Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta.

PURPOSE: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12. METHODS: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids. RESULTS: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment. CONCLUSION: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

Classic Metaphyseal Lesions among Victims of Abuse.

OBJECTIVE: To use legal statements by perpetrators to gain new insights into the causative mechanism of classic metaphyseal lesion (CML). The CML, so called "corner fracture," is considered a highly specific marker for abuse in infants. However, the precise correlation between CMLs and abusive head trauma is still unknown. STUDY DESIGN: In this retrospective observational study, we selected 67 cases with at least 1 CML from a 15-year cohort of legally prosecuted child abuse cases. Their clinical, radiologic, and forensic records were analyzed. In 27 cases, the perpetrator confessed to abusing the child and described the events. Potential associations with subdural hematoma and with confession were evaluated using 2 separate binary logistic regression models. RESULTS: All 67 infants showed other signs of abuse. Median age was 3.4 months. Over 65% had multiple CMLs. Knees and ankles were predominantly involved (64%). Only CMLs of the shoulder were significantly associated with subdural hematoma (P = .03). Different-age fractures were more common in the nonsubdural hematoma group (P = .01). In the group with confessions, perpetrators admitted inflicting violent indirect skeletal forces (torsion, traction, compression, and forced movements). The most common circumstance was diapering (44%), reported by male perpetrators only (P = .03) followed by dressing/undressing (30%). The violence was habitual in 67% of cases. CONCLUSIONS: This unique forensic case series shows that CMLs are caused by violent acts inflicted most during physical care of infants. The frequency of habitual violence responsible for CMLs deserves greater attention.

Evaluation of a Temporal Association between Vaccination and Subdural Hematoma in Infants.

OBJECTIVE: To investigate a temporal association between vaccination and subdural hematoma, the main feature of abusive head trauma. STUDY DESIGN: From a prospective population-based survey carried out in 1 administrative district in France between January 2015 and April 2017, including all infants between 11 and 52 weeks old who underwent a first cerebral imaging (computerized tomography scan or magnetic resonance imaging), we conducted a nested case-control study. Vaccine exposure was compared between cases (infants with subdural hematoma) and 2-3 paired controls, without subdural hematoma or any other imaging findings compatible with abusive head trauma. Cases and controls were matched on chronological (±7 days) and gestational (≤33 vs >33 weeks) ages, respectively. Vaccination status was collected in the personal national pediatric health booklet. RESULTS: Among the 228 prospectively surveyed infants, 28 had subdural hematoma including 22 with abusive head trauma. The mean chronological age at imaging was 5.3 months among the 28 cases and the 62 controls, who did not differ significantly in median time since last vaccination (1.4 vs 1.3 months, P = .62) or frequency of at least 1 vaccination since birth (86% vs 89%; matched-pairs OR 0.77, 95% CI 0.17-3.86) or within 7 days (0.94, 0.08-6.96), 14 days (0.70, 0.12-2.92), or 21 days (0.48, 0.08-1.98) before cerebral imaging. CONCLUSIONS: We found no significant temporal association between vaccination and subdural hematoma diagnosis, which must continue to be considered a red flag for abusive head trauma and child abuse.

Stapes Surgery for Otosclerosis in Patients Presenting with Mixed Hearing Loss.

OBJECTIVES: To evaluate the efficacy of stapes surgery in patients presenting with a preoperative mixed hearing loss (bone conduction thresholds ≥40 dB; 40 < air conduction thresholds (AC) < 85 dB). PATIENTS AND METHODS: A total of 30 patients (32 ears) with mixed hearing loss who underwent primary stapedotomy were evaluated. Audiometric parameters were assessed before and after surgery. Contralateral thresholds were also reported. The need for a hearing aid (HA) after surgery and its impact on quality of life were also measured. RESULTS: AC and word recognition at 40, 55 and 70 dB were significantly improved after stapes surgery. Only 16.6% of the patients needed an HA after surgery and reported being satisfied with the aid. CONCLUSION: Stapes surgery improved auditory function in patients with mixed hearing loss, allowing most patients to delay the need for an HA without worsening their quality of life.

Feasibility of an implanted microphone for cochlear implant listening.

