School Absenteeism Longer Than Two Weeks Is a Red Flag of Somatic Symptom and Related Disorders in Hospitalised Children and Adolescents: A Matched Cohort Study.

Chronic school absenteeism is a common problem in childhood and adolescence, and it is frequently observed in patients with somatic symptom and related disorders (SSRDs). This study aimed to determine whether and to what extent the presence of school absenteeism may be a risk factor for the diagnosis of SSRDs in hospitalised patients. This matched cohort study included children and adolescents aged between 8 and 17 years, admitted to the paediatric ward of the IRCCS Burlo Garofolo in Trieste from 2021 to 2023, who were divided into two groups, the first including children with at least 15 days of absence from school for medical reasons and the second including children with regular school attendance, matched to the former group by age and sex. We consecutively enrolled 70 patients, 35 in the absentee group and 35 in the control group. In the absentee group, 30/35 (85.7%) patients were diagnosed with an SSRD, while in the control group, 1/35 (2.9%) was diagnosed with an SSRD. The absentee group had a 30-fold higher risk of being diagnosed with SSRDs than the control group (RR = 30 [95% CI = 4.3-208]; p < 0.001). This study shows that in hospitalised children, a history of school absenteeism of more than two weeks is an important risk factor for the diagnosis of SSRDs.

The Hidden Impact of ADHD Symptoms in Preschool Children with Autism: Is There a Link to Somatic and Sleep Disorders?

Neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), do often present in comorbidity among them and with other medical conditions, including sleep and gastrointestinal (GI) disorders and somatic complaints. An anonymous online survey based on standardized questionnaires (SDSC, KL-ASD, APSI, ROME V CRITERIA, CPRS, CBCL) was completed by the parents of 46 preschoolers diagnosed with ASD. A high prevalence (47%) of ADHD symptoms in this population was found, surpassing previous estimates. Sleep disturbances, especially difficulties in initiating and maintaining sleep and sleep-wake transition, are more pronounced in ASD patients with comorbid ADHD. Additionally, in patients over 4 years old, there is a high prevalence of functional GI symptoms (Rome V criteria: 38%). Parental stress is significantly associated with ADHD symptoms, sleep disorders, and GI symptoms. Comprehensive assessments considering both core symptoms of neurodevelopmental disorders and associated comorbidities are crucial for more effective treatment strategies and improved wellbeing in affected individuals and their families.

More Arrows in the Quiver: Investigating the Use of Auxiliary Models to Localize In-View Components with Augmented Reality.

The creation and management of content are among the main open issues for the spread of Augmented Reality. In Augmented Reality interfaces for procedural tasks, a key authoring strategy is chunking instructions and using optimized visual cues, i.e., tailored to the specific information to convey. Nevertheless, research works rarely present rationales behind their choice. This work aims to provide design guidelines for the localization of in-view and not occluded components, which is recurrent information in technical documentation. Previous studies revealed that the most suited visual cues to convey this information are auxiliary models, i.e., abstract shapes that highlight the space region where the component is located. Among them, 3D arrows are widely used, but they may produce ambiguity of information. Furthermore, from the literature, it is unclear how to design auxiliary model shapes and if they are affected by the component shapes. To fill this gap, we conducted two user studies. In the first study, we collected the preference of 45 users regarding the shape, color, and animation of auxiliary models for the localization of various component shapes. According to the results of this study, we defined guidelines for designing optimized auxiliary models based on the component shapes. In the second user study, we validated these guidelines by evaluating the performance (localization time and recognition accuracy) and user experience of 24 users. The results of this study allowed us to confirm that designing auxiliary models following our guidelines leads to a higher recognition accuracy and user experience than using 3D arrows.

Pediatric Emergency Cases in the First Year of the COVID-19 Pandemic in a Tertiary-Level Emergency Setting.

