The Real-World Efficacy and Safety of Direct-Acting Antivirals for Chronic Hepatitis C in Patients Active Malignancies.

BACKGROUND: Over the past years, the introduction of direct-acting antivirals (DAAs) revolutionized chronic hepatitis C treatment. We aimed to characterize and assess treatment efficacy in three specific groups of patients treated with DAAs: those with active solid malignant tumors (SMTs), hematological diseases (HDs) and hepatocellular carcinomas (HCCs). METHODS: A total of 203 patients with active oncological disease (SMT n = 61, HD = 67, HCC n = 74) during DAA treatment in 2015-2020 selected from the EpiTer-2 database were analyzed retrospectively and compared to 12,983 patients without any active malignancy. RESULTS: Extrahepatic symptoms were more frequent in HD patients (17.2% vs. SMT = 10.3%, HCC = 8.2%, without = 7.8%, p = 0.004). HCC patients characterized with the highest ALT activity (81 IU/L vs. SMT = 59.5 IU/L, HD = 52 IU/L, without = 58 IU/L, p = 0.001) more often had F4 fibrosis as well (86.11% vs. SMT = 23.3%, HD = 28.8%, controls = 24.4%, p = 0.001). A significant majority of subjects in HCC, HD and SMT populations completed the full treatment plan (HCC = 91%; n = 67, HD = 97%; n = 65, SMT = 100%; n = 62). Concerning the treatment efficacy, the overall sustained virologic response, excluding non-virologic failures, was reported in 93.6% HD, 90.16% SMT and 80.6% in HCC patients. CONCLUSIONS: As presented in our study, DAA therapy has proven to be highly effective and safe in patients with active SMTs and HDs. However, therapy discontinuations resulting from liver disease progression remain to be the major concern in HCC patients.

Switching from inotersen to eplontersen in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: analysis from NEURO-TTRansform.

BACKGROUND: The phase 3 NEURO-TTRansform trial showed eplontersen treatment for 65 weeks reduced transthyretin (TTR), halted progression of neuropathy impairment, and improved quality of life (QoL) in adult patients with hereditary TTR-mediated amyloidosis with polyneuropathy (ATTRv-PN), vs. historical placebo. METHODS: NEURO-TTRansform enrolled patients with ATTRv-PN. A subset of patients were randomized to receive subcutaneous inotersen 300 mg weekly (Weeks 1-34) and subsequently switched to subcutaneous eplontersen 45 mg every 4 weeks (Weeks 37-81). Change in serum TTR and treatment-emergent adverse events (TEAEs) were evaluated through Week 85. Effects on neuropathy impairment, QoL, and nutritional status were also evaluated. RESULTS: Of 24 patients randomized to inotersen, 20 (83%) switched to eplontersen at Week 37 and four discontinued due to AEs/investigator decision. Absolute change in serum TTR was greater after switching from inotersen (-74.3%; Week 35) to eplontersen (-80.6%; Week 85). From the end of inotersen treatment, neuropathy impairment and QoL were stable (i.e., did not progress) while on eplontersen, and there was no deterioration in nutritional status. TEAEs were fewer with eplontersen (Weeks 37-85; 19/20 [95%] patients) compared with inotersen (up to Week 35; 24/24 [100%] patients). Mean platelet counts decreased during inotersen treatment (mean nadir reduction ‒40.7%) and returned to baseline during eplontersen treatment (mean nadir reduction, ‒3.2%). CONCLUSIONS: Switching from inotersen to eplontersen further reduced serum TTR, halted disease progression, stabilized QoL, restored platelet count, and improved tolerability, without deterioration in nutritional status. This supports a positive benefit-risk profile for patients with ATTRv-PN who switch from inotersen to eplontersen.

Rhekiss-The German Register for Child Wish and Pregnancies in Inflammatory Rheumatic Diseases.

In pharmacoepidemiology, robust data are needed to judge the impact of drug treatment on pregnancy, pregnancy outcomes and breast-fed infants. As pregnant and breastfeeding women are usually excluded from randomised clinical trials, observational studies are required. One of those data sources are pregnancy registers specifically developed to focus on certain diseases or disease groups. The German Rhekiss register investigates pregnancies in women with chronic inflammatory rheumatic diseases (IRD). Rhekiss is a nationwide, multicentre, longitudinal study, in which women aged 18 years or older with an underlying IRD can be enrolled by a rheumatologist either when planning a pregnancy or in the first half of pregnancy. Data are collected prospectively at regular follow-up visits. Rheumatologists and patients provide information in a web-based system before conception (if enrolment was at the time of pregnancy planning), during and after pregnancy. A smartphone app is available for patients. Maternal and clinical information, general laboratory markers, treatment with antirheumatic and other drugs, adverse events, items related to course and outcome of pregnancy and the health of the child are uniformly assessed for all diseases. Individual information on the IRD includes classification criteria, diagnosis-specific laboratory parameters, clinical parameters and validated instruments to measure disease activity or damage. Furthermore, patient-reported outcome measures are captured. A total of 2013 individual patients have been enrolled in the register, and data on 1801 completed pregnancies are available. In summary, Rhekiss is a comprehensive and complex register that can answer various research questions about pregnancy in women with chronic IRDs.

