Diagnostic Delay of Celiac Disease in Childhood.

Importance: The extent and factors associated with risk of diagnostic delay in pediatric celiac disease (CD) are poorly understood. Objectives: To investigate the diagnostic delay of CD in childhood, and to assess factors associated with this delay. Design, Setting, and Participants: Multicenter, retrospective, cross-sectional study (2010-2019) of pediatric (aged 0-18 years) patients with CD from 13 pediatric tertiary referral centers in Italy. Data were analyzed from January to June 2023. Main Outcomes and Measures: The overall diagnostic delay (ie, the time lapse occurring from the first symptoms or clinical data indicative of CD and the definitive diagnosis), further split into preconsultation and postconsultation diagnostic delay, were described. Univariable and multivariable linear regression models for factors associated with diagnostic delay were fitted. Factors associated with extreme diagnostic delay (ie, 1.5 × 75th percentile) and misdiagnosis were assessed. Results: A total of 3171 patients with CD were included. The mean (SD) age was 6.2 (3.9) years; 2010 patients (63.4%) were female; and 10 patients (0.3%) were Asian, 41 (1.3%) were Northern African, and 3115 (98.3%) were White. The median (IQR) overall diagnostic delay was 5 (2-11) months, and preconsultation and postconsultation diagnostic delay were 2 (0-6) months and 1 (0-3) month, respectively. The median (IQR) extreme overall diagnostic delay (586 cases [18.5%]) was 11 (5-131) months, and the preconsultation and postconsultation delays were 6 (2-120) and 3 (1-131) months, respectively. Patients who had a first diagnosis when aged less than 3 years (650 patients [20.5%]) showed a shorter diagnostic delay, both overall (median [IQR], 4 [1-7] months for patients aged less than 3 years vs 5 [2-12] months for others) and postconsultation (median [IQR], 1 [0-2] month for patients aged less than 3 years vs 2 [0-4] months for others). A shorter delay was registered in male patients, both overall (median [IQR], 4 [1-10] months for male patients vs 5 [2-12] months for female patients) and preconsultation (median [IQR], 1 [0-6] month for male patients vs 2 [0-6] months for female patients). Family history of CD was associated with lower preconsultation delay (odds ratio [OR], 0.59; 95% CI, 0.47-0.74) and lower overall extreme diagnostic delay (OR, 0.75; 95% CI, 0.56-0.99). Neurological symptoms (78 patients [21.5%]; OR, 1.35; 95% CI, 1.03-1.78), gastroesophageal reflux (9 patients [28.1%]; OR, 1.87; 95% CI, 1.02-3.42), and failure to thrive (215 patients [22.6%]; OR, 1.62; 95% CI, 1.31-2.00) showed a more frequent extreme diagnostic delay. A previous misdiagnosis (124 patients [4.0%]) was more frequently associated with gastroesophageal reflux disease, diarrhea, bloating, abdominal pain, constipation, fatigue, osteopenia, and villous atrophy (Marsh 3 classification). Conclusions and Relevance: In this cross-sectional study of pediatric CD, the diagnostic delay was rather short. Some factors associated with risk for longer diagnostic delay and misdiagnosis emerged, and these should be addressed in future studies.

Investigating Perampanel Antiepileptic Drug by DFT Calculations and SERS with Custom Spinning Cell.

SERS, a clinical practice where medical doctors can monitor the drug concentration in biological fluids, has been proposed as a viable approach to therapeutic drug monitoring (TDM) of the antiepileptic drug Perampanel. The adoption of an acidic environment during the SERS experiments was found to be effective in enhancing the spectroscopic signal. In this work, we combine SERS experiments, conducted with a custom spinning cell in controlled acidic conditions, with DFT calculations aimed at investigating the possible protonated forms of Perampanel. The DFT-simulated Raman spectra of protonated Perampanel accounts for most of the observed SERS signals, thus explaining the effective role of protonation of the analyte. Our results suggest protonation as a viable approach to fostering SERS of alkaline drugs.

Suicide attempts and eating disorders in adolescents, the mental health wave of the second year of the COVID-19 pandemic: A paediatric emergency department perspective.