Aim: Emergency cases are uncommon events in the pediatric emergency setting. This study aimed to evaluate the effect of the Coronavirus disease 2019 (COVID-19) pandemic by describing the number and type of pediatric emergency cases that arrived at the pediatric emergency department (PED) of a tertiary-level children's hospital in Italy. Methods: We performed a retrospective study, collecting the main features of pediatric emergency patients who arrived during the first year of the COVID-19 pandemic (March 2020-February 2021) compared to the pre-pandemic period (March 2016-February 2020). Results: During the study period, 112,168 patients were visited at the PED, and 237 (0.21%) were emergency cases, median age of 4 years (IQR: 1-12). In the first year of the pandemic, 42 children were coded as emergency cases compared to 195 (49/year) during the pre-pandemic period. The proportion of emergency cases was stable (0.27% during the COVID-19 period versus 0.20% during the pre-COVID-19 period, p = 0.19). No differences were found regarding the age, gender, hour of arrival, and outcome of patients. We found a significant decrease in the proportion of emergency cases related to respiratory diseases (9/42, 21.4% during the COVID-19 period versus 83/195 during the pre-COVID-19 period (42.6%), p = 0.01). Conclusion: In conclusion, our data suggest that the pandemic had a more significant impact on respiratory emergency cases than on pediatric emergencies in general.

A serpiginous lesion of scrotum.

BACKGROUND: Median raphe cyst is usually benign and asymptomatic male genitalia lesions. Although uncommon, infection may be a complication. CASE PRESENTATION: We report the case of a 4-year-old child presented to the emergency department for a serpiginous and redness lesion extended from the basis of the penis until the perineum. An infected median raphe cyst was suspected, and the patient underwent surgical treatment and antibiotic therapy with complete resolution of symptoms. Liquid culture resulted positive for Serratia Marcescens. CONCLUSION: Infection is a rare complication, especially in childhood. To prevent relapses and clinical symptoms, the majority of authors recommend surgical excision followed by primary closure. In case of infections caused by Serratia Marcescens, chronic granulomatous disease should always be rule out.

Cardio-pulmonary function among children with mild or asymptomatic COVID-19 infection needing certification for return-to-play.

AIM: To explore the cardio-pulmonary function of children returning to play sports after mild or asymptomatic SARS-CoV-2 infection. METHODS: This is a consecutive case series conducted at the Institute for Maternal and Child Health, Trieste, Italy. Paediatric patients who accessed the Institute for cardiologic and pneumological evaluation before the return-to-play competitive sports were recruited, according to the Italian Sports Medical Federation recommendations. Echocardiogram, electrocardiogram, treadmill ECG test and pulmonary function tests were performed. RESULTS: One hundred and thirty-two patients (aged 8-17 years old, mean age 12.8 ± 2.5) were recruited. Among these, 127 children were considered for the final analysis (49.6% females). Out of 127, 84 (66.1%) had a mild symptomatic form of SARS-CoV-2 infection, while 43 (33.9%) were asymptomatic. The main referred symptoms were fever (n = 37, 44%), asthenia (n = 14, 16.7%), rhinitis (n = 16, 19%), ageusia (n = 19, 22.6%), anosmia (n = 24, 28.6%), sore throat (n = 3, 3.6%), cough (n = 9, 10.7%), arthralgia-myalgia (n = 11, 13.1%), headache (n = 23, 27.4%) and gastrointestinal symptoms (n = 7, 8.3%). No child presented evidence of cardio-pulmonary function impairment after an average time of 77.3 days (SD 35) from SARS-CoV-2 swab positivity and a median of 68 days (IQ1 52, IQ3 92.5). CONCLUSION: This preliminary study suggests that, in the absence of specific symptoms, the diagnostic yield of cardio-pulmonary tests before returning to play sports may be very low.

Infectious spondylodiscitis and kyphosis correction in an infant: a case report.

BACKGROUND: Neonatal infectious spondylodiscitis is a rare bony infection with atypical clinical presentation and non-specific systemic symptoms. Diagnosis and treatment are often delayed resulting in vertebral destruction and severe complications. We retrospectively reviewed the case of an infant with infectious spondylodiscitis resulting in T12 body destruction and marked angular kyphosis. CASE-REPORT: A 4-week-old infant developed an infectious spondylodiscitis resulting in destruction of the T12 vertebral body and involvement of disc between T12 and L1. At 6 months of age, X-ray showed a marked thoracolumbar angular kyphosis above 50 Cobb degrees. Therefore, the patient underwent single time surgery with double anterior and posterior approach. At 9 years follow up, clinical and radiological findings show a stable correction with good aesthetic appearance. CONCLUSION: Neonatal spondylodiscitis could lead to marked kyphosis similar to the congenital one. Since treatment with casts and tutors is often inefficacious, prompt surgery should be considered. The double anterior and posterior approach is the best option in this condition.

Intranasal dexmedetomidine and intravenous ketamine for procedural sedation in a child with alpha-mannosidosis: a magic bullet?

