durante la broncoscopia y se decidió extirparlo quirúrgicamente. En la sección seriada, durante el examen macroscópico en el mismo bronquio, se encontró un área amarillenta ovalada de 3 mm de diámetro a lo largo de la pared bronquial. De acuerdo a las características macroscópicas e histomorfológicas y de inmunofenotipo de las células tumorales, se estableció el diagnóstico de tumor carcinoide. El diagnóstico de carcinoides de tipo tumorlet suele ser un hallazgo accidental y se observan en la TC en forma de cambios nodulares subcentimétricos, únicos o múltiples. En consideración de que el cuadro clínico es inespecífico, siempre debe tenerse en cuenta como posible diagnóstico diferencial.

Neoadjuvant Cabozantinib and Nivolumab Converts Locally Advanced HCC into Resectable Disease with Enhanced Antitumor Immunity.

A potentially curative hepatic resection is the optimal treatment for hepatocellular carcinoma (HCC), but most patients are not candidates for resection and most resected HCCs eventually recur. Until recently, neoadjuvant systemic therapy for HCC has been limited by a lack of effective systemic agents. Here, in a single arm phase 1b study, we evaluated the feasibility of neoadjuvant cabozantinib and nivolumab in patients with HCC including patients outside of traditional resection criteria (NCT03299946). Of 15 patients enrolled, 12 (80%) underwent successful margin negative resection, and 5/12 (42%) patients had major pathologic responses. In-depth biospecimen profiling demonstrated an enrichment in T effector cells, as well as tertiary lymphoid structures, CD138+ plasma cells, and a distinct spatial arrangement of B cells in responders as compared to non-responders, indicating an orchestrated B-cell contribution to antitumor immunity in HCC.

Development, Practice Patterns, and Early Clinical Outcomes of a Multidisciplinary Liver Cancer Clinic.

Multidisciplinary care has been associated with improved survival in patients with primary liver cancers. We report the practice patterns and real world clinical outcomes for patients presenting to the Johns Hopkins Hospital (JHH) multidisciplinary liver clinic (MDLC). We analyzed hepatocellular carcinoma (HCC, n = 100) and biliary tract cancer (BTC, n = 76) patients evaluated at the JHH MDLC in 2019. We describe the conduct of the clinic, consensus decisions for patient management based on stage categories, and describe treatment approaches and outcomes based on these categories. We describe subclassification of BCLC stage C into 2 parts, and subclassification of cholangiocarcinoma into 4 stages. A treatment consensus was finalized on the day of MDLC for the majority of patients (89% in HCC, 87% in BTC), with high adherence to MDLC recommendations (91% in HCC, 100% in BTC). Among patients presenting for a second opinion regarding management, 28% of HCC and 31% of BTC patients were given new therapeutic recommendations. For HCC patients, at a median follow up of 11.7 months (0.7-19.4 months), median OS was not reached in BCLC A and B patients. In BTC patients, at a median follow up of 14.2 months (0.9-21.1 months) the median OS was not reached in patients with resectable or borderline resectable disease, and was 11.9 months in patients with unresectable or metastatic disease. Coordinated expert multidisciplinary care is feasible for primary liver cancers with high adherence to recommendations and a change in treatment for a sizeable minority of patients.

Is exposure to indoor secondhand smoke associated with poor mental health? Results from non-conflict and post-conflict setting.

The purpose of this study was to examine the association between exposure to indoor SHS and self-reported HRQoL among healthy non-smoking students at the University of Belgrade, Serbia and Kosovska Mitrovica located in the post-conflict Kosovo province. Students who presented at Student Public Health Center in Belgrade in 2009 and Kosovska Mitrovica in 2015 for mandatory health checks were invited to participate. Data were collected using socio-demographic and behavioral questionnaire, health-related quality of life questionnaire Short Form-36 (SF-36) and Beck Depression Inventory (BDI). A total of 82.3% students in Belgrade sample and 76.0% in Kosovska Mitrovica sample reported daily exposure to indoor SHS. After adjustment for socio-demographic characteristics and behavior, daily exposure to indoor SHS for more than 6 hours was associated with poorer Vitality (ß = -5.55, 95% confidence interval [CI] -9.49, -1.61) and Mental Health (ß = 5.00, 95% CI-8.94, -1.07) only among students at the University of Belgrade. This study showed that the association between longer daily indoor SHS exposure and poor mental health HRQoL was not consistent in non-conflict and post-conflict setting. This association was not found in a post-conflict setting. Strict no smoking policies are needed in student housing, university campuses and all public spaces.

