Reported Adverse Events in a Multicenter Cohort of Patients Ages 6-18 Years with Cystic Fibrosis and at Least one F508del Allele Receiving Elexacaftor/Tezacaftor/Ivacaftor.

OBJECTIVE: To describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers. STUDY DESIGN: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period. RESULTS: Among 608 patients on ETI, 109 (17.9%) reported at least one AE. The majority (N=85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs. 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA p-value 0·026). CONCLUSIONS: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted.

Sudden death after facial impacts: Is the brainstem involved?

Three deaths following facial impacts in the presence of witnesses and resulting in brain lesions that were visualized only on pathological examination were studied at the forensic medicine institute of Marseille. Craniofacial impacts, even of low intensity, received during brawls may be associated with brain lesions ranging from a simple knock-out to fatal injuries. In criminal cases that are brought to court, even by autopsy it is still difficult to establish a direct link between the violence of the impact and the injuries that resulted in death. During a facial impact, the head undergoes a movement of violent forced hyperextension. Death may thus be secondary to the transmission of forces to the brain, either by a mechanism involving nerve conduction that may be termed a reflex mechanism (for example by vagal hyperstimulation) or by injury to the central nervous system (axonal damage). In such situations, autopsy does not make it possible to determine the cause of death, but only to suspect it in a context of voluntary violence in the presence of witnesses, with or without violent injury observed on external examination or on superficial incisions to determine the extent of bruises or hematoma. Systemic and comprehensive investigation involving pathology and toxicology is essential in any medicolegal case for positive interpretation and discrimination of other causes of death.

Forensic use of the Greulich and Pyle atlas: prediction intervals and relevance.

OBJECTIVE: The Greulich and Pyle (GP) atlas is one of the most frequently used methods of bone age (BA) estimation. Our aim is to assess its accuracy and to calculate the prediction intervals at 95% for forensic use. METHODS: The study was conducted on a multi-ethnic sample of 2614 individuals (1423 boys and 1191 girls) referred to the university hospital of Marseille (France) for simple injuries. Hand radiographs were analysed using the GP atlas. Reliability of GP atlas and agreement between BA and chronological age (CA) were assessed and prediction intervals at 95% were calculated. RESULTS: The repeatability was excellent and the reproducibility was good. Pearson's linear correlation coefficient between CA and BA was 0.983. The mean difference between BA and CA was -0.18 years (boys) and 0.06 years (girls). The prediction interval at 95% for CA was given for each GP category and ranged between 1.2 and more than 4.5 years. CONCLUSION: The GP atlas is a reproducible and repeatable method that is still accurate for the present population, with a high correlation between BA and CA. The prediction intervals at 95% are wide, reflecting individual variability, and should be known when the method is used in forensic cases. KEY POINTS: • The GP atlas is still accurate at the present time. • There is a high correlation between bone age and chronological age. • Individual variability must be known when GP is used in forensic cases. • Prediction intervals (95%) are large; around 4 years after 10 year olds.

Serum uric acid and its relationship with metabolic syndrome and cardiovascular risk profile in patients with hypertension: insights from the I-DEMAND study.

BACKGROUND AND AIMS: The independent role of serum uric acid (SUA) as a marker of cardio-renal risk is debated. The aim of this study was to assess the relationship between SUA, metabolic syndrome (MS), and other cardiovascular (CV) risk factors in an Italian population of hypertensive patients with a high prevalence of diabetes. METHODS AND RESULTS: A total of 2429 patients (mean age 62 ± 11 years) among those enrolled in the I-DEMAND study were stratified on the basis of SUA gender specific quartiles. MS was defined according to the NCEP-ATP III criteria, chronic kidney disease (CKD) as an estimated GFR (CKD-Epi) <60 ml/min/1.73 m(2) or as the presence of microalbuminuria (albumin-to-creatinine ratio ≥2.5 mg/mmol in men and ≥3.5 mg/mmol in women). The prevalence of MS, CKD, and positive history for CV events was 72%, 43%, and 20%, respectively. SUA levels correlated with the presence of MS, its components, signs of renal damage and worse CV risk profile. Multivariate logistic regression analysis revealed that SUA was associated with a positive history of CV events and high Framingham risk score even after adjusting for MS and its components (OR 1.10, 95% CI 1.03-1.18; P = 0.0060; OR 1.28, 95% CI 1.15-1.42; P < 0.0001). These associations were stronger in patients without diabetes and with normal renal function. CONCLUSIONS: Mild hyperuricemia is a strong, independent marker of MS and high cardio-renal risk profile in hypertensive patients under specialist care. Intervention trials are needed to investigate whether the reduction of SUA levels favorably impacts outcome in patients at high CV risk.

