TBI (traumatic brain injury) is one of the most common causes of deaths and failure to return to society according to the latest statistics. Cerebrolysin is a drug approved for use in patients diagnosed with TBI. It is a mixture of neuropeptides derived from purified porcine brain proteins and multiple experimental studies have proven its neuroprotective and neurorestorative properties both in vitro and in vivo. In our meta-analysis, we analyze the latest clinical study reports on the use of Cerebrolysin in patients with TBI. The authors searched the databases: Pub Med, Cinahl, Web Of Science, and Embase from database inception until 11th July 2022. Ten clinical studies were eligible and included in the final analysis, including both retrospective and prospective studies of 8749 patients. Treatment with Cerebrolysin was associated with a statistically significant change in GCS and GOS. Mortality of any cause and the length of stay was not affected by the treatment. Our findings support and confirm the beneficial effects of Cerebrolysin treatment on the clinical outcome of patients after TBI. Further multi-center studies to optimize dosing and time of administration should be conducted. TBI is one of the most common causes of death and failure to return to society according to recent literature. Depending on the region, the mortality rate due to TBI ranges from 13/100,000 (China) . AttemptCerebrolysin is a low molecular weight neuropeptide preparation obtained from purified porcine brain proteins that has proven neuroprotective properties in vitro and in vivo, including modeling the permeability of endothelial membranes and anti-inflammatory effects ,7,8. FiaIn vivo studies with rats have shown the reduction of astrocyte activation, reduction in axonal damage, and increase in neurogenesis in closed experimental brain injury . In vivoAccording to the recommendations, Cerebrolysin could be administrated in various dosages at 10–50 mL per day. The intravenous infusion should be prepared in 100 mL total volume after adding the Cerebrolysin to 0.9% saline or Ringers or 5% glucose solution. The duration of infusion should take at least 15 min.The time of administration seems to be crucial, especially in the condition of TBI. In animal studies, it has been shown that early administration is associated with better outcomes, in terms of sensory–motor functions, brain edema, and blood–brain barrier leakage .Contraindications for Cerebrolysin administration are: allergy, seizure, severe renal failure. The aim of the following meta-analysis was to search the literature in terms of the analysis of the clinical effect of Cerebrolysin on the mortality, Glasgow Outcome Scale (GOS), Glasgow Coma Scale (GCS), and Length Of  Stay (LOS) in patients after traumatic brain injuries.Two independent authors (KK and KJ) searched the Pub Med, Cinahl, Web Of Science, and Embase databases from the database’s inception until 11th July 2022 with language restriction (only English) for studies aiming to evaluate the effect of Cerebrolysin in the treatment effect of patients with TBI diagnosis. The search strings the authors used are listed in The electronic search was supplemented by a manual review of the reference lists from eligible publications and relevant reviews.Human studiesAdult patients (>18 y)Diagnosis of mild, moderate, or severe TBI The following inclusion criteria were applied:Animal studies, in vitro studies, reviews, systematic reviews, editorials, individual case reports, and opinion, editorial, or perspectives articlesPediatric patients (<18 y)Pregnant patientsMultiorgan failureStudies in language other than EnglishExclusion criteria were as follows:Data on study design, patient characteristics, and treatment  were independently extracted from each study in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard by two independent investigators (KJ and KK). Whenever data were missing for the review, authors were contacted for additional information. Inconsistencies were resolved by consensus with a senior author (JSP).Co-primary outcomes were the GOS and GCS, as well as mortality and LOS, all reflecting drug efficacy in patients admitted to hospital due to TBI.http://www.meta-analysis.com (accessed on 28 August 2022) [p < 0.05 indicating significant heterogeneity. All analyses were two-tailed with alpha equal to 0.05.We conducted a random effects meta-analysis of outcomes, in which ≥2 studies contributed data, using Comprehensive Meta-Analysis V3 (st 2022) . Study hFor continuous outcomes, we analyzed the standardized differences in means of endpoint scores using observed cases (OC). Categorical outcomes were analyzed by risk ratio (RR). We aimed to conduct subgroup and exploratory maximum likelihood random effects meta-regression analyses of the co-primary outcomes , however, due to insufficient data, we were not able to conduct this. Finally, we inspected funnel plots and used Egger’s regression test as well