This study aimed at evaluating the feasibility of an implanted microphone for cochlear implants (CI) by comparison of hearing outcomes, sound quality and patient satisfaction of a subcutaneous microphone to a standard external microphone of a behind-the-ear sound processor. In this prospective feasibility study with a within-subject repeated measures design comparing the microphone modalities, ten experienced adult unilateral CI users received an implantable contralateral subcutaneous microphone attached to a percutaneous plug. The signal was pre-processed and fed into their CI sound processor. Subjects compared listening modes at home for a period of up to 4 months. At the end of the study the microphone was explanted. Aided audiometric thresholds, speech understanding in quiet, and sound quality questionnaires were assessed. On average thresholds (250, 500, 750, 1k, 2k, 3k, 4k and 6 kHz) with the subcutaneous microphone were 44.9 dB, compared to 36.4 dB for the external mode. Speech understanding on sentences in quiet was high, within approximately 90% of performance levels compared to hearing with an external microphone. Body sounds were audible but not annoying to almost all subjects. This feasibility study with a research device shows significantly better results than previous studies with implanted microphones. This is attributed to technology enhancements and careful fitting. Listening effort was somewhat increased with an implanted microphone. Under good sound conditions, speech performance is nearly similar to that of external microphones demonstrating that an implanted microphone is feasible in a range of normal listening conditions.

Audiometric Results after Stapedotomy Operations in Patients with Otosclerosis and Preoperative Small Air-Bone Gaps.

OBJECTIVES: The efficacy of stapedotomies performed on patients with small air-bone gaps (<25 dB) was compared with the efficacy of the operation in patients who had otosclerosis with high air-bone gaps (≥25 dB). METHODS: This retrospective study evaluates the short-term postoperative air and bone conduction thresholds and air-bone gaps after 182 CO2 laser stapedotomies. RESULTS: A significantly smaller air-bone gap and lower air conduction thresholds after surgery were observed in the group of patients who underwent surgery with preoperative air-bone gaps of less than 25 dB. Bone conduction thresholds improve in the group with small air-bone gaps after surgery. CONCLUSIONS: The results after stapedotomies are good even if the preoperative air-bone gap is small and the overall risk of hearing deterioration due to stapes surgery remains low.

Dating the abusive head trauma episode and perpetrator statements: key points for imaging.

Shaken baby syndrome/abusive head trauma is a leading cause of morbidity and mortality in infants. The presence of a diffuse subdural hematoma without evidence of accident is a key diagnostic clue. The hematoma is typically attributed to rupture of the cerebral bridging veins due to violent shaking, with or without impact. Dating the incident, however, remains controversial. The aim of this article is to review the most reliable features used for dating the incident, based on both legal statements by perpetrators and medical documentation. The key points are: 1) The high (yet likely underestimated) frequency of repeated shaking is around 50%, 2) Children do not behave normally immediately after shaking, and the time of onset of even mild symptoms appears to be the best clue for dating the incident and 3) Brain imaging provides strong indicators of "age-different" injuries but the ranges for dating the causal event are wide. The density pattern in a single subdural hematoma location provides no reliable clues for assessing repeated violence. Only the finding of different density in two distant subdural hematomas argues in favor of "age-different" injuries, i.e. repeated violence. MRI is difficult to interpret in terms of dating subdural hemorrhages and must be analyzed in conjunction with CT. Most importantly, all of the child's previous clinical and radiological data must be carefully studied and correlated to provide accurate information on the date and repetition of the trauma.

Detection of residual packets in cocaine body packers: low accuracy of abdominal radiography-a prospective study.

OBJECTIVE: To evaluate the accuracy of abdominal radiography (AXR) for the detection of residual cocaine packets by comparison with computed tomography (CT). METHODS: Over a 1-year period unenhanced CT was systematically performed in addition to AXR for pre-discharge evaluation of cocaine body packers. AXR and CT were interpreted independently by two radiologists blinded to clinical outcome. Patient and packet characteristics were compared between the groups with residual portage and complete decontamination. RESULTS: Among 138 body packers studied, 14 (10 %) had one residual packet identified on pre-discharge CT. On AXR, at least one reader failed to detect the residual packet in 10 (70 %) of these 14 body packers. The sensitivity and specificity of AXR were 28.6 % (95 % CI: 8.4-58.1) and 100.0 % (95 % CI: 97.0-100.0) for reader 1 and 35.7 % (95 % CI: 12.8-64.9) and 97.6 % (95 % CI: 93.1-99.5) for reader 2. There were no significant patient or packet characteristics predictive of residual portage or AXR false negativity. All positive CT results were confirmed by delayed expulsion or surgical findings, while negative results were confirmed by further surveillance. CONCLUSION: Given the poor performance of AXR, CT should be systematically performed to ensure safe hospital discharge of cocaine body packers. KEY POINTS: • Both abdominal radiography and computed tomography can identify gastrointestinal cocaine packets. • Ten per cent of body packers had residual packets despite two packet-free stools. • Seventy per cent of these residual packets were missed on AXR. • No patient or packet characteristics predicted residual packets or AXR false negativity. • CT is necessary to ensure safe medical discharge of body packers.