Medication misuse and abuse: duties and responsibilities of dispensing pharmacists.

Misuse of medications can have major consequences for the consumer or patient's health. In the case of a drug delivered only on medical prescription, the misuse usually results from an error or negligence on the part of the prescribing doctor and/or the pharmacist dispensing the medication. But whereas, under French Law, doctors are regularly prosecuted for their irresponsibility, pharmacists frequently avoid any legal charges. This is even more surprising in view of the fact that French Legislation controls the practice of pharmacy very strictly. The authors discuss four cases that illustrate this issue and present a study of comparative pharmaceutical law requirements.

3D CT scan study of fetal cranial base: interests of occipital bone measurements in age estimation.

OBJECTIVES: Cranial base development during fetal life is of major interest for many research purposes. In this study, we focused on fetal age estimations which are extremely important in forensic contexts. Nevertheless, there have been very few studies using occipital measurements to determine fetal age. OBJECTIVES: To evaluate change in the sagittal length/maximum width ratio of the basilar part of the occipital bone and to propose a simple and reliable method for fetal age determination. METHODS: A sample of 30 male and 7 female fetuses aged 24 to 41 weeks amenorrhea underwent CT scan. Occipital bones were reconstructed (Amira 4.0) and measurements were carried out on each part. RESULTS: A multivariate analysis (ANOVA) gave an age formula using right exoccipital measurements and a linear regression supplied the age of reversion of the sagittal length/maximum width ratio. CONCLUSION: This preliminary study clearly highlighted the promises of 3D CT-Scan studies of fetal cranial base and gave interesting results and the method deserves to be tested on a larger sample.

[The Dintilhac report and its implications for forensic neuropsychological evaluation]. / Implication du rapport Dintilhac dans l'expertise neuropsychologique.