BACKGROUND: Procedural sedation is increasingly needed in pediatrics. Although different drugs or drugs association are available, which is the safest and most efficient has yet to be defined, especially in syndromic children with increased sedation-related risk factors. CASE REPORT: we report the case of a five-year-old child affected by alpha-mannosidosis who required procedural sedation for an MRI scan and a lumbar puncture. We administered intranasal dexmedetomidine (4 µg/kg) 45 min before intravenous cannulation, followed by one bolus of ketamine (1 mg/kg) for each procedure. The patient maintained spontaneous breathing and no desaturation or any complication occurred. CONCLUSION: intranasal dexmedetomidine and intravenous ketamine could be a feasible option for MRI and lumbar puncture in children with alpha-mannosidosis needing sedation.

Gender differences on benefits and risks associated with oral antithrombotic medications for coronary artery disease.

INTRODUCTION: Despite the significant advances in the pharmacological and interventional management of patients with cardiovascular disease (CVD) over the last decades, cardiovascular mortality remains the leading cause of death. Large randomized clinical trials have investigated the efficacy and safety of different antithrombotic medications in patients with CVD. Although female gender is generally underrepresented in these clinical trials, most analyses clearly indicate that both men and women may accrue therapeutic benefits from antithrombotic management strategies. AREAS COVERED: This review aims to provide a comprehensive and focused update on gender-related comparative clinical studies of antithrombotic therapies in patients suffering from CVD. EXPERT OPINION: Current evidence supports the understanding of a similar therapeutic effect between genders with signals of an increased risk of bleeding in women. However, important gaps in evidence exist due to the overall limited percentage of women that have been enrolled in randomized controlled trials. A greater awareness of gender-related issues in antithrombotic therapy should be promoted among physicians and further evidence from large clinical trials looking at the safety and efficacy balance of different antithrombotic strategies in women is warranted.

Decision Analytic Markov Model Weighting Expected Benefits and Current Limitations of First-Generation Bioresorbable Vascular Scaffolds: Implications for Manufacturers and Next Device Iterations.

BACKGROUND: Relative benefits of bioresorbable vascular scaffolds (BVS) compared with everolimus-eluting stents (EES) are expected to accrue after complete bioresorption. METHODS AND RESULTS: We built a decision analytic Markov model comparing BVS and EES for a contemporary percutaneous coronary intervention population. Procedure-related morbidity and outcome data from the available literature were used to derive model probabilities. The net benefit of BVS and EES was estimated in terms of quality-adjusted life expectancy. Under the assumption of no risk for device thrombosis and target lesion revascularization with BVS beyond 3 years, the equipoise in quality-adjusted life expectancy (12.86) between BVS and EES was achieved 19 years after implantation. The maximum tolerable excess risk of 3-year BVS thrombosis equalizing the model-predicted quality-adjusted life expectancy of BVS and EES at 10 years was 1.40, corresponding to an absolute tolerable rate of 1.45%. CONCLUSIONS: At the currently observed relative increase in device thrombosis and under the extreme hypothesis of no scaffold thrombosis and target lesion revascularization beyond 3 years, the incremental benefit of BVS over EES becomes apparent only after 19 years. This simulation suggests that there is a small degree of benefit that clinicians and decision-makers may expect from the first-generation BVS at the current risk of device thrombosis. Manufacturers should target scaffold thrombosis rates <1.45% at 3 years to make their technologies attractive during a 10-year horizon.

Clinical Outcomes Following Intravascular Imaging-Guided Versus Coronary Angiography-Guided Percutaneous Coronary Intervention With Stent Implantation: A Systematic Review and Bayesian Network Meta-Analysis of 31 Studies and 17,882 Patients.