Aim: We compared adolescents' visits to a tertiary-level paediatric emergency department (PED) in Italy during the pre-pandemic year and the first and second years of the COVID-19 pandemic, focusing on mental health presentations. Methods: This was a retrospective study. We collected the number of visits, the demographical features, triage codes, discharge diagnoses, and outcomes of adolescents 13-17 years old who accessed the PED from 1 March 2019 to 28 February 2022. Results: During the study period, 13,410 adolescents accessed the PED. The number of visits related to mental health problems was 304 (6.4%) in the second year of the pandemic and 306 (5.6%) in the pre-pandemic year, p = 0.07. In the same periods, females' prevalence was higher, 220 (72.4%) vs. 197 (64.4%), p = 0.03. The absolute number of subjects needing admission increased, 44 vs. 34, p = 0.21, and more urgent psychiatric consultations were needed, 161 vs. 114, p < 0.0001. The number of suicide attempts was 23 vs. 8, +188%, p = 0.01. The number of adolescents with eating disorders was 21 vs. 5, +320%, p = 0.001. Conclusion: PED visits for suicide attempts and eating disorders in adolescents sharply increased in the second year of the pandemic.

Druggable monogenic immune defects hidden in diverse medical specialties: Focus on overlap syndromes.

In the last two decades two new paradigms changed our way of perceiving primary immunodeficiencies: An increasing number of immune defects are more associated with inflammatory or autoimmune features rather than with infections. Some primary immune defects are due to hyperactive pathways that can be targeted by specific inhibitors, providing innovative precision treatments that can change the natural history of diseases. In this article we review some of these "druggable" inborn errors of immunity and describe how they can be suspected and diagnosed in diverse pediatric and adult medicine specialties. Since the availability of precision treatments can dramatically impact the course of these diseases, preventing the development of organ damage, it is crucial to widen the awareness of these conditions and to provide practical hints for a prompt detection and cure.

The Effects of Ring Strain on Cyclic Tetraaryl[5]cumulenes.

Cyclic tetraaryl[5]cumulenes (1 a-f) have been synthesized and studied as a function of increasing ring strain. The magnitude of ring strain is approximated by the extent of bending of the cumulenic core as assessed by a combination of X-ray crystallographic analysis and DFT calculations. Trends are observed in 13 C NMR, UV-vis, and Raman spectra associated with ring strain, but the effects are small. In particular, the experimental HOMO-LUMO gap is not appreciably affected by bending of the [5]cumulene framework from ca. 174° (λmax =504 nm) in 1 a to ca. 178° (λmax =494 nm) in 1 f.

Does a standard triage tool adequately detect the needs of children and adolescents admitted for mental health problem?

BACKGROUND: the visits to the paediatric emergency department for mental problems are increasing exponentially, but the emergency department team in not ready enough to manage them, due to the lack of adequate training. This study aimed to evaluate how the Italian Society of Paediatric Emergency Medicine and Urgency triage system was able to estimate urgency in patients accessing the paediatric emergency department for a mental health problem. METHODS: We conducted a retrospective study at the emergency department of the Institute for Maternal and Child Health, IRCCS Burlo garofolo of Trieste (Italy), from December 2015 to April 2017. During the study period, we identified all the patients undergoing an urgent psychiatric consultation. We collected demographic variables, triage code, diagnosis, and outcomes of each patient. Subsequently, we have assigned a degree of psychiatric urgency, based on Gail and Rosenn's classificationwhich is a specific tool to evaluate psychiatric urgency. The primary study outcome was the comparison between the degree of urgency assigned using the triage system and the Gail and Rosenn's classification. RESULTS: In this series, 567 patients underwent an urgent psychiatric consultation, and 280 of them received a diagnosis of a mental health problem. The degree of urgency assigned at the triage was: emergency for 5 cases (2%), urgency for 96 (34%) and non-urgency for 179 (64%). Instead, the degree assigned with GRC was: emergency for 95 cases (34%), urgency for 112 (42%) and non-urgency for 73 (26%). The number of patients, detected as emergency and urgency by the two tools, was significantly different (p = 0.0001). CONCLUSIONS: In this study, we demonstrated that the Italian Society of Paediatric Emergency Medicine and Urgency triage system underestimated the urgency of patients with mental health problems compared to a specific tool to assess the degree of psychiatric urgency.

Young boy with a long history of splenomegaly and cytopenia.