Robot-assisted laparoscopy repair of uterine isthmocele: A two-center observational study.

OBJECTIVE: To analyze outcomes and postoperative complications in patients undergoing robot-assisted isthmocele repair. METHOD: This retrospective cohort study included 33 patients who had robot-assisted laparoscopic surgical management of an isthmocele between September 2013 and August 2020 in two French university hospitals. All charts were reviewed to identify patient characteristics, preoperative and postoperative anatomical findings, complications, and postoperative fertility and symptoms. Patients who had undergone this procedure were asked to complete a telephone questionnaire about their treatment satisfaction and symptoms. RESULTS: The isthmocele was discovered most often as a result of subfertility (57.6%), but also ectopic pregnancy (18.2%), pelvic pain (15.2%), and postmenstrual bleeding (9.1%). Robot-assisted repair of the isthmocele significantly improved myometrial thickness (from 1.55 mm before surgery to 4.26 mm after surgery [mean difference 2.71; 95% confidence interval, 1.91-3.51], P = 0.0005). Among 20 patients who still desired a child after surgery, 15 became pregnant and 14 had full-term live births. Among the nine patients who had surgery for disabling symptoms, five had no persistent symptoms, three reported global improvement, and one had the same gynecologic discomfort. Seventeen patients agreed to complete the questionnaires (51.5%), and all stated that they would choose to have this surgery again. CONCLUSION: Robot-assisted repair of an isthmocele is a viable minimally invasive procedure.

[Examination and care of sexual assault victims]. / Examen et prise en charge des victimes d'agression sexuelle.

Any general practitioner might have to examine and care for a sexual assault victim in their professional practice. Taking time to listen to the victim's story is essential to direct the examination and sample collection. The general physical examination screens for physical injuries. Perineal examination is specialized, and should be performed within a very short period of time in the event of a recent assault with sexual penetration. The purpose of further examination is to collect evidence and identify the victim's sexually transmitted disease status to screen for any seroconversion during follow-up. Preventive measures should be considered on an individual basis: contragestion, triple antiretroviral therapy, immunoglobulins and hepatitis B immunization. Lastly, referrals to social or psychotherapeutic services and/or associations are extremely helpful to the victim.

[How to take care of a victim of sexual assault in the doctor's office ?] / Comment prendre en charge une victime d'agression sexuelle au cabinet médical ?

How to take care Of a victim of sexual Assault in the doctor's Office ? The care of a victim of sexual assault is a legal And medical emergency. Before 48 hours, an Initial medical certificate will describe any lesions. A prescription for antiretroviral therapy and emergency Contraception will be made before a possible Complaint is lodged and examination at the Medico-forensic unit (umj). After 48 hours, Contraception and testing for sexually transmitted Disease may still be indicated. Secondly, referral To specialized associations and psychological Support will be systematically offered. From 2018 To 2020, 1,127 sa victims were received at the Umj of the hôtel-dieu de paris: 48% were Between 18 and 25 years old, 31% between 26 And 35 years old and 21% over 35 years old. The Victims had intentionally consumed alcohol in 53% of cases and other toxicants or treatment Related.

Comment prendre En charge une victime D'agression sexuelle Au cabinet médical ? La prise en charge d'une victime d'agression Sexuelle (as) constitue une urgence judiciaire et Médicale. Avant 48 h, un certificat médical initial Décrit les éventuelles lésions. Une trithérapie Antirétrovirale et une contraception d'urgence Doivent être prescrites avant le possible dépôt de Plainte et l'examen à l'unité médico-judiciaire(umj).Après 48 h, une contraception et une Recherche d'ist peuvent rester indiquées. Dans Un second temps, une orientation vers des associations Spécialisées et une prise en charge Psychologique seront systématiquement proposées. De 2018 à 2020, 1 127 victimes d'as ont Eté reçues à l'umj de l'hôtel-dieu de paris : 48 % Avaient entre 18 et 25 ans, 31 % entre 26 et 35 ans et 21 % plus de 35 ans. Les victimes Avaient consommé volontairement de l'alcool dans 53 % des cas et d'autres toxiques ou un traitement En lien avec une pathologie psychiatrique Dans 20 % et 10 % des cas respectivement.L'étude a mis en évidence la problématique de Ces agressions dans un contexte d'alcoolisation Festive. Le rôle du médecin traitant est primordial Auprès de ces victimes et afin de les guider tout Au long de leur prise en charge.