Machine learning prediction and explanatory models of serious infections in patients with rheumatoid arthritis treated with tofacitinib.

BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased risk of developing serious infections (SIs) vs. individuals without RA; efforts to predict SIs in this patient group are ongoing. We assessed the ability of different machine learning modeling approaches to predict SIs using baseline data from the tofacitinib RA clinical trials program. METHODS: This analysis included data from 19 clinical trials (phase 2, n = 10; phase 3, n = 6; phase 3b/4, n = 3). Patients with RA receiving tofacitinib 5 or 10 mg twice daily (BID) were included in the analysis; patients receiving tofacitinib 11 mg once daily were considered as tofacitinib 5 mg BID. All available patient-level baseline variables were extracted. Statistical and machine learning methods (logistic regression, support vector machines with linear kernel, random forest, extreme gradient boosting trees, and boosted trees) were implemented to assess the association of baseline variables with SI (logistic regression only), and to predict SI using selected baseline variables using 5-fold cross-validation. Missing values were handled individually per prediction model. RESULTS: A total of 8404 patients with RA treated with tofacitinib were eligible for inclusion (15,310 patient-years of total follow-up) of which 473 patients reported SIs. Amongst other baseline factors, age, previous infection, and corticosteroid use were significantly associated with SI. When applying prediction modeling for SI across data from all studies, the area under the receiver operating characteristic (AUROC) curve ranged from 0.656 to 0.739. AUROC values ranged from 0.599 to 0.730 in data from phase 3 and 3b/4 studies, and from 0.563 to 0.643 in data from ORAL Surveillance only. CONCLUSIONS: Baseline factors associated with SIs in the tofacitinib RA clinical trial program were similar to established SI risk factors associated with advanced treatments for RA. Furthermore, while model performance in predicting SI was similar to other published models, this did not meet the threshold for accurate prediction (AUROC > 0.85). Thus, predicting the occurrence of SIs at baseline remains challenging and may be complicated by the changing disease course of RA over time. Inclusion of other patient-associated and healthcare delivery-related factors and harmonization of the duration of studies included in the models may be required to improve prediction. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01164579; NCT00976599; NCT01059864; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT02831855; NCT02092467.

Safety of Growth Hormone Replacement Therapy in Childhood-Onset Craniopharyngioma: A Systematic Review and Cohort Study.

INTRODUCTION: Survival of childhood-onset craniopharyngioma (cCP) is excellent; however, many survivors suffer from hypothalamic-pituitary dysfunction. Growth hormone replacement therapy (GHRT) is of high importance for linear growth and metabolic outcome. Optimal timing for initiation of GHRT in cCP is on debate because of concerns regarding tumor progression or recurrence. METHODS: A systematic review and cohort studys were performed for the effect and timing of GHRT on overall mortality, tumor progression/recurrence, and secondary tumors in cCP. Within the cohort, cCP receiving GHRT ≤1 year after diagnosis were compared to those receiving GHRT >1 year after diagnosis. RESULTS: Evidence of 18 included studies, reporting on 6,603 cCP with GHRT, suggests that GHRT does not increase the risk for overall mortality, progression, or recurrent disease. One study evaluated timing of GHRT and progression/recurrence-free survival and found no increased risk with earlier initiation. One study reported a higher than expected prevalence of secondary intracranial tumors compared to a healthy population, possibly confounded by radiotherapy. In our cohort, 75 of 87 cCP (86.2%) received GHRT for median of 4.9 years [0.0-17.1]. No effect of timing of GHRT was found on mortality, progression/recurrence-free survival, or secondary tumors. CONCLUSION: Although the quality of the evidence is low, the available evidence suggests no effect of GHRT or its timing on mortality, tumor progression/recurrence, or secondary neoplasms in cCP. These results support early initiation of GHRT in cCP aiming to optimize linear growth and metabolic outcome. Prospective studies are needed to increase the level of evidence upon the optimal timing to start GHRT in cCP patients.

An update on the long-term outcomes of prenatal dexamethasone treatment in congenital adrenal hyperplasia.