BACKGROUND: When preparing neuropsychological expert reports, the neuropsychologist is asked to make a precise assessment of the victims' cognitive dysfunction, generally after traumatic head injury. The expert is usually required to assess the nature of the neuropsychological deficits, their correlation with any brain lesions and their imputability to the accident or crime in question, to estimate a possible date of stabilisation and to evaluate the heads of damage. The basic principle of compensation for personal injury is to consider the circumstances in which the victim would have been if the prejudicial event (for example, the accident) had not occurred and to assess, on the basis of these various heads of damage, compensation for the injury suffered. While it is not the neuropsychologist's role to evaluate the compensation as such, he or she has however to specify which aspects of cognitive function are deficient and what impact this dysfunction has on a personal and occupational level. Until recently, compensation for personal injury, and notably for cognitive deficits, was assessed with reference to nine principal heads of damage, in particular the conventional concepts of total temporary disability (incapacité temporaire totale [ITT]), defined as the period during which the victim was temporarily unable to carry out their usual occupational and personal activities, and partial permanent disability (incapacité partielle permanente [IPP]), defined as a percentage and corresponding to the reduction, after stabilisation, in the victim's functional capacity - that is, their physical and psychological potential - here again from an occupational and personal viewpoint. However, concretely, the emphasis had shifted to take into account only the pecuniary aspects of injury relating to the domain of "having", that is the loss of income due to cessation of work, while the non-pecuniary aspects relating to the domain of "being" were often ignored. NEW CLASSIFICATION: The Dintilhac report has established a new classification of heads of physical damage which abandons these two ambiguous concepts of ITT and IPP. Damage now includes three categories: pecuniary and non-pecuniary; temporary and permanent and damage to direct and indirect victims. We define the new heads of damage to direct victims, illustrate them with examples from neuropsychological expert reports, compare the old and the new classifications and discuss the implications of the Dintilhac report for expert assessment. The report appears to remove the ambiguities previously mentioned, since ITT has been replaced by two new heads of damage which are clearly defined as pecuniary and non-pecuniary: "loss of present occupational income" (pertes de gains professionnels actuels [PGPA]) and "temporary functional deficiency" (déficit fonctionnel temporaire [DFT]), respectively. Similarly, IPP is replaced by two new heads of damage, which are also clearly defined as pecuniary and non-pecuniary and are the poststabilisation equivalents of PGDA and DFT: these are "loss of future earnings" (pertes de gains professionnels futurs [PGPF]) and "permanent functional deficiency" (déficit fonctionnel permanent [DFP]). Concerning the other heads of damage, the amendments introduced by the new classification do not basically modify the earlier concepts but are nevertheless more precise in certain respects. The "pretium doloris", or "price of pain", is replaced by "suffering sustained" (souffrances endurées [SE]) with little fundamental change. The same is true of "loss of amenity" (préjudice d'agrément [PA]). The term of "aesthetic impairment" (préjudice esthétique [PE]) also remains the same, but whereas it previously related only to permanent impairment, it now includes temporary impairment, before stabilisation. What was formerly termed "loss of sexual function" now consists of "loss of sexual function" (préjudice sexuel [PS]) as well as "loss of the prospect of founding a family" (préjudice d'établissement [PE]), allowing a finer distinction to be made between the damages sustained. The former "third party" (tierce personne) is now covered under the headings of "assistance by a third party" (assistance par tierce personne [ATP]), "expenses of accommodation conversion" (frais de logement adapté [FLA]) and "expenses of vehicle conversion" (frais de véhicule adapté [FVA]), which here again provides greater precision in the heads of compensation. Lastly, what was previously known as "loss of opportunity" (perte de chance) is divided into three different categories: "loss of education, whether at school, university or in training" (préjudice scolaire, universitaire ou de formation [PSU]), "loss of future occupational earnings" (perte de gains professionnels futurs [PGPF]) and in part the "occupational impact" (incidence professionnelle [IP]). CONCLUSION: In summary, these various heads of damage concerning direct victims that are proposed by the Dintilhac report result in a more detailed evaluation of compensation for personal injury. Assessment of a certain number of heads of damage is an integral part of the preparation of a neuropsychological expert report and the fact that these heads of damage are now better defined makes the expert's task easier. As the neuropsychologist, generally called upon to give an expert opinion, now has better knowledge of this new classification, he or she will be able to give clearer and fuller answers to the questions raised and so comply with the principle of civil law relating to compensation for personal injury: "compensate the injury, all the injury, but nothing except the injury".

[Value of the sesamoid bone of the thumb in the determination of bone age]. / Quelle valeur accorder à l'os sésamoïde du pouce dans la détermination de l'âge osseux?

PURPOSE: To assess the presence of ossification of the sesamoid bone of the thumb as a function of age and compare the results to data from the atlas by Greulich and Pyle describing the ossification of this bone in girls of 11 years and boys of 13 years. Materials and methods. Prospective study of 1372 children (780 boys and 592 girls between the ages of 0.4 and 19.7 years, mean age of 9.7 years) with known chronological age requiring radiographic evaluation of the wrist-hand after minor trauma. The presence of a sesamoid was analyzed by logistic regression using the method of probits. RESULTS: The minimum and maximum ages in our sample population were 10-15.1 years for boys and 8.8-15.2 years for girls. The P50 value (method of probits) corresponded to the chronological age at which 50% of the population had a visible sesamoid. It was 12.1 years for boys and 10.2 years for girls. CONCLUSION: The timing of ossification of the sesamoid of the thumb is widely variable. Ossification of this sesamoid should not be used as a precise indicator when determining bone age using the atlas by Greulich and Pyle.