[Population of people placed in police custody, hidden barometer of diverted medicines]. / La population des personnes placées en garde à vue à Paris, baromètre du détournement invisible des médicaments.

PURPOSE OF THE STUDY: The population of people in police custody is a sentinel niche that is poorly represented in the "usual panels" of public health studies. The aim is to make an overview of their diversion of drugs. PATIENTS AND METHODS: A retrospective study based on cases of misuse in a sample of people in custody examined between 2015 and 2016 at the forensic medicine unit of the hospital Hôtel-Dieu-Paris. RESULTS: Of the 5149 medical examinations, 302 were for substance use disorder or drug misuse. In 2016, the number of notifications for misuse of clonazepam increased (n=65); the user population appears to be getting younger (average age=23.5 years) and to be supplied mainly by deal (63%). Regarding opioid substitution treatments, the indicators of abuse and diversion are confirmed, while morphine sulfate stands out with a strong deal (>75%), IV injection (62%) and polydrug use, including methadone, cocaine (62%). CONCLUSION: From our results, national surveys in general population and studies carried out in the context of deprivation of liberty, people in police custody constitute a real barometer of the parallel market for street drugs. Clinical impacts can be major; a better monitoring is needed. For caregivers, it is also a matter of better identification of misuse, substance use disorder for a future orientation of the patient.

Variations in Guidelines for Diagnosis of Child Physical Abuse in High-Income Countries: A Systematic Review.

Importance: The highly variable practices observed regarding the early detection and diagnostic workup of suspected child physical abuse contribute to suboptimal care and could be partially related to discrepancies in clinical guidelines. Objective: To systematically evaluate the completeness, clarity, and consistency of guidelines for child physical abuse in high-income countries. Evidence Review: For this systematic review, national or regional guidelines that were disseminated from 2010 to 2020 related to the early detection and diagnostic workup of child physical abuse in infants aged 2 years or younger by academic societies or health agencies in high-income countries were retrieved. The definitions of sentinel injuries and the recommended diagnostic workup (imaging and laboratory tests) for child physical abuse were compared. Data were analyzed from July 2020 to February 2021. Findings: Within the 20 included guidelines issued in 15 countries, 168 of 408 expected statements (41%) were missing and 10 statements (4%) were unclear. Among 16 guidelines characterizing sentinel injuries, all of them included skin injuries, such as bruises, hematoma, or burns, but only 8 guidelines (50%) included intraoral injuries and fractures. All 20 guidelines agreed on the indication for radiological skeletal survey, head computed tomography, and head magnetic resonance imaging but differed for those of bone scintigraphy, follow-up skeletal survey, spinal magnetic resonance imaging, cranial ultrasonography, chest computed tomography, and abdominal ultrasonography and computed tomography. Additionally, 16 guidelines agreed on exploring primary hemostasis and coagulation but not on the tests to perform, and 8 guidelines (50%) mentioned the need to investigate bone metabolism. Conclusions and Relevance: These findings suggest that guidelines for the diagnosis of child physical abuse in infants were often clear but lacked completeness and were discrepant on major issues. These results may help identify priorities for well-designed original diagnostic accuracy studies, systematic reviews, or an international consensus process to produce clear and standardized guidelines to optimize practices and infant outcomes.

How to explore and report children with suspected non-accidental trauma.

Child abuse is a controversial problem of special concern. Recent reports have focused on the broad variability of reporting to child protection services. Radiologists play a key role in the early diagnosis and imaging of suspected inflicted injury. Imaging must be performed and then interpreted with rigour.The aims of this review are: To review the recent recommended guidelines for imaging in cases of suspicion of abuse. These include a highly detailed complete skeletal survey with centered views, whilst brain CT and/or MRI are mandatory in children younger than 2 years. The use of abdominal imaging is debatable if the child has no symptoms. All siblings younger than 2 years should be assessed in the same way while the diagnosis of abuse is investigated. Body MRI is an interesting modality that remains a "work-in-progress". To highlight that dating of both brain and skeletal injuries is imprecise. The main point is, however, to determine if the pattern is of "age-different" lesions. This not only provides a strong argument for the diagnosis of abuse, but also indicates repetitive violence with a high risk for further injury and death. To remember that the medical perspective is to protect the child. Thus, radiologists must communicate clearly the suspicion of abuse and the degree of certainty to clinicians to aid reporting or hospitalization.