First-trimester prenatal treatment with glucocorticoid (GC) dexamethasone (DEX) in pregnancies at risk for classic congenital adrenal hyperplasia (CAH) is associated with ethical dilemmas. Though effective in reducing virilisation in girls with CAH, it entails exposure to high doses of GC in fetuses that do not benefit from the treatment. The current paper provides an update on the literature on outcomes of prenatal DEX treatment in CAH cases and unaffected subjects. Long-term follow-up research is still needed to determine treatment safety. In addition, advances in early prenatal diagnostics for CAH and sex-typing as well as studies assessing dosing effects of DEX may avoid unnecessary treatment and improve treatment safety.

Drug-Related Problems in Pulmonary Hypertension with Valvular Heart Disease.

Purpose: The occurrence of drug-related problems (DRPs) and their causes specifically among pulmonary hypertension (PH) with valvular heart disease (VHD) has not been evaluated and is unknown. Therefore, this study aimed to determine the percentage of occurrence, types, and causes of DRPs among PH with VHD patients. Patients and Methods: An observational retrospective study was conducted at Cardiology Centre, Hospital Serdang, from 1st January to 30th April 2021. Data were collected from medication charts, medical progress notes, laboratory and operative charts through electronic Health Information System (eHIS). The types and causes of DRPs were identified and classified based on Pharmaceutical Care Network of Europe's (PCNE) classification system V9.02. The data were analyzed using descriptive statistics. Results: All patients (100%) experienced at least one DRP. Total number of DRPs identified was 120 encounters which were associated with 503 causes. The majority of problems were related to treatment effectiveness (59.1%) and treatment safety (33.4%). The causes of DRPs are mainly related to inappropriate monitoring including therapeutic drug monitoring (18.6%), inappropriate combination of drugs, or drugs and dietary/herbal supplement (10.3%), drug dose was too high (8.9%), drug dose was too low (8.2%) and inappropriate timing of administration or dosing intervals (7.7%). Conclusion: The percentage of DRP occurrence was high in the studied population. Treatment effectiveness and treatment safety issues were the main DRPs identified with various preventable causes. The findings may be useful to guide the planning of measures to prevent and solve future DRPs in the population.

The safety of neoadjuvant hormonal treatment in infants with cryptorchidism.

BACKGROUND/PURPOSE: The standard treatment for boys with non-syndromic cryptorchidism is an early orchidopexy. It is unclear if surgical intervention alone is enough for future fertility. Recent studies show benefit of neoadjuvant or adjuvant hormonal treatment with gonadorelin (GnRH) for spermatogonia maturation based on testicular biopsy. The aim of this prospective study was to assess the safety of this treatment in infants with undescended testis at the recommended timing of early gonadorelin administration and timing of orchidopexy. METHODS: Unilateral cryptorchid full term boys were initially examined (including hormonal, physical and ultrasound examination) at the age of 2.5-3.5 months. At 6 months of age, cryptorchidism was confirmed. Those with non-syndromic cryptorchidism and palpable or sonographically detected testis were randomly assigned into two groups: with and without intranasal gonadorelin treatment. Inclusion criteria were met by 36 boys (21 in GNRH and 15 in the control groups). The following orchidopexy was performed before 12 months of age with repeated examination at time of surgery. Penile size and testicular volume (using ultrasound) and basal serum levels of LH, FSH, testosterone, Inhibin B and AMH were recorded at age of 3.0 (mean) months and 11.0 (mean) months (date of surgery). The stimulation hormonal levels were checked during GnRH administration. RESULTS: Between minipuberty (mean 3 months) and time of orchidopexy (mean 11 months of age) the penile size increased significantly and similarly in both groups. There was no significant difference in the change of the volume of descended testis between the groups nor of the volume of undescended testis. In addition, we did not find any significant difference in the change (drop) of hormonal levels of LH, FSH, Testosterone, Inhibin B and AMH (Table 1a) CONCLUSION: The neoadjuvant gonadorelin stimulation in infants with unilateral undescended testis has not shown any specific effect on the development of penile size, testicular volume and hormonal levels at time of orchidopexy in comparison with boys without stimulation, and in the mid-term, this treatment can be considered safe. Further follow-up is necessary to evaluate the long-term effect of this early treatment.

Axitinib Trough Concentration and its Influence on the Efficacy and Toxicity of Second-line Renal Cell Carcinoma Treatment.