[No-fault medical accidents: review of two years' activity of the regional commission for the compensation of medical accidents of the Provence-Alpes-Côtes d'Azur region (PACA)]. / L'accident médical non fautif: bilan de deux années d'activité de la commission régionale de conciliation et d'indemnisation des accidents médicaux de la région PACA.

Compensation for victims of medical accidents identified as no-fault medical accidents (NFMA) will be financed by national solidarity: this is a major and innovative feature of the Law of March 4, 2002 relative to Patients' Rights. In this review, we analyse the decisions of the regional commission on compensation of medical accidents in the Provence-Alpes-Côtes d'Azur (PACA) region of France in 2004 and 2005, and we attempt to identify the prevalence of certain surgical procedures liable to result in NFMA and to define the concept of "unintended consequences" in the context of state of health of the patient and the predictable course of the malady. We hope to improve the medical information given to the patient and thereby the overall quality of management. NFMA was acknowledged in 57 claims, about 10% of all those received by the commission during this period. Nearly half of the claims were within the competence of the commission because of the existence of serious sequelae (Permanent Partial Disability) in 47%. No typical profile of age or gender emerged in the patients with NFMA. The majority of cases occurred after surgical procedures, in particular gastrointestinal surgery and orthopaedic surgery; 91% were planned procedures. We did not identify increased risk related to any given type of surgery, particular disease condition, or precise anatomic region. Complications were those usually observed such as neurological complications in vascular surgery or perforations in gastrointestinal surgery. The interpretation of NFMA has undergone an evolution during this two-year period. In 2004, previous poor health status precluded acknowledgment of a medical accident, the argument being that there was a predisposition to the complication which occurred. In 2005, compensation was based on a reduced Partial Permanent Disability score compared to the patient's previous health status. This became a means of measuring the impact of the medical complication on an already predictably unfavorable clinical course without medical intervention, and the legal aspect of the "ineluctable nature" of this course.

[Cervico-thoracic liposarcoma in an HIV patient]. / Liposarcoma dorsocervicale in un paziente HIV-positivo.

Association between cervico-thoracic liposarcoma and HIV infection is uncommon. The etiopathology remains unclear and clinical symptoms can be various, often not very evident or absolutely absent. Preoperative diagnosis is based on modern imaging techniques. In selected cases, the ideal procedure is surgical treatment which allows good long-term results. A case of cervico-thoracic liposarcoma in HIV patient is presented.

[Integrated treatment of breast cancer: review of our experience]. / Trattamento integrato del carcinoma della mammella: revisione della nostra esperienza.

In the industrialized West countries the breast cancer represents the most frequent malignant neoplasia in the women. From over 30 years we have a progressive increase of frequency of breast carcinoma. Mortality is substantially unchanged. The Authors, on the base of casuistry accumulated in five years of activity, trace a diagnostic-therapeutic run to the purpose to favour a line of behavior, practice and actual, for the management of breast cancer.

Short term effects of physical exercise and low calorie diet on left ventricular function in obese subjects: a tissue Doppler study.