OBJECTIVES: The authors sought to explore the comparative clinical efficacy of different imaging modalities for guiding percutaneous coronary interventions (PCI). BACKGROUND: Coronary angiography (CA) is the standard imaging modality for intraprocedural guidance of PCI. Intracoronary imaging techniques, including intravascular ultrasound (IVUS) and optical coherence tomography (OCT), can overcome some limitations of CA. METHODS: Comprehensive hierarchical Bayesian network meta-analysis of randomized clinical trials and adjusted observational studies comparing clinical outcomes of PCI with stent implantation guided by CA, IVUS, or OCT. RESULTS: A total of 31 studies encompassing 17,882 patients were included. Compared with CA guidance, the risks of all-cause death (odds ratio [OR]: 0.74; 95% credible interval [CrI]: 0.58 to 0.98), myocardial infarction (OR: 0.72; 95% CrI: 0.52 to 0.93), target lesion revascularization (OR: 0.74, 95% CrI: 0.58 to 0.90) and stent thrombosis (OR: 0.42; 95% CrI: 0.20 to 0.72) were significantly reduced by IVUS guidance. PCI guidance using either IVUS or OCT was associated with a significant reduction of major adverse cardiovascular events (OR: 0.79; 95% CrI: 0.67 to 0.91 and OR: 0.68; 95% CrI: 0.49 to 0.97, respectively) and cardiovascular death (OR: 0.47; 95% CrI: 0.32 to 0.66 and OR: 0.31; 95% CrI: 0.13 to 0.66, respectively). No differences in terms of comparative clinical efficacy were found between IVUS and OCT for all the investigated outcomes. Pooled estimates were consistent across several sensitivity analyses. However, the treatment effect of IVUS on all-cause death was neutralized in the analysis restricted to randomized clinical trials (OR: 1.03; 95% CrI: 0.41 to 2.14). CONCLUSIONS: Compared with CA, the use of intravascular imaging techniques for PCI guidance reduces the risk of cardiovascular death and adverse events.

EFEITOS DO TREINAMENTO AERÓBICO E DO FORTALECIMENTO EM PACIENTES COM INSUFICIÊNCIA CARDÍACA / EFFECTS OF AEROBIC TRAINING AND STRENGTHENING IN PATIENTS WITH HEART FAILURE / EFECTOS DEL ENTRENAMIENTO AERÓBICO Y DEL FORTALECIMIENTO EN PACIENTES CON INSUFICIENCIA CARDÍACA

RESUMO Introdução: A intolerância ao exercício e a dispneia são os principais sintomas da insuficiência cardíaca (IC). Objetivo: Avaliar os efeitos de um programa de exercícios aeróbicos e de fortalecimento sobre a aptidão cardiorrespiratória, o pico de torque dos flexores e extensores de joelho e a qualidade de vida de pacientes com IC. Métodos: Estudo prospectivo, com avaliação pré e pós-reabilitação cardiovascular (RCV) de sete pacientes, com idade de 61 ± 6 anos, classe funcional II e III e fração de ejeção do ventrículo esquerdo 45,4 ± 2,3%. O programa de RCV consistiu em 24 sessões de 60 minutos com treinamento aeróbico na intensidade do limiar de anaerobiose (LA) e fortalecimento dos membros inferiores usando caneleiras de 3 a 5 kg. No início e após RCV os pacientes realizaram prova de esforço, dinamometria isocinética do joelho dominante e responderam o questionário WHOQOL-bref. Resultados: Após RCV, o tempo de exercício para atingir o LA foi atrasado (p= 0,04) e houve aumento significativo no consumo de oxigênio (VO2) (p < 0,01), da frequência cardíaca (FC) (p= 0,04), pulso de oxigênio (VO2/FC) (p = 0,02) e ventilação (VE) (p = 0,01) na intensidade do LA. Houve aumento do pico de torque dos músculos extensores de joelho (p = 0,02) e melhora significativa do domínio psicológico (p = 0,04) do questionário de qualidade de vida. Conclusão: O programa de RCV foi seguro e resultou em melhora do desempenho de exercícios submáximos, da força dos músculos extensores de joelho e da qualidade de vida de pacientes com IC.

ABSTRACT Introduction: Exercise intolerance and dyspnea are the main symptoms of heart failure (HF). Objective: To evaluate the effects of a program of aerobic exercises and strengthening on cardiorespiratory fitness, maximum torque of knee flexors and extensors, and quality of life of patients with HF. Methods: Prospective, pre- and post-cardiovascular rehabilitation (CVR) study of seven patients, aged 61 ± 6 years, functional class II and III and left ventricular ejection fraction 45.4 ± 2.3%. The CVR program consisted of 24 sessions of 60 minutes with aerobic training in intensity of the anaerobic threshold (AT) and strengthening of the lower limbs using ankle weights of 3 to 5 kg. At the beginning and after CVR, the patients performed stress test, isokinetic dynamometry of the dominant knee and completed the WHOQOL-bref questionnaire. Results: After CVR, exercise time to reach AT was delayed (p=0.04) and there was a significant increase in oxygen consumption (VO2) (p<0.01), heart rate (HR) (p=0.04), pulse of oxygen (VO2/HR) (p=0.02) and ventilation (VE) (p=0.01) in the intensity of AT. There was an increase in maximum torque of knee extensor muscles (p=0.02) and significant improvement in the psychological domain (p=0.04) of the quality of life questionnaire. Conclusion: The CVR program was safe and resulted in improved performance of submaximal exercises, knee extensor muscles strength and quality of life of patients with HF.