Integrated immunological analysis of a successful conversion of locally advanced hepatocellular carcinoma to resectability with neoadjuvant therapy.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide with a minority of patients being diagnosed early enough for curative-intent interventions. We report the first use of preoperative cabozantinib plus nivolumab to successfully downstage what presented as unresectable HCC as part of an ongoing phase 1b study. Preoperative treatment with cabozantinib and nivolumab led to >99% reduction in alpha-fetoprotein, -37.3% radiographic reduction by RECIST 1.1 and a near complete pathologic response (80% to 100% necrosis). An integrated immunological analysis was performed on the post-treatment surgical tumor sample and matched pre-treatment and post-treatment peripheral blood samples with high-dimensional imaging and cytometry techniques. Bayesian non-negative matrix factorization (CoGAPS, Coordinated Gene Activity in Pattern Sets) and self-organizing map (FlowSOM) algorithms were used to distinguish changes in functional markers across cellular neighborhoods in the single cell data sets. Brisk immunological infiltration into the tumor microenvironment was observed in non-random, organized cellular neighborhoods. Systemically, combination therapy led to marked promotion of effector cytotoxic T cells and effector memory helper T cells. Natural killer cells also increased with therapy. The patient remains without disease recurrence and with a normal alpha-fetoprotein approximately 2 years from presentation. Our study provides proof-of-concept that borderline resectable or locally advanced HCC warrants consideration of downstaging with effective neoadjuvant systemic therapy for subsequent curative resection.

Tumor Mutational Burden, Toxicity, and Response of Immune Checkpoint Inhibitors Targeting PD(L)1, CTLA-4, and Combination: A Meta-regression Analysis.

PURPOSE: Tumor mutational burden (TMB) has emerged as a potential predictive biomarker for clinical response to ICI therapy, but whether TMB also predicts toxicity remains unknown. We investigated the relationship between TMB, objective response rate (ORR), overall survival (OS), and toxicity for ICI therapy across multiple cancer types. EXPERIMENTAL DESIGN: We searched MEDLINE, PubMed, and ASCO/ESMO/AACR meetings for clinical trials of anti-PD(L)1, CTLA-4, or combination in 29 cancer types. We assessed ICI administered, responses (complete or partial response), median OS, OS HR, and grade 3/4 toxicity. We conducted a systematic review, meta-analysis and meta-regression using tumor level TMB data from Foundation Medicine. RESULTS: One hundred seventeen clinical trials, which included 12,450 patients treated with ICI therapy were analyzed. Meta-regression analysis revealed that TMB was significantly associated with ORR for anti-PD(L)1, anti-CTLA-4, and combination (P < 0.0001 for all), but not associated with toxicity in all treatment groups. OS data were unavailable for most studies included in our meta-analysis, and the relationship between TMB and OS in this subset was not significant (P = 0.26). In high TMB tumor types (≥10 mut/megabase) the improvement of ORR and increase in grade 3/4 toxicity with combination ICI therapy as compared with PD(L)1 monotherapy were 21.13% and 25.41%, respectively, as compared with 3.73% and 18.78% in low TMB tumor types (<10 mut/megabase). CONCLUSIONS: There is a positive association between TMB and clinical response with anti-PD(L)1, anti-CTLA-4, and combination ICIs, but no association between TMB and toxicity. These results imply a favorable risk/benefit ratio for ICIs in tumors with a higher TMB.

Feasibility and accuracy of a robotic guidance system for navigated spine surgery in a hybrid operating room: a cadaver study.

The combination of navigation and robotics in spine surgery has the potential to accurately identify and maintain bone entry position and planned trajectory. The goal of this study was to examine the feasibility, accuracy and efficacy of a new robot-guided system for semi-automated, minimally invasive, pedicle screw placement. A custom robotic arm was integrated into a hybrid operating room (OR) equipped with an augmented reality surgical navigation system (ARSN). The robot was mounted on the OR-table and used to assist in placing Jamshidi needles in 113 pedicles in four cadavers. The ARSN system was used for planning screw paths and directing the robot. The robot arm autonomously aligned with the planned screw trajectory, and the surgeon inserted the Jamshidi needle into the pedicle. Accuracy measurements were performed on verification cone beam computed tomographies with the planned paths superimposed. To provide a clinical grading according to the Gertzbein scale, pedicle screw diameters were simulated on the placed Jamshidi needles. A technical accuracy at bone entry point of 0.48 ± 0.44 mm and 0.68 ± 0.58 mm was achieved in the axial and sagittal views, respectively. The corresponding angular errors were 0.94 ± 0.83° and 0.87 ± 0.82°. The accuracy was statistically superior (p < 0.001) to ARSN without robotic assistance. Simulated pedicle screw grading resulted in a clinical accuracy of 100%. This study demonstrates that the use of a semi-automated surgical robot for pedicle screw placement provides an accuracy well above what is clinically acceptable.

Inhibition of miR-21 Regulates Mutant KRAS Effector Pathways and Intercepts Pancreatic Ductal Adenocarcinoma Development.