BACKGROUND AND AIM: The effects of combined physical exercise and a hypocaloric diet on left ventricular function in obese subjects without heart disease are not well defined and have never been studied with the tissue Doppler technique. The purpose of our study was to describe the modification of left ventricular systolic and diastolic functions after a short period of physical exercise and a hypocaloric diet in obese patients. METHODS AND RESULTS: Fifteen patients (10 females and 5 males) aged 29.7+/-6.1 years with uncomplicated obesity (mean body mass index=41.4+/-5.5 kg/m(2)) were subjected to a low calorie diet and physical exercise. Systolic and diastolic functions were evaluated by Doppler and tissue Doppler echocardiography. After 3 weeks echocardiographic and conventional Doppler measurements were unchanged, while Sa increased (0.109+/-0.019 vs 0.118+/-0.016 m/s) and Ea decreased (0.162+/-0.029 vs 0.147+/-0.022 m/s, P=0.044) resulting in a decrease in Ea/Aa (1.66+/-0.53 vs 1.40+/-0.28, P=0.033) and an increase in E/Ea (5.65+/-1.00 vs 6.35+/-1.21, P=0.038). CONCLUSION: Physical exercise and a hypocaloric diet in obese healthy subjects result in an improvement of a TDI index of systolic function and a slight reduction in early diastolic velocity of mitral annulus.

[Endoscopic resection of a gastric haemangioma: case report]. / Resezione endoscopica di un emangioma dello stomaco: a proposito di un caso clinico.

Gastric haemangiomas are an infrequent histological type of gastrointestinal benign tumors. Diagnosis is based on imaging but only pathological examination can give certainty. Endoscopic resection, according some specific criteria, is the gold standard procedure. Authors present a case of cavernous haemangioma diagnosed and treated by endoscopic procedure.

The court medical expert in France: changes in status.

In France the status of the court expert has undergone a significant change with the adoption of statute no. 2004-130 of 11 February 2004 and its implementing regulations no. 2004-1463 of 23 December 2004. This article looks at the two most outstanding aspects of this change in status: (i) the conditions for registering on a court of appeal list and, (ii) the practical details of the quality control of the court expert's work as exercised by the judge. The article concludes with a brief comparison with the expert witness situation in England and Wales.

[Complications of the Lichtenstein inguinal hernioplasty]. / L'ernioplastica secondo Lichtenstein: a proposito delle complicanze.

The Lichtenstein inguinal hernioplasty in the original version or with small variations currently allows good results both from the surgical point of view and in terms of reduction of the sanitary expenses. "Tension free" repair and diffusion of local anesthesia allow a drastic reduction of the hospital stay, a early time of the working activity and the diffusion of the admission to the Day Hospital. The authors introduce the own casuistic that comprise 1116 inguinal hernioplasty in 1,034 patients and on the base of two studies, a retrospective one and another prospective, they conclude that a greater attention in the behavior of the intervention and a more accurate preparation of the patients represent fundamental moments to obtain even more satisfactory results.

Spigelian hernia: a case report and review of the literature.

Spigelian hernia is a rare abdominal hernia that occurs through Spigelian aponeurosis. The Authors present a case of Spigelian hernia associated with narrowing of sigmoid colon and diverticular pathology. They also described historical background, surgical anatomy and etiopathogenesis of this hernia. By a remarkable revision of literature, they sum up epidemiology and clinical features of Spigelian hernia. Furthermore, they discuss diagnostic and therapeutic principles.

[The clinical significance of lymph node micrometastases and of concept of sentinel lymph node]. / Significato biologico delle micrometastasi linfonodali e del concetto di linfonodo sentinella.

Micrometastases, (metastases smaller than 2 mm), had benn subject of several studies. In literature is documented a prognostic worsening due to their presence. Research of micrometastases in sentinel lymph node is of great interest and can allow a clinical application with profitable cost efficacy ratio. The Authors discuss about clinical, prognostical and therapeutical implicationes in case of micrometastases into sentinel lympho nodes.

[Leiomyosarcoma of brachiocephalic vein: case report]. / Leiomiosarcoma del tronco brachiocefalico: a proposito di un caso clinico.

Primary leiomyosarcoma of venous origin is a rare but frequently lethal disease. Clinical symptoms can be different, often not much evident or absolutely absent. Preoperative diagnosis is difficult also with modern imaging and only pathological examination can identify this malignant tumor. Successful therapy requires early surgery but the long-term survival is poor. A case of leiomyosarcoma arising from veins has been presented.