as the Duval and Tweedie’s trim and fill method to quantify whether publication bias could have influenced the results ,19.n = 3), wrong language (n = 2), no access to full text (n = 4), duplicate (n = 3), and animal study (n = 1), yielding 10 studies, which were included in the meta-analysis. The flowchart of the database search is presented below in the The initial search yielded 27 results. There were four studies, which were excluded being duplicates after evaluation on the title or abstract. There were no additional articles identified via a hand search. Then, 23 full-text articles were reviewed. Of those, 13 were excluded due to not fitting inclusion criteria. Reasons for exclusion were wrong study aim (n = 8749) were included and are presented in Altogether, 10 studies . Results are shown in p = 0.71).Using random-effects analysis, the DM for the GCS score at endpoint in patients treated with Cerebrolysin compared to control arms was 1.344 with a 95% confidence interval of −0.258 to 2.945; p = 0.000. The heterogeneity was high . Results are presented in Using random-effects analysis, the DM for the GOS score at endpoint in patients treated with Cerebrolysin, compared to non-interventional arms, was 0.422 with a 95% confidence interval of 0.262 to 0.581; p = 0.14).An Egger’s test did not suggest a publication bias regarding the net effect of Cerebrolysin on GOS . Results are presented in Using random-effects analysis, the DM for the LOS in patients treated with Cerebrolysin compared to non-interventional arms was −1.255 with a 95% confidence interval of −6.422 to 3.913; p = 0.76).An Egger’s test did not suggest a publication bias regarding the net effect of Cerebrolysin on LOS . Results are presented in Using random-effects analysis, the risk ratio for mortality in patients treated with Cerebrolysin compared to non-interventional arms was 0.469 with a 95% confidence interval of 1.174 to −1.596. The heterogeneity was low .An Egger’s test did not suggest a publication bias regarding the net effect of Cerebrolysin on mortality  and has also been demonstrated in vivo in animal studies ,16,33,34In analyzed research, the authors mentioned different outcomes measured as main findings of their work. In the work of Muresanu et al., the 2015 work’s results showed that Cerebrolysin in dosages 20 mg/day and also 30 mg/day improved the GOS and RDS (Modified Rankin Disability Score) in moderate and severe patients after 10 and 30 days after TBI . The resTo this date, several manuscripts summarizing the effects of Cerebrolysin and other neuroprotective drugs have been published ,35,36. OIn the basic treatment of TBI, we generally followed the Traumatic Brain Foundation algorithms . In the Our meta-analysis confirms the positive treatment effect of Cerebrolysin on clinical outcomes in the aspects of GCS and GOS in patients with TBI. We were not able to detect significant effects on mortality or LOS, possibly also due to the relatively small sample size. Therefore, more randomized studies in the field of Cerebrolysin in TBI are needed to confirm and extend our findings with respect to the clinical utility of Cerebrolysin in TBI.


Sacrococcygeal teratomas (SCT) are known as rare tumors, but they are the most common tumor in fetuses and newborns. This study aims to present fetal magnetic resonance imaging (MRI) findings of SCT diagnosed prenatally and compare them with that of the prenatal Ultrasound (US) findings.Eleven patients diagnosed as SCT prenatally by US and further assessed by MRI are included. MRI was performed via a 1.5-T magnet with a body coil. The presence, size, content extension, and compressive effects of each mass were determined and correlated with US findings and with postnatal examinations, including surgery and pathology. As complications, the presence of ascites and skin edema or pleural or pericardial effusion was diagnosed as hydrops. The amniotic fluid index was calculated for the assessment of oligo- or polyhydramnios.US findings are found strongly correlated with MRI findings. An agreement on the extent of each mass was observed in eight patients, disagreement in one fetus was an extension of the tumor within the spinal canal recognized only at MR and assessment of intrapelvic-abdominal extension was superior in MRI. There were n = 6 type I, n = 2 type II, n = 1 type III and, n = 2 type IV tumors. MRI was superior to US for detecting displacement of the colon (n = 3), intrapelvic-intraabdominal extension (n = 1), urinary tract complication (n = 2), and intraspinal extension (n = 1).MRI is found to be superior to US especially in the assessment of intrapelvic and intraspinal extension of the tumor, colonic displacement, and complications. Sacrococcygeal teratomas (SCT) are known as rare tumors, but they are the most common tumor in fetuses and newborns. The incidence reported in the literature is 1/35,000 to 40,000 live births ,7. The vDiagnosis is usually made during the Ultrasonography (US) scan performed in the second or third trimester of pregnancy ,12. On UThe University Hospital research ethics committee approved this study (ID 2021-340). Written informed consent was waived for the retrospective analyses by the Institutional Review Board. We conducted a retrospective single-center study at our University Hospital to review all fetal SCT cases suspected before birth and confirmed postnatally between January 2011–2021. Data were collected from the digital patient archiving system . Most cases were submitted with a presumed diagnosis of tumor or fetal hydrops. All pregnant women underwent a detailed fetal anomaly scan using high-resolution US equipment.Type I: developing only outside the fetus ; the majority of cases, Type II: extra-fetal with intra-pelvic presacral extension, Type III: extra-fetal with abdominopelvic extension, Type IV: tumor developing entirely in the fetal pelvis. As complications, the presence of ascites and skin edema or pleural or pericardial effusion was diagnosed as hydrops. The presence of oligo- or polyhydramnios was determined by calculating the amniotic fluid index. Descriptive statistics were used due to the small number of cases. Categorical data are given as numbers (n) and percentages (%).Fetal ultrasonographic evaluations were performed by a perinatologist (at least 10 years of experience) and a radiologist (at least 15 years of experience) experienced in the obstetric US, separately. Fetal growth, exact tumor dimensions, morphology, and location, the presence or absence of additional malformations, and assessment of amniotic fluid volume were evaluated. There was no conflict between the experts in the interpretation of the images. It was agreed that MRI should be performed as advanced imaging to evaluate the extent of SCT and additional anomalies. MRI was performed via a 1.5-T magnet  with a body coil. In our center, fetal MRI (1.5 Tesla) is standard for additional evaluation. The mother was positioned either supine or in a partial left lateral decubitus position. The following imaging sequences were performed: T2-weighted Turbo Spin Echo sequences of fetus in sagittal, coronal, and axial planes ; T1-weighted gradient-echo relative to the fetus in the axial plane ; and diffusion-weighted imaging in the axial plane . The scanning time for all was 16–18 min. All MR studies were reviewed and interpreted by two radiologists, who also knew the results of MRI results were compared with US reports and images. The presence, size, content extension, and compressive effects of each mass were determined and correlated with US findings and with postnatal studies, including surgery and pathology. MRI findings were confirmed at surgery or autopsy in all patients. Depending on the radiological findings, the extent of the SCT was classified according to the American Academy of Pediatrics, Surgical Section classification which includes four categories : Type I:Eleven patients diagnosed as SCT prenatally by US and further defined by MRI are included. Diagnostic quality MR images were obtained in all patients. All images taken in MR examination were evaluated. US findings are strongly correlated with MRI findings. An agreement on the extent of each mass was observed in eight patients, disagreement in one fetus was an extension of the tumor within the spinal canal recognized only at MR, and assessment of intrapelvic-abdominal extension was superior in MRI. On MRI, sacrococcygeal teratomas (n = 11) were completely cystic in four fetuses, mixed and solid in seven . AccordiSCT causes displacement of the bladder by the effect of pelvic mass, hydronephrosis, and large convoluted ureters. The bladder displacement was observed in 3 of 11 fetuses (27.2%), and bilateral hydronephrosis in 2 fetus and unilateral hydronephrosis in 1 fetus on MRI, but only hydronephrosis was detected by sonography. In the patient with unilateral hydronephrosis, no other kidney was observed , and oligohydramnios was present. In the pathological examination, the cases were documented as mature (n = 8), immature (n = 2) and mixed teratomas (n = 1).In this study, we aimed to evaluate imaging findings and analyze which imaging approaches are most valuable in fetuses diagnosed with prenatal SCT. SCTs are the most common tumors of the fetus and the neonate, carrying a variable prognosis. The majority tend to be benign (~80%). Alpha-fetoprotein (AFP) and beta HCG may be elevated. A pathology-based classification is as: benign (mature) 70%–80% or malignant (immature). Those presenting in older infants tend to have a higher malignant potential and those presenting in utero have a poor prognosis due to complications. It has been reported that fetal mortality is higher if the gestational week at the time of diagnosis is early in SCT . Mass siComplications include urologic complications (the most common cause of morbidity), high output cardiac failure from AV shunting: which in turn can cause hydrops