INTRODUCTION: There are known correlations between axitinib exposure and treatment response. The aim of the article was to study relationships between the axitinib steady-state trough concentration and the treatment efficacy and toxicity. PATIENTS AND METHODS: 35 patients (24 men and 11 women), treated or initiating treatment with axitinib, were included in the study over the period 2016-2019. Blood samples were collected following 2 weeks of treatment (in patients who initiated the therapy) and at the end of Cycles 1, 2, and 3 thereafter (in the entire study population). For concentration measurements, high-performance liquid chromatography - mass spectrometry (HPLC-MS) was applied. Treatment efficacy was assessed according to the RECIST 1.1 criteria. Therapy toxicity was evaluated according to the CTCAE criteria. RESULTS: A statistically significant relationship between the first measured axitinib trough concentration (Ctrough first) value and treatment response (P = .004) as well as the median progression-free survival (mPFS) (P = .003) was observed. The association between axitinib Ctrough first and the median overall survival (mOS) was not statistically significant (P = .142). A statistically significant relationship was observed between the mean trough concentration from 3-month observation (Ctrough 1-3m) and treatment response (P = .008) as well as mPFS (P = .001), without a significant relationship for mOS (P = .097). At least grade 3 adverse reactions were meaningfully associated with Ctrough first (P = .012) and Ctrough 1-3m (P = .003). CONCLUSION: There are significant relationships between axitinib Ctrough and treatment response, PFS, and grade ≥ 3 toxicity. The data collected may be used to determine indications for axitinib therapy monitoring based on Ctrough measurements.

A New Approach for a Safe and Reproducible Seeds Positioning for Diffusing Alpha-Emitters Radiation Therapy of Squamous Cell Skin Cancer: A Feasibility Study.

The purpose of this study is to discuss how to use an external radio-opaque template in the Diffusing Alpha-emitters Radiation Therapy (DaRT) technique's pre-planning and treatment stages. This device would help to determine the proper number of sources for tumour coverage, accounting for subcutaneous invasion and augmenting DaRT safety. The procedure will be carried out in a first phase on a phantom and then applied to a clinical case. A typical DaRT procedure workflow comprises steps like tumour measurements and delineation, source number assessment, and therapy administration. As a first step, an adhesive fiberglass mesh (spaced by 2 mm) tape was applied on the skin of the patient and employed as frame of reference. A physician contoured the lesion and marked the entrance points for the needles with a radio opaque ink marker. According to the radio opaque marks and metabolic uptake the clinical target volume was defined, and with a commercial brachytherapy treatment planning system (TPS) it was possible to simulate and adjust the spatial seeds distribution. After the implant procedure a CT was again performed to check the agreement between simulations and seeds positions. With the procedure described above it was possible to simulate a DaRT procedure on a phantom in order to train physicians and subsequently apply the novel approach on patients, outlining the major issues involved in the technique. The present work innovates and supports DaRT technique for the treatment of cutaneous cancers, improving its efficacy and safety.

[Latest findings from the RABBIT register]. / Neues aus dem RABBIT-Register.

Since 2001 rheumatologists throughout Germany have been recruiting patients with rheumatoid arthritis into the biologics register (rheumatoid arthritis: observation of biologics treatment, RABBIT) to investigate the long-term safety and efficacy of modern antirheumatic treatment. Over the past 20 years more than 20,000 patients have been enrolled in the prospective cohort study. This article summarizes the research findings published in 2020/2021, focusing on safety aspects, factors influencing treatment efficacy and patient-reported outcomes. With herpes zoster, facial nerve palsy and psoriasis, several adverse events were investigated that were either reported as a safety signal from clinical trials or through the EudraVigilance database or occurred as a paradoxical reaction under drug treatment. For these events, the influence of biological disease-modifying antirheumatic drug (DMARD) treatment was analyzed. In the publication on herpes zoster, we also considered drug treatment with Janus kinase inhibitors. Severe overweight can influence the success of treatment. There are gender-specific differences and the mode of action of a treatment also determines whether obesity reduces the response to treatment. The majority of patients observed in RABBIT were satisfied with the treatment they have received after 1 year. We were able to show which factors either favor or negatively influence satisfaction with the effectiveness and safety of the treatment. This review article shows that long-term observational studies such as the RABBIT register contribute to the understanding of treatment risks and can identify factors that influence the effects of treatment even after two decades of data collection.

[Insights into pregnancy and breastfeeding in inflammatory rheumatic diseases through observational data]. / Erkenntnisse zu Schwangerschaft und Stillzeit bei entzündlich rheumatischen Erkrankungen durch Beobachtungsdaten.