A 15-year-old boy was admitted with a history of cytopenia (white blood cell count 3.170/µm, platelets 90.000/µm) associated with splenomegaly, found during investigations for recurrent mild jaundice due to Gilbert's syndrome.He was in good general health, without systemic symptoms; therefore, the leading causes of asymptomatic splenomegaly were excluded. Coagulation, liver tests and abdomen ultrasound (US) were normal, showing a hepatopetal portal flow to the colour-Doppler. There was no sign of haemolysis on haematology investigations. The C reactive protein, immune globulins levels and erythrocyte sedimentation rate were normal, excluding both an infective and an immune regulation disorder. We excluded the haematological malignancy and lymphoproliferative disorders through a peripheral blood smear and a bone marrow biopsy.His history was remarkable for neonatal sepsis, which required umbilical venous catheter during hospitalisation in a neonatal intensive care unit (NICU). The patient follow-up was interrupted for a while, probably due to his good health condition.At age 17 years, the child accessed our emergency department. for a minor trauma to the limbs, and his physical examination was unremarkable, except for the splenomegaly. We repeated the abdomen US, with colour flow Doppler (figure 1).

Unarousable child with a short bowel.

Unarousable child with short bowelA 4-year-old boy was admitted with progressive lethargy of a few hours' duration and no other symptoms. His medical history was relevant for short bowel syndrome (SBS), following neonatal volvulus, with residual bowel length of 23 cm and intact ileocecal valve. He had similar self-limiting episodes in the past, after weaning parenteral nutrition, especially after eating large meals. The day before, he had consumed a large amount of apples.Arterial blood gas (ABG) analysis showed metabolic acidosis with normal lactacidaemia (pH 7.09, pCO2 19 mm Hg, pO2 101 mm Hg, HCO3 5.8 mmol/L, BE -24, anion gap 29.4, chloride 116 mmol/L, L-lactate level 4 mmol/L).On admission, the child could be awakened, but he was confused with slurred speech (Glasgow Coma Scale 14), with a body temperature of 37 C°, a heart rate of 125 beats/min and a respiratory rate of 38 breaths/min. The abdomen was distended, without guarding and with normal bowel sounds. Blood glucose levels were normal, as well as white blood cell count, liver and kidney function test and C reactive protein. An abdominal ultrasound ruled out an intussusception. An abdominal X-ray was performed too (see figure 1).

20-Year Follow-up Study of Celiac Patients Identified in a Mass School Screening: Compliance to Gluten-Free Diet and Autoimmunity.

OBJECTIVES: To investigate the compliance to the gluten-free diet in a cohort of adult celiac patients 20 years after the diagnosis, received in childhood through a mass screening. METHODS: This is an observational historic cohort follow-up study. It was carried out at the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy. Two matched cohorts of adult celiac patients, diagnosed in childhood through a mass screening or for symptoms were enrolled. Adherence to the gluten free-diet and development of autoimmune diseases were investigated through a questionnaire administrated in the course of a phone interview.The primary study outcome was the adherence to the gluten-free diet, measured through the Biagi questionnaire, in the two cohorts of celiac patients. RESULTS: We contacted 25 patients (mean age 28 years, 19 females) diagnosed with screening and 34 patients (mean age 25 years, 26 females) diagnosed in the same period for symptoms. After 20 years, in the cohort diagnosed with screening and in the cohort diagnosed for symptoms the adherence to the gluten-free diet was optimal in 14 (56%) and 26 (81%), improvable in 5 (20%) and 3 (9%), inadequate in 6 (24%) and 3 (9%), respectively. In the two cohorts, four patients (16%) and six patients (18%) developed other autoimmune diseases. CONCLUSIONS: Twenty years after the diagnosis, near half of the patients diagnosed in a mass screening, does not have an optimal adherence to the gluten-free diet and a remarkable proportion of them have developed another autoimmune disease.

Fifteen-Years Follow-Up in a Cohort of Children with Functional Gastrointestinal Disorders: Prevalence and Risk Factors to Develop Neuropsychiatric Disorders and Other Comorbidities.