RESUMEN Introducción: La intolerancia al ejercicio y la disnea son los síntomas principales de la insuficiencia cardiaca (IC) . Objetivo: Evaluar los efectos de un programa de ejercicio aeróbico y fortalecimiento en la capacidad cardiorrespiratoria, el par máximo de los flexores y extensores de rodilla y la calidad de vida de los pacientes con IC. Métodos: Estudio prospectivo, con evaluación pre y post-rehabilitación cardiovascular (RCV) de siete pacientes, edad 61 ± 6 años, clase funcional II y III y fracción de eyección del ventrículo izquierdo de 45,4 ± 2,3%. El programa de RCV consistió en 24 sesiones de 60 minutos con la intensidad del entrenamiento aeróbico en el umbral de anaerobiosis (UA) y el fortalecimiento de las extremidades inferiores utilizando pesos de tobillo de 3 a 5 kg. Al principio y después de la RCV los pacientes se sometieron a la prueba de esfuerzo, dinamometría isocinética de la rodilla dominante y respondieron el cuestionario WHOQOL-bref. Resultados: Después de la RCV, el tiempo de ejercicio para alcanzar UA se retrasó (p = 0,04) y hubo un aumento significativo en el consumo de oxígeno (VO2) (p < 0,01), frecuencia cardiaca (FC) (p = 0,04), pulso de oxígeno (VO2/FC) (p = 0,02) y la ventilación (VE) (p = 0,01) en la intensidad del UA. Hubo un aumento del par máximo de los músculos extensores de la rodilla (p = 0,02) y una mejora significativa en el dominio psicológico (p = 0,04) del cuestionario de calidad de vida. Conclusión: El programa de RCV fue seguro y mejoró el rendimiento de los ejercicios submáximos, la fuerza de los músculos extensores de la rodilla y la calidad de vida de los pacientes con IC.

Novel HBsAg mutations correlate with hepatocellular carcinoma, hamper HBsAg secretion and promote cell proliferation in vitro.

BACKGROUND: An impaired HBsAg-secretion can increase HBV oncogenic-properties. Here, we investigate genetic-determinants in HBsAg correlated with HBV-induced hepatocellular carcinoma (HCC), and their impact on HBsAg-secretion and cell-proliferation. METHODS: This study included 128 chronically HBV-infected patients: 23 with HCC (73.9% D; 26.1% A HBV-genotype), and 105 without cirrhosis/HCC (72.4% D, 27.6% A) as reference-group. The impact of mutations on HBsAg-secretion was assessed by measuring the ratio [secreted/intracellular HBsAg] until day 5 post-transfection. The impact of mutations on cell-cycle advancement was assessed by flow-cytometry. RESULTS: Two HBsAg mutations significantly correlated with HCC: P203Q (17.4% [4/23] in HCC vs 1.0% [1/105] in non-HCC, P=0.004); S210R (34.8% [8/23] in HCC vs 3.8% [4/105] in non-HCC, P <0.001); P203Q+S210R (17.4% [4/23] in HCC vs 0% [0/110] in non-HCC, P=0.001). Both mutations reside in trans-membrane C-terminal domain critical for HBsAg-secretion. In in-vitro experiments, P203Q, S210R and P203Q+S210R significantly reduced the ratio [secreted/intracellular HBsAg] compared to wt at each time-point analysed (P <0.05), supporting an impaired HBsAg-secretion. Furthermore, P203Q and P203Q+S210R increased the percentage of cells in S-phase compared to wt, indicating cell-cycle progression (P203Q:26±13%; P203Q+S210R:29±14%; wt:18%±9, P <0.01. Additionally, S210R increased the percentage of cells in G2/M-phase (26±8% for wt versus 33±6% for S210R, P <0.001). CONCLUSIONS: Specific mutations in HBsAg C-terminus significantly correlate with HBV-induced HCC. They hamper HBsAg-secretion and are associated with increased cellular proliferation, supporting their involvement in HCC-development. The identification of viral genetic markers associated with HCC is critical to identify patients at higher HCC-risk that may deserve intensive liver monitoring, and/or early anti-HBV therapy.