Information on pregnancy and breastfeeding in women with chronic inflammatory rheumatic diseases is relevant for a successful pregnancy and also for maternal and child health. In general, pregnant and breastfeeding women are excluded from randomized clinical trials and therefore evidence for clinical care and counselling has to be generated from observational studies. In the past decades, various data collections have been established for this purpose in addition to the existing spontaneous reporting systems initiated by drug authorities, with the aim of monitoring the teratogenic risk of a drug. Health insurance claims data, electronic health records and Scandinavian registers are also increasingly being used for research on pregnancy-associated events; however, all these data sources lack the inclusion of the maternal disease, especially with respect to its inflammatory component. Established cohort studies, biologics and disease registries record disease activity but are not designed for pregnancy-specific questions. Pregnancy registries and studies in rheumatology close this gap. In order to be able to make a better assessment of the possibilities and limitations of existing data sources on pregnancy and lactation, they are presented in detail in the following review including their respective advantages and disadvantages and examples from rheumatology are given. In addition, existing collaborations as well as studies for investigating the influence of paternal rheumatic disease are highlighted.

Patient interviews in interprofessional and intercultural contexts (PinKo) - project report on interdisciplinary competence development in students of medicine, pharmacy, and community interpreting.

Background: Hospitals and other medical institutions must prepare for a further increase in patients who are either immigrants or Germans with a migration background. In spite of the unquestionable educational and socio-political relevance of this topic, most German universities do not offer a comprehensive curriculum aimed at increasing intercultural awareness and putting it into practice in the training of students in medicine and pharmacy. Against this background, this article presents the innovative teaching project "Die Triade", which was jointly implemented by the Departments of Medicine, Pharmacy and Translation Studies at the University of Mainz. Aim: The aim is to give an overview of the development, realisation, implementation and consolidation of the course "Patient interviews in interprofessional and intercultural contexts" (PinKo), which was designed in the project "Die Triade". Project description: A two-day course was developed, starting with a block session for all participating students to teach the basics of interprofessional and intercultural competence development. On the second practical training day, students learn and practice triadic conversation in different language groups using scripted roles. While the trainee doctors and pharmacists represent their respective professions in the prepared conversational situations, the interpreting students take on the roles of interpreters and patients. The event is jointly supervised by lecturers from the participating professions and language groups. Results: In the 2016 summer semester and the following winter semester, the course was organised for a total of 112 students. The event as a whole was evaluated by means of a questionnaire by the students of the participating departments (Medicine (M) N=8, Pharmacy (P) N=60; Translation (T) N=44). Overall, the event was rated as good (1=very good, 6=insufficient) ((M) 1.67/2.00; (P) 2.29/3.33; (T) 1.50/1.86). The course tended to be rated lower by pharmacy students; this also applies to the rating of the development of interprofessional competences ((M) 1.33/2.00, (P) 2.00/2.93, (T) 1.82/2.25). Discussion: The course is suitable for the acquisition of interprofessional as well as intercultural competences. However, in order to improve the course in a participant-centred way, train larger numbers of participants and include additional healthcare occupations such as nursing or assistant medical professions, adaptations of the concept would be necessary. In this context, the digitalisation of the learning content appears to be particularly useful for ensuring that the course can be adapted to heterogeneous groups of participants and to optimise in-person times for further opportunities for practice.

Relación entre el uso de glucocorticoides y el daño crónico en Lupus Eritematoso Sistémico: una asociación precoz y nociva. Estudio exploratorio / Glucocorticoids related damage in Systemic Lupus Erythematosus: an early and harmful association. An exploratory analysis / Relação entre o uso de glicocorticóides e dano crônico no Lupus Eritematoso Sistêmico: uma associação precoce e prejudicial. Estudo exploratório

Resumen: Introducción: La actividad inflamatoria persistente el Lupus Eritematoso Sistémico provoca daño permanente. El daño permanente puede ser atribuido a la enfermedad y/o al tratamiento, en particular los glucocorticoides. El objetivo de este trabajo fue conocer la relación entre el daño crónico y la exposición a glucocorticoides. Material y métodos: Se realizó un muestreo no probabilístico de pacientes con lupus eritematoso sistémico. Se analizaron variables demográficas, niveles de actividad, dosis prednisona iniciales y acumuladas y niveles de daño medidos por "SLICC Damage Index " en diferentes periodos de la enfermedad. El daño fue clasificado en "relacionado" y "no relacionado" con el uso de glucocorticoides. Resultados: Se analizaron 30 pacientes, todos de sexo femenino. La media de seguimiento fueron 155 (DE 127) meses. Al final del seguimiento 13/30 (43,3%) pacientes presentaron daño orgánico. Los pacientes que presentaron daño orgánico "relacionado" con glucocorticoides al final del seguimiento presentaron dosis de inicio de prednisona significativamente mayores que los que no presentaron daño 53,3 (DE 10,3) mg/día vs. 28, 3 (DE 24) mg/día, p<0,05. Dosis de inicio mayores a 30 mg/día se relacionaron con el daño al final del seguimiento, independientemente de los niveles de actividad considerados, OR 2,05 (IC 95% 1,5 - 4,0). Las dosis acumuladas de prednisona mayores a 3000 mg en el primer año se asociaron con daño relacionado con glucocorticoides al final del seguimiento (p < 0,05). Conclusiones: Existe una acumulación de daño a lo largo del tiempo relacionado con los glucocorticoides. Esta relación es precoz, esto es, las dosis de inicio pueden relacionarse con la acumulación de daño a largo plazo, particularmente considerando los dominios relacionados con glucocorticoides, independientemente del nivel de actividad considerado.