fetalis, gastrointestinal tract obstruction, compression of underlying nerves leading to urinary/fecal incontinence, anemia, dystocia, tumor rupture. Tumor compression of the bladder outlet caused retention in the urinary system, followed by renal impairment, oligohydramnios, and pulmonary hypoplasia , also tuDifferential diagnoses include sacral chordoma, sacral meningocele, terminal myelocystocoele, and enteric (tailgut) cyst for cystic types and for type IV lesions also low-lying neuroblastoma, rhabdomyosarcoma, small round blue cell tumor in the sacral region. Treatment is with surgical excision inclusive of coccygectomy with additional chemotherapy for malignant ones.MRI is widely used in these fetuses, although there are few studies in the literature that it is effective ,21–23. MThe limitation of our study is that it was designed retrospectively, US were performed by a perinatologist and a radiologist, separately. Although there was no conflict among our researchers, perhaps consensus would be a better alternative.MRI is found to be superior to US, especially in the assessment of intrapelvic and intraspinal extension of the tumor, colonic displacement, and complications. While MRI contributes to the diagnosis, it also serves as a guide for treatment, birth planning, and counseling. In order to optimize pre and postnatal management for the evaluation of fetal sacrococcygeal teratoma, fetuses with SCT detected by US should be referred to MRI to evaluate tumor size, content, and extent.


As the semiconductor industry has grown tremendously over the last decades, its environmental impact has become a growing concern, including the withdrawal of fresh water and the generation of harmful wastewater. Tetramethylammonium hydroxide (TMAH), one of the toxic compounds inevitably found in semiconductor wastewater, should be removed before the wastewater is discharged. However, there are few affordable technologies available to remove TMAH from semiconductor wastewater. Therefore, the objective of this study was to compare different treatment options, such as Membrane Capacitive Deionization (MCDI), Reverse Osmosis (RO), and Nanofiltration (NF), for the treatment of semiconductor wastewater containing TMAH. A series of bench-scale experimental setups were conducted to investigate the removal efficiencies of TMAH, TDS, and TOC. The results confirmed that the MCDI process showed its great ability as well as RO to remove them, while the NF could not make a sufficient removal under identical recovery conditions. MCDI showed higher removals of monovalent ions, including TMA+, than divalent ions. Moreover, the removal of TMA+ by MCDI was higher under the basic solution than under both neutral and acidic conditions. These results were the first to demonstrate that MCDI has significant potential for treating semiconductor wastewater that contains TMAH. The exceptional situation of the pandemic has brought about a great change in the trend of all industries as well as our lifestyle for the past two years. Non-face-to-face services that utilize the advancement of technology to provide services or products without direct contact with customers, also known as “no contact”, have prevailed; moreover, the “on-tact”, which means business by online, has emerged. As a result, the market size of information technology is flourishing, and therefore related industries such as display and microelectronics are benefiting. Naturally, the semiconductor manufacturing markets are entering the golden age, and it has been reported that the size of the global semiconductor market was estimated to be USD 43.6 billion in 2021 and is expected to reach USD 115.78 billion or more by 2030, growing at a projected CAGR of 11.5% from 2022 to 2030 [According to several reports ,8,9, ensMycobacterium sp. and Hypomicrobium sp. [There exist two primary categories of technologies that can effectively treat effluents containing tetramethyl ammonium hydroxide (TMAH), namely, destruction processes and separation processes. The destruction processes encompass various techniques such as biodegradation (including both aerobic and anaerobic treatment), advanced oxidation processes (AOPs), and hydrodynamic cavitation. On the other hand, the separation processes include adsorption, ionic exchange, electrodialysis, and other membrane-based separation processes. Lei et al.  investigbium sp. . However2, CO2, and H2O. However, to avoid the creation of hazardous gas, a conversion procedure should be added to convert nitrogen oxides to nitrogen, water, and carbon dioxide. Furthermore, it was showed that the combined UV/H2O2 and fluidized bed biodegradation methods were able to remove over 95% of TMAH, but the biodegradation of TMAH was difficult with cultures adapted from activated sludge [Chemical oxidation could be used to remove TMAH from wastewater. Hirano et al.  developed sludge .In the case of the separation processes, Chang et al.  proposedSince its