BACKGROUND: Functional gastrointestinal disorders (FGIDs) are chronic and recurrent disorders, which affect up to 23% of children and adolescents and represent 50% of gastroenterological accesses. The association between FGIDs diagnosed at paediatric age and the onset of migraine or headache and neuropsychiatric diseases in adolescence and adulthood is widely reported in the literature. However, there is still limited knowledge about the long-term prognosis and risk factors for neuropsychiatric pathologies and other comorbidities. AIM: The aim is to assess the prevalence and persistence of FGIDs as well as the occurrence of migraine or headache and neuropsychiatric disorders in a cohort of patients diagnosed with FGIDs 15 years ago compared with a control group of peers. MATERIALS AND METHODS: We enrolled a group of patients diagnosed with FGIDs at paediatric age, at least 10 years ago (FGIDs group, n = 79; median age 23), and control subjects (control group, n = 201; median age 23). In both groups, an online questionnaire created explicitly for the study was submitted in order to investigate the presence of chronic intestinal diseases, migraine, headache or neuropsychiatric disorders. RESULTS: 45.6% (36 out of 79) of patients previously diagnosed with FGIDs still suffer from FGIDs versus 12% (24 out of 201) of healthy controls (p < 0.0001). The prevalence of chronic organic gastrointestinal disorders was comparable in the two groups (2.5% in FGIDs group versus 1% in healthy group, p = 0.3). Thirty-three percent (26 out of 79) of FGIDs patients reported headache or migraine versus 13% (26 out of 201) of healthy peers (p < 0.001). No differences were found regarding the prevalence of anxiety and depression. CONCLUSION: The outcome at 15 years of FGIDs was characterized by a high prevalence of persisting functional symptoms along with a significant incidence of headaches and migraines. Abbreviation: FGIDs: Functional gastrointestinal disorders; IBS: Inflammatory Bowel Syndrome.

A floppy infant without lingual frenulum and kyphoscoliosis: Ehlers Danlos syndrome case report.

BACKGROUND: Ehlers-Danlos syndrome (EDS) represents a group of connective tissue disorders characterized by the fragility of the soft connective tissues resulting in widespread skin, ligament, joint, blood vessel and internal organ involvement. The clinical spectrum is highly variable in terms of clinical features, complications, severity, biochemical characteristics and genes mutations. The kyphoscoliotic type EDS (EDS VIA) is a rare variant of the disease, with an incidence of 1:100.000 live births. EDS VIA presents at birth as severe muscular hypotonia, early onset of progressive kyphoscoliosis, marked hyperelasticity and fragility of the skin with abnormal scarring, severe joint hypermobility, luxations and osteopenia without a tendency to fractures. This condition is due to a mutation in the PLOD1 gene, and less commonly in FKBP14 gene, which results in the erroneous development of collagen molecules with consequent mechanical instability of the affected tissue. CASE PRESENTATION: A female newborn, found to be floppy at birth, presented a remarkable physical examination for joint hypermobility, muscle weakness, hyperelastic skin, a slight curve of the spine, the absence of the inferior labial and lingual frenulum. Due to severe hypotonia, neuromuscular disorders such as Spinal Muscular Atrophy (SMA), genetic diseases such as Prader Willi syndrome (PWS), myopathies and connective tissue disorders were considered in the differential diagnosis. Targeted gene sequencing were performed for SMN1, PLOD1, FKBP14, COL6A1, COL6A2, COL6A3. The urinary lysyl and hydroxy-lysyl pyridinoline ratio was diagnostic before discovering the homozygous duplication in the PLOD1 gene, which confirmed kyphoscoliotic EDS diagnosis. CONCLUSION: In front of a floppy infant, a large variety of disorders should be considered, including some connective diseases. The presence at the birth of kyphoscoliosis, associated with joint hypermobility and the absence of the lingual and lower lip frenulum, should suggest an EDS.

Nanoparticles Engineering by Pulsed Laser Ablation in Liquids: Concepts and Applications.

Laser synthesis emerges as a suitable technique to produce ligand-free nanoparticles, alloys and functionalized nanomaterials for catalysis, imaging, biomedicine, energy and environmental applications. In the last decade, laser ablation and nanoparticle generation in liquids has proven to be a unique and efficient technique to generate, excite, fragment and conjugate a large variety of nanostructures in a scalable and clean way. In this work, we give an overview on the fundamentals of pulsed laser synthesis of nanocolloids and new information about its scalability towards selected applications. Biomedicine, catalysis and sensing are the application areas mainly discussed in this review, highlighting advantages of laser-synthesized nanoparticles for these types of applications and, once partially resolved, the limitations to the technique for large-scale applications.

Diagnostic accuracy and applicability of intestinal auto-antibodies in the wide clinical spectrum of coeliac disease.