Specific mutations in the C-terminus domain of HBV surface antigen significantly correlate with low level of serum HBV-DNA in patients with chronic HBV infection.

BACKGROUND: To define HBsAg-mutations correlated with different serum HBV-DNA levels in HBV chronically-infected drug-naive patients. METHODS: This study included 187 patients stratified into the following ranges of serum HBV-DNA:12-2000 IU/ml, 2000-100,000 IU/ml, and >100,000 IU/ml. HBsAg-mutations were associated with HBV-DNA levels by applying a Bayesian-Partitional-Model and Fisher-exact test. Mutant and wild-type HBV genotype-D genomes were expressed in Huh7 cells and HBsAg-production was determined in cell-supernatants at 3 days-post-transfection. RESULTS: Specific HBsAg-mutations (M197T,-S204N-Y206C/H-F220L) were significantly correlated with serum HBV-DNA <2000 IU/ml (posterior-probability>90%, P < 0.05). The presence of Y206C/H and/or F220L was also associated with lower median (IQR) HBsAg-levels and lower median (IQR) transaminases (for HBsAg:250[115-840] IU/ml for Y206C/H and/or F220L versus 4300[640-11,838] IU/ml for wild-type, P = 0.023; for ALT:28[21-40] IU/ml versus 53[34-90] IU/ml, P < 0.001). These mutations were localized in the HBsAg C-terminus, known to be involved in virion and/or HBsAg secretion. The co-occurrence of Y206C + F220L was found significant by cluster-analysis, (P = 0.02). In addition, in an in-vitro model Y206C + F220L determined a 2.8-3.3 fold-reduction of HBsAg-amount released in supernatants compared to single mutants and wt (Y206C + F220L = 5,679 IU/ml; Y206H = 16,305 IU/ml; F220L = 18,368 IU/ml; Y206C = 18,680 IU/ml; wt = 14,280 IU/ml, P < 0.05). CONCLUSIONS: Specific HBsAg-mutations (compartmentalized in the HBsAg C-terminus) correlated with low-serum HBV-DNA and HBsAg-levels. These findings can be important to understand mechanisms underlying low HBV replicative potential including the inactive-carrier state.

Anti-HBV treatment induces novel reverse transcriptase mutations with reflective effect on HBV S antigen.

INTRODUCTION: The identification of novel reverse-transcriptase (RT) drug-resistance mutations is critical in predicting the probability of success to anti-HBV treatment. Furthermore, due to HBV-RT/HBsAg gene-overlap, they can have an impact on HBsAg-detection and quantification. METHODS: 356 full-length HBV-RT sequences from 197 drug-naive patients and 159 patients experiencing virological-breakthrough to nucleoside/nucleotide-analogs (NUCs) were analyzed. Mutants and wild-type HBs-antigens were expressed in HuH7-hepatocytes and quantified in cell-supernatants and cell-lysates by Architect HBsAg-assay. RESULTS: Ten novel RT-mutations (rtN53T-rtS78T-rtS85F-rtS135T-rtA181I-rtA200V-rtK212Q-rtL229V/F-rtM309K) correlated with specific NUC-treatments and classical drug-resistance mutations on divergent evolutionary pathways. Some of them reduced RT-binding affinity for anti-HBV drugs and altered S-antigen structure. Indeed, rtS78T (prevalence: 1.1% in drug-naïve and 12.2% in adefovir-failing patients) decreased the RT-affinity for adefovir more than the classical adefovir-resistance mutations rtA181 T/V (WT:-9.63 kcal/mol, rtA181T:-9.30 kcal/mol, rtA181V:-7.96 kcal/mol, rtS78T:-7.37 kcal/mol). Moreover, rtS78T introduced a stop-codon at HBsAg-position 69, and completely abrogated HBsAg-quantification in both supernatants and cell-lysates, indicating an impaired HBsAg-secretion/production. Furthermore, the HBsAg-mutation sP217L, silent in RT, significantly correlated with M204V/I-related virological-breakthrough and increased HBsAg-quantification in cell-lysate. CONCLUSIONS: Mutations beyond those classically known can affect drug-binding affinity of mutated HBV-RT, and may have potential effects on HBsAg. Their cumulative effect on resistance and HBV-pathogenicity indicates the importance of preventing therapeutic failures.