Abstract: Introduction: Persistent activity causes irreversible organ damage in Systemic Lupus Erythematosus (SLE). Permanent damage can be attributed to the disease and to the treatment, particularly glucocorticoids. We aimed to know the relationship between the presence of organ damage and the exposure to glucocorticoids (GCC). Methodology: A non-probabilistic retrospective study of patients with SLE was performed. Demographic variables, activity levels, initial, accumulated prednisone dose and damage measured by "SLICC Damage Index (SDI)" at various stages from the diagnosis of the disease, were analyzed. Damage was classified in related and not related to GCC. Results: Thirty patients were analyzed, all women. The mean follow-up was 155 (SD: 127) months. At the end of follow-up 13/30 (43.3%) patients presented organ damage. Patients who had GCC-related damage at the end of follow-up had a significantly higher mean starting dose of prednisone, 53.3 (SD: 10.3) mg/d vs. 28.3 (SD: 24) mg/d, p <0.05. The effect on damage was observed with prednisone starting dose greater than 30 mg/d, regardless of the level of activity at the onset of the disease, OR 2.05 (CI 95% 1.5 - 4.0). Cumulative doses of prednisone at one year greater than 3000 mg, were related to GCC-related damage at the end of the follow-up (p < 0.05). Conclusions: There is an accrual of damage over time associated to glucocorticoids exposure. It is highlighted that the relationship is early, that is, the starting dose will probably signify the accumulation of damage, especially in glucocorticoid-related domains, regardless of activity levels.

Resumo: Introdução: A atividade inflamatória persistente do Lúpus Eritematoso Sistêmico (LES) causa danos permanentes. Danos permanentes podem ser atribuídos a doenças e / ou tratamento, particularmente glicocorticóides. O objetivo deste trabalho foi conhecer a relação entre dano crônico e exposição a glicocorticóides. Material e métodos: Foi realizada uma amostragem não probabilística de pacientes com LES. Variáveis demográficas, níveis de atividade, doses iniciais e acumuladas de prednisona e níveis de dano medidos pelo "SLICC Damage Index (SDI)" foram analisados em diferentes períodos da doença. O dano foi classificado como "relacionado" e "não relacionado" ao uso de glicocorticóides. Resultados: 30 pacientes, todos do sexo feminino, foram analisados. O seguimento médio foi de 155 (DP 127) meses. Ao final do seguimento 13/30 (43,3%) pacientes apresentavam lesão orgânica. Os pacientes que apresentaram lesão orgânica "relacionada" aos glicocorticoides ao final do seguimento tiveram doses iniciais de prednisona significativamente maiores do que aqueles que não apresentaram lesão: 53,3 (DP 10,3) mg / dia vs. 28,3 (SD 24) mg / dia, p <0,05. Doses iniciais maiores que 30 mg / dia foram relacionadas a danos ao final do seguimento, independentemente dos níveis de atividade considerados, OR 2,05 (IC 95% 1,5 - 4,0). Doses cumulativas de prednisona maiores que 3000 mg no primeiro ano foram associadas a danos relacionados aos glicocorticoides no final do acompanhamento (p <0,05). Conclusões: Há um acúmulo de danos ao longo do tempo relacionados aos glicocorticóides. Essa relação é precoce, ou seja, as doses iniciais podem estar relacionadas ao acúmulo de danos em longo prazo, principalmente considerando os domínios relacionados aos glicocorticóides, independentemente do nível de atividade considerado.

Effect of therapeutic UVC on corneal DNA: Safety assessment for potential keratitis treatment.