Almost all pancreatic ductal adenocarcinomas (PDA) develop following KRAS activation, which triggers epithelial transformation and recruitment of desmoplastic stroma through additional transcriptional and epigenetic regulation, but only a few of these regulatory mechanisms have been described. We profiled dysregulated miRNAs starting with the earliest premalignant pancreatic intraepithelial neoplasias (PanIN) in genetically engineered mutated KRAS and P53 (KPC) mice programmed to recapitulate human PDA tumorigenesis. We identified miR-21 and miR-224 as cell-specific and compartment-specific regulators in PanINs and PDA. miR-21 is overexpressed in tumor epithelial cells of premalignant ducts, while miR-224 is overexpressed in cancer-associated fibroblasts in PDA stroma. Inhibition of miR-21 reverted protumorigenic functionalities to baseline levels. Overexpression of miR-224 induced activated phenotypes in normal fibroblasts. In vivo miR-21 inhibition improved survival in established PDA. Importantly, early systemic miR-21 inhibition completely intercepted premalignant progression. Finally, an evaluation of miR-21 expression in the PDA cohort of The Cancer Genome Atlas identified a correlation between tumor epithelial cell content and miR-21 expression in human tumors providing further rationale for conducting human studies. Thus, miR-21 may be useful for early PanIN detection, and for intercepting developing premalignant pancreatic lesions and other KRAS-driven premalignancies.

Design and control of an image-guided robot for spine surgery in a hybrid OR.

BACKGROUND: Minimally invasive spine (MIS) fusion surgery requires image guidance and expert manual dexterity for a successful, efficient, and accurate pedicle screw placement. Operating room (OR)-integrated robotic solution can provide precise assistance to potentially minimize complication rates and facilitate difficult MIS procedures. METHODS: A 5-degrees of freedom robot was designed specifically for a hybrid OR with integrated surgical navigation for guiding pedicle screw pilot holes. The system automatically aligns an instrument following the surgical plan using only instrument tracking feedback. Contrary to commercially available robotic systems, no tracking markers on the robotic arm are required. The system was evaluated in a cadaver study. RESULTS: The mean targeting error (N = 34) was 1.27±0.57 mm and 1.62±0.85°, with 100% of insertions graded as clinically acceptable. CONCLUSIONS: A fully integrated robotic guidance system, including intra-op imaging, planning, and physical guidance with optimized robot design and control, can improve workflow and provide pedicle screw guidance with less than 2 mm targeting error.

Tobacco smoking and health-related quality of life among university students: Mediating effect of depression.

The aim of this study was to assess the association between cigarette smoking and health-related quality of life (HRQoL) among students in two different universities, and the potential mediating effect of depression. Participants were students who came for mandatory check-ups at Student Health Care Centers in two Universities in Serbia, differing by socio-politically and economically environments. Students completed socio-demographic questionnaire, Beck Depression Inventory (BDI) and the SF-36 questionnaire for assessment of HRQoL. In both populations, after adjustment for socio-demographic, behavioral and health factors, smoking was associated with poorer Mental Composite Score (MCS) and Physical Composite Score (PCS) (Belgrade 1,624 students: MCS ß = 3.38, 95% confidence interval [CI] 1.31, 5.44, PCS ß = 1.01, 95% CI -0.50, 2.52; Kosovska Mitrovica 514 students: MCS ß = 5.06, 95% CI 1.74, 8.37, PCS ß = 3.29, 95% CI 0.75, 5.83). After additional adjustment for BDI score, the observed associations were lost (Belgrade: MCS ß = 1.12, 95% CI -0.57, 2.80, PCS ß = -0.40, 95% CI -1.71, 0.92; Kosovska Mitrovica: MCS ß = 0.77, 95% CI -2.06, 3.60, PCS ß = 0.56, 95% CI -1.75, 2.87). Higher BDI score was associated with poorer PCS and MCS across all quintiles. The association of smoking with impairment of HRQoL among university students in two different settings was mediated by higher levels of depressive symptoms. These findings highlight the need for further research on the interaction between smoking, mental health and quality of life, with implications for prevention, diagnosis and treatment.

Emerging strategies for combination checkpoint modulators in cancer immunotherapy.

Current immune checkpoint-modulating agents have demonstrated clinical efficacy in certain tumor types, particularly those with a high burden of tumor-specific neoantigens, high tumor-mutational burden, and abundant tumor-infiltrating T cells. However, these tumors often stop responding, with signs of T cells exhaustion, decreased T cell effector function, and upregulated inhibitory checkpoints. To enhance antitumor immunity and rescue exhausted T cells, newer inhibitory and stimulatory checkpoint modulators are being tested as monotherapy or in combination with approved checkpoint inhibitors. In contrast, tumors with low tumor-mutational burden, low neoantigen burden, and a paucity of T cells are immunologically "cold," and therefore first require the addition of agents to facilitate the induction of T cells into tumors. Cold tumors also often recruit immunosuppressive cell subsets, including regulatory T cells, myeloid-derived suppressor cells, and macrophages, and secrete immunosuppressive soluble cytokines, chemokines, and metabolites. To unleash an optimal antitumor immune response, combinatorial therapeutics that combine immune checkpoints with other modalities, such as vaccines, are being developed. From current preclinical data, it appears that combinatorial strategies will provide robust and durable responses in patients with immunologically cold cancers.