BACKGROUND: Intestinal coeliac auto-antibodies are the marker of coeliac disease (CD). Since the determination of these antibodies is still not widely available, we used immunoassays to identify the most suitable technology for revealing intestinal auto-antibodies in the wide clinical spectrum of CD. METHODS: Intestinal auto-antibodies have been prospectively investigated in CD suspected children using two immunoassays: intestinal-deposits of IgA anti-tissue transglutaminase antibodies (anti-tTG) and biopsy-culture IgA anti-endomysium (AEA). Intestinal IgM antibodies have been determined in IgA-deficient subjects. FINDINGS: Two-hundred and twenty-one suspected CD patients were enrolled. Intestinal antibodies were tested positive for both assays in classical CD patients (n = 178) with villous atrophy and positive serum-CD antibodies, potential CD patients (n = 16) with normal intestinal mucosa and positive serum-CD antibodies, and pre-potential CD patients (n = 14) with normal intestinal mucosa and negative serum-CD antibodies. In 13/221 with normal intestinal mucosa, negative CD-serum antibodies and negative intestinal antibodies CD has been excluded. All classical, 14/16 potential and 11/14 pre-potential CD patients on gluten-free diet (GFD) improved their symptoms. In 9/11 pre-potential patients intestinal antibodies disappeared on GFD. Both assays were negative in 69/71 control subjects. The two assays showed high diagnostic sensitivity (100%) and specificity (99%). INTERPRETATION: Intestinal CD-antibodies make prompt diagnosis in the wide clinical spectrum of CD reducing the delay in diagnosis and treatment, especially in pre-potential CD patients. The easy handling biopsy culture assay is an effective diagnostic tool which should be carried out by any gastroenterology unit to recognize all CD clinical manifestations. FUNDING: Interreg Central-Europe, IRCCS "Burlo Garofolo".

Pain Intensity and Risk of Bone Fracture in Children With Minor Extremity Injuries.

OBJECTIVES: Injuries are one of the most common causes of pediatric emergency department (ED) visit. The aim of this study was to investigate the relationship between the intensity of pain at the ED visit of children presenting with an extremity injury and the risk of fracture. METHODS: We conducted a retrospective study, considering all patients presenting to the ED of a children's hospital in Italy, with an accidental extremity injury, between May and December 2015. We selected all children aged 8 to 17 years who underwent an x-ray. Children with major, multiple, or nonextremity injuries were excluded. Age, sex, spontaneous and palpation pain, local swelling, time between injury, and medical evaluation were recorded. Sensibility and specificity of spontaneous and palpation pain in detecting a fracture were calculated. RESULTS: We reviewed 994 medical records; of these, 344 (34.6%) reported a fracture. Children's median age was 12 years (interquartile range [IQR], 10-14). Median spontaneous pain at the ED visit was not significantly different between children with and without a fracture: 4.0 (1.0-6.0) and 5 (1.0-6.0), respectively (P = 0.129). Children with mild palpation pain and children without an increase of pain of at least 2 points between spontaneous and palpation pain were fractured in 3.2% and 0.97% of cases, respectively. CONCLUSIONS: In this series, pain intensity in children with a minor extremity injury was not a good marker of fracture. Nevertheless, children with mild palpation pain or with a mild increase of pain between spontaneous and palpation pain had a low risk of fracture.

Laser-Synthesized SERS Substrates as Sensors toward Therapeutic Drug Monitoring.

The synthesis by pulsed laser ablation and the characterization of both the surface nanostructure and the optical properties of noble metal nanoparticle-based substrates used in Surface Enhanced Raman Spectroscopy are discussed with reference to application in the detection of anti-epileptic drugs. Results on two representative drugs, namely Carbamazepine and Perampanel, are critically addressed.

Administering analgesia sublingually is a suitable option for children with acute abdominal pain in the emergency department.

AIM: Acute abdominal pain is a frequent complaint in children attending emergency departments. The aim of this study was to investigate the pain score reductions when children with acute abdominal pain received medication sublingually. METHODS: We carried out a multicentre randomised controlled trial in three children's hospitals in Italy between March 2015 and June 2017. Children from four to 18 years of age with acute abdominal pain were recruited if their self-reported pain was at least six on a scale from 0-10. The children were randomised to receive ketorolac 0.5 mg/kg (n = 70) or tramadol 2 mg/kg (n = 70) sublingually or a melt in the mouth powder of 20 mg/kg paracetamol (n = 70). The main study outcome was the pain scores for the three drugs after two hours. RESULTS: The 210 children (58.6% girls) had a median age of 12 years with an interquartile range of 9-14.3. The median pain scores at two hours were not significantly different between ketorolac 2.0 (interquartile ranges, IQR 0.0-4.3) and tramadol 3.0 (IQR 1.0-5.0) vs paracetamol 3.0 (IQR 0.8-5.0). The median pain reductions were all 5.0 points. CONCLUSION: Delivering analgesia sublingually was a suitable option for pain relief in children with acute abdominal pain in the emergency department.