introduction in the 1970s , capacit2+ deposition via production of Ca(OH)2 on the electrode surface would rapidly lead to a decrease in accessible adsorption sites, resulting in a decrease in CDI performance, and Yoon et al. [Based on the above advantages, MCDI has been used in versatile methods. Choi et al.  reportedn et al.  conducten et al.  reportedn et al.  reportedn et al. . HoweverAccordingly, the objective of our study is to investigate the efficient removal of TMAH using MCDI. To achieve this goal, real semiconductor wastewater containing multiple dissolved ions, TOC, and TMAH was obtained from a microelectronics manufacturing company. The wastewater underwent a series of purification tests using MCDI, and the results were compared with conventional processes, i.e., reverse osmosis (RO) and nanofiltration (NF) processes. The removal efficiency of each process was evaluated using a laboratory-scale experimental device. The pH of the solution was also varied to estimate the difference in TOC and TMAH removal in the MCDI process.Thin-film composite membranes made of polyamide (CSM RE4040-BE and CSM NE2540-70) were purchased from Toray Chemical Korea Co., Ltd. for RO and NF processes, respectively. The operating pH range of both membranes was from 3.0 to 10.0 and has the negatively charged surface in this boundary. The IEM was fabricated with pol-yethylene, and its ion penetration capacity was 1.6 meq. /g. The MCDI electrode was composed of graphite and the activated carbon was coated, and it has an adsorption capacity of 16 mg/g . Before each experiment, both the IEM and the electrode were soaked with UPW for at least two hours to remove the loaded air inside the pores. Other details of the membranes and electrode are shown in 2O) and was a mixture of citric acid, sodium hydroxide, and hydrogen chloride; the alkaline buffer (CAS No. 13840-56-7) had a pH of 10.0 and was composed of boric acid, potassium chloride, and sodium hydroxide. An ultrapure water (UPW) was produced by an ultrapure water system  and used for flushing membranes, modules, and experimental devices.High-purity sodium chloride (NaCl) was purchased from Samchun Chemicals, Republic of Korea. Two types of pH buffers were purchased from Sigma-Aldrich, City, Republic of Korea; the acidic buffer (CAS No. 55965-84-9) had a pH of 2.0  device was organized and constructed by Pureechem Co., Ltd., Cheongju-si, Republic of Korea; the schematic diagram of the device is shown in RO and NF: Both systems were conducted by stirred cell apparatus . The real wastewater sample was prepared with 20 °C (±1) of temperature adjustment; the initial volume of wastewater was 200 mL, respectively; and the processes were carried out until the recovery reached 90%; permeate product samples were collected and analyzed its conductivity along with TOC and TMAH concentrations.® C-MAG HS7). Solution conductivity and pH were monitored and recorded by the portable conductivity meter set . All experiments, including MCDI, RO, and NF, were tested at least three times to validate the reproducibility of the results. Additional experimental conditions are summarized in MCDI: As shown in The efficiency of RO and NF membranes in removing contaminants from the semiconductor wastewater was investigated using the stirred cell device. The difference in the removals of TOC and TMAH between RO and NF is attributed to the characteristics of these solutes and the membranes. The organic matters in the wastewater may be either charged or uncharged. In general, RO and NF have higher rejection for charged solutes than uncharged ones . Since TAlthough RO removed up to 92% of TMAH, the disadvantages of RO technology should be also considered. RO fouling may be a serious issue because the RO feed is the industrial wastewater. Furthermore, RO uses more energy than other conventional processes . The useIn addition to RO and NF, MCDI was also considered as a treatment option for the wastewater. The first set of experiments (MCDI Test #1) for MCDI were conducted by separating the product and concentrate (single pass mode), which led to relatively low product recovery (~48%). As depicted in 2+) and sulfate (SO42−) ions were lower than those of other ions . The removal of monovalent ions was at least 92%, but that of the divalent ions was only about 80%. These results can be explained by two mechanisms. The first one is the difference in electrosorption rates between the monovalent and divalent ions. According to the literature, monovalent ions generally have higher electrosorption rates than divalent ions due to their weaker EDL overlapping [+ ion) shows lower removal than the monovalent ions (Na+ and Cl−) but has higher removal than the divalent ions (Ca2+ and SO42−). This implies that the effect of the atomic valency  is more important than the hydration radius.To evaluate the ion electrosorption of the MCDI process, the permeate product was examined by ion chromatography. The initial