PURPOSE: Antimicrobial ultraviolet C (UVC) has proven efficacy in vitro against keratitis isolates and has potential to treat corneal infection if safety can be confirmed. METHOD: Safety of 265 nm, 1.93 mW/cm2 intensity UVC (15-300 s exposures) was investigated in vitro via cyclobutane pyrimidine dimer (CPD) formation in DNA of human cultured corneal epithelial cells; ex vivo, by evaluating UVC transmissibility as a function of porcine corneal thickness; and in vivo, by evaluating CPD induction in the mouse cornea following UVC exposure. RESULTS: A single exposure of 15 s UVC did not induce significant CPD formation (0.92 ± 1.45%) in vitro relative to untreated control (p = 0.93) whereas 300 s exposure caused extensive CPD formation (86.8 ± 13.73%; p < 0.0001). Cumulative exposure to 15 s UVC daily for 3 days induced more CPD (14.6 ± 8.2%) than a single equivalent 45 s exposure (8.3 ± 4.0%) (p < 0.001) but levels returned to baseline within 72 h (p = 0.29), indicating highly efficient DNA repair. Ex vivo, UVC transmission decreased sharply with increasing corneal thickness, confirming UVC effects are limited to the superficial corneal layers. In vivo evaluations demonstrated no detectable CPD after three consecutive daily 15 s UVC exposures, whereas a single 300 s exposure induced extensive CPD formation in superficial corneal epithelium. CONCLUSION: Up to three daily doses of 15 s UVC, in vivo, appear safe with respect to CPD formation. Ongoing research exploring UVC as a possible treatment for microbial keratitis is warranted.

[Effectiveness and safety of sofosbuvir/velpatasvir combination ± ribavirin in the treatment of Chinese adults with chronic hepatitis C virus infection].

Objective: To understand the effectiveness and safety sofosbuvir/velpatasvir (SOF/VEL) combination ±ribavirin in the treatment of chronic hepatitis C virus (HCV) infection in China. Methods: A total of 96 Chinese adults with chronic HCV infection who were treated with SOF/VEL combination ± ribavirin for 12 weeks between July 2018 and February 2020 were selected. HCV RNA, routine blood test, liver, kidney and coagulation function, abdominal Color Doppler ultrasound or CT and liver stiffness were detected at baseline, 4 weeks of treatment, end of treatment and 12 weeks of follow-up. Adverse events and laboratory abnormalities during the treatment were recorded. A t-test was used to compare the measurement data between the two groups, and the analysis of variance was used for multiple group comparison. Results: A total of 93 cases (96.9%) achieved sustained virological response (SVR12), of which 3 cases had relapsed. 88 cases (91.7%, 88/96) had achieved rapid virological response (RVR). 96 cases (100%) had achieved virological response by the end of treatment (EOT). In patients with decompensated liver cirrhosis, the average baseline Child-Pugh score and Model for End-Stage Liver Disease score was 7.4±1.0, and 11.4±1.7, respectively. Among them, 12 cases of the SOF/VEL combined with RBV treatment had achieved SVR12 (100%) at 12 weeks, while only 3 of the 5 cases of single-tablet regimen of SOF/VEL had achieved SVR12 (60%). There was no significant difference between creatinine levels and baseline during or 12 weeks after treatment. The incidence of adverse events in patients with chronic hepatitis C and compensated cirrhosis was 6.3% (5/79), while that in patients with decompensated cirrhosis was 35.3% (6/17). The most common adverse events were hyperbilirubinemia, fatigue and anemia. There were no serious adverse events, deaths or discontinuation of treatment due to adverse events. Conclusion: SOF/VEL combination ± ribavirin in the treatment of various common genotypes of chronic hepatitis C, compensated cirrhosis, decompensated cirrhosis and hepatocellular carcinoma has higher SVR12 in China, and the tolerance and safety are good.

Low Incidence of SARS-CoV-2 in Patients with Solid Tumours on Active Treatment: An Observational Study at a Tertiary Cancer Centre in Lombardy, Italy.

Background: The incidence and prognosis of SARS-CoV-2-positive cancer patients on active oncologic treatment remain unknown. Retrospective data from China reported higher incidence and poorer outcomes with respect to the general population. We aimed to describe the real-word incidence of SARS-CoV-2 in cancer patients and the impact of oncologic therapies on the infection. Materials & Methods: In this study, we analysed all consecutive cancer patients with solid tumours undergoing active intravenous treatment (chemotherapy, immunotherapy, targeted therapy, alone or in combination) between 21 February and 30 April 2020, in a high-volume cancer centre in Lombardy, Italy. We focused on SARS-CoV-2-positive patients, reporting on the clinical characteristics of the cancer and the infection. Results: We registered 17 SARS-CoV-2-positive patients among 1267 cancer patients on active treatment, resulting in an incidence of 1.3%. The median age was 69.5 years (range 43-79). Fourteen patients (82%) required hospitalisation for COVID-19 with a median in-hospital stay of 11.5 days (range 3-58). Fourteen of the seventeen (82%) were treated for locally advanced or metastatic disease. We could not demonstrate any correlation between SARS-CoV-2 infection and tumour or treatment type. The COVID-19-related fatality rate was 29% (5/17), which was higher than that of the general population cared for in our centre (20%). Conclusions: Active oncologic treatments do not represent a risk factor for SARS-CoV-2 infection in cancer patients. However, the prognosis of infected cancer patients appears to be worse compared with that of the non-oncologic population. Given the low number of SARS-CoV-2-positive cases and the uncertainties in risk factors that may have an impact on the prognosis, we advocate for the continuum of cancer care even during the current pandemic.