The attack on November 13, 2015: organisation of the medico-judicial unit of the Hôtel-Dieu Hospital in Paris.

The main aims of a medico-judicial unit are to ensure the examination of assault victims or persons in custody and to perform sampling necessary for investigations. Forensic examination is essential to describe the wounds and to evaluate the consequences of an assault by determining days of total incapacity for work (ITT). After the Paris attack on November 13, 2015, 121 victims were examined at the medico-judicial units of Paris. An initial forensic certificate was issued by forensic physicians with an assessment of physical ITT. A consultation with a forensic psychiatrist was systematically scheduled on the same day to obtain a forensic certificate for the psychological ITT. The average age of the victims was (33 ± 7) years and the sex ratio was 1.26. Most victims were in the Bataclan concert hall (78/121 or 64.5%). Of the 121 victims, 73 (60.3%) had projectile lesions (bullets, bolts and nuts, metal fragments, etc.) and 48 (39.7%) had non-projectile lesions (bruises, hematomas, etc.). The average physical ITT was 27 days (0; 190). The evaluation of the number of days of physical ITT was often complicated as some patients were still in medical care at the time of the initial examination. This experience enabled the Paris medico-judicial unit to anticipate the management required should any future event of this magnitude occur. It also reinforced cooperation between the medico-judicial unit and other departments, mostly emergency services and the forensic psychiatric unit. The Paris medico-judicial unit was thus able to offer a unique place of care by providing both physical and psychological examinations.

Abusive Head Trauma in Day Care Centers.

BACKGROUND: Abusive head trauma (AHT) warrants particular attention in terms of prevention. One of the key questions asked is how often AHT occurs in infant day care centers compared with private parental or nonparental homes. To investigate this, we studied the caretaking arrangement and child's location at the time of injury in a cohort of cases involving AHT from the courts. METHODS: This multicenter retrospective study covering an 18-year period included all medical and court records of 323 children (2.5 months to 3 years) with AHT, confirmed by the authors acting as medical experts. All markers for abuse and forensic written reports were analyzed by using a standardized data collection tool. The usual child care arrangement and the child's location at the time of injury were noted. The percentage of day care centers found in the study was compared to the expected rate in the French population (19.5%) by using the χ2 test. RESULTS: In 317 AHT cases (98.5%), the assault occurred in a private home (4 in other indoor settings and 1 with missing data). In only 1 case, shaking occurred in a day care center when the nurse was alone with the infant for a few minutes. In 317 cases (98.5%), the usual child care arrangement was by a single adult in charge of 1 or more children. CONCLUSIONS: The fact that AHT is an unusual occurrence in day care centers could help social service agencies make decisions in terms of prevention. Recent government policies regarding stay-at-home orders during a pandemic have given this issue new relevance.

cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing.

Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.

[Practical approach to a suspicion of child sexual abuse]. / Conduite à tenir face à une suspicion d'abus sexuel chez l'enfant.

Child sexual abuse is very common. Whether it is a spontaneous revelation, a sign or an evocative symptom, the suspicion of sexual assault on a child requires the doctor to act, regardless of his specialty or mode of exercise. After the interview, the doctor carries out a general somatic examination and writes an initial descriptive medical certificate. Whatever the situation, it is advisable to send the child to hospital for immediate management -gynecological and anal examination, additional examinations, medication prescriptions-. He must explain to the parents the obligatory nature of the hospital summons and its obligation of protection which may lead to an alert to the Republic prosecutor. Physicians must have anticipated these situations and have contact information for their direct child protection contacts.

CONDUITE À TENIR FACE À UNE SUSPICION D'ABUS SEXUEL CHEZ L'ENFANT Les cas d'abus sexuel chez l'enfant sont très fréquents. Qu'il s'agisse d'une révélation spontanée, d'un signe ou d'un symptôme évocateur, la suspicion d'agression sexuelle sur un enfant impose au médecin d'agir, quelle que soit sa spécialité ou son mode d'exercice. Après l'entretien, le médecin réalise un examen somatique général et rédige un certificat médical initial descriptif. Quelle que soit la situation, il lui est conseillé d'adresser l'enfant en milieu hospitalier pour la prise en charge immédiate -examen gynécologique et anal, examens complémentaires, prescriptions médicamenteuses-. Il doit expliquer aux parents le caractère obligatoire de la convocation hospitalière et son obligation de protection pouvant aboutir à un signalement au procureur de la République. Le médecin doit avoir anticipé ces situations et disposer des coordonnées de ses interlocuteurs directs de la protection de l'enfance.