El tratamiento intralesional de Leishmaniasis cutánea es seguro frente al riesgo de complicaciones mucosas? / Is the intralesional treatment of cutaneous Leishmaniasis safe against the risk of mucosal complications?

OBJETIVO: evaluar la seguridad a largo plazo frente al riesgo de complicaciones mucosas del uso intralesional de antimoniales pentavalentes en pacientes con leishmaniasis cutánea comparado con el uso sistémico de los mismos. MÉTODOS: estudio observacional, cuantitativo de tipo longitudinal retrospectivo. Se analizó un total de 66 registros clínicos de pacientes, con diagnóstico de Leishmaniasis cutánea del parque Isiboro Secure durante el periodo 2012 a 2016. Se evaluó un total de 46 tratamientos sistémicos y 20 intralesionales. RESULTADOS: la evaluación clínica realizada entre 4 y 7 años posteriores a la cicatrización de las lesiones cutáneas de Leishmaniasis mostró la ausencia de desarrollo de lesiones mucosas. Así mismo no se reportó fallas terapéuticas, recidivas ni efectos adversos a corto plazo. CONCLUSIONES: el tratamiento intralesional fue seguro y eficaz a largo plazo y es una opción confiable para el tratamiento de leishmaniasis cutánea evitando las complicaciones futuras de la enfermedad.

OBJECTIVE: to assess the long-term safety against the risk of mucosal complications of intralesional pentavalent antimonials (PA) in patients with cutaneous Leishmaniasis compared to the systemic use of PA. METHODS: retrospective longitudinal quantitative observational study. A total of 66 clinical records of patients diagnosed with cutaneous Leishmaniasis in Isiboro Secure Park were analyzed between 2012 and 2016. A total of 46 systemic and 20 intralesional treatments were evaluated. RESULTS: clinical evaluation 4-7 years after healing of Leishmaniasis skin lesions showed no development of mucosal lesions. Likewise, no therapeutic failures, relapses or short-term adverse effects were reported. CONCLUSIONS: intralesional treatment was safe and effective in the long term and is a reliable option for the treatment of cutaneous Leishmaniasis avoiding the future complications of the disease.

Guidelines, good practices and best clinical health practices: valuable guidance for physicians and judges?

Enactment of law n. 24, 8th March 2017, (so-called "Gelli-Bianco" law), has given rise to substantial innovations in the realm of medical liability: on the one hand, an attempt has been made towards redefining the boundaries of professional liability, for the purpose of curbing the use of "defensive medicine"; on the other hand, there is the effort to delineate good medical conduct by means of "institutionalization" and a greater degree of consistency of guidelines and good clinical health care practices. There are, however, thought-provoking cues concerning the relationship between the two concepts, which can be sensibly developed, even in light of international scientific literature. This paper has been designed to critically analyze both principles and their relation within the framework of the newly enacted piece of legislation denominated "Gelli-Bianco", in light of the Italian jurisprudence while at the same time, searching for common ground in international law, particularly Anglo-Saxon countries, aiming to clarify the lawmakers' ultimate goal as well as the law's practical scope of application.

Treatment modalities for hip and knee osteoarthritis: A systematic review of safety.

Current guidelines on the management of hip and knee osteoarthritis (OA) do not compare safety of treatment modalities. We therefore systematically reviewed 20 studies investigating mortality and serious complications of both medical and surgical treatments for hip and knee OA using PubMed, Scopus, Web of Knowledge and Google Scholar. Mortality was the highest for naproxen (hazard ratio (HR) = 3 (1.9, 4.6)) and lowest for total hip replacement (relative risk (RR) = 0.7 (0.7, 0.7)). Highest gastrointestinal complications were reported for diclofenac (odds ratio (OR) = 4.77 (3.94, 5.76)) and lowest for total knee replacement (HR = 0.6 (0.49, 0.75)). Ibuprofen had the highest renal complications (OR = 2.32 (1.45, 3.71)), whereas celecoxib had the highest cardiovascular risk (OR = 2.26 (1, 5.1)) and lowest was for tramadol (RR = 1.1 (0.87, 1.4)). Results show that medical management of hip and knee OA, particularly with non-steroidal anti-inflammatory drugs, may carry higher mortality compared to surgery. Careful consideration should be given to medical management taking into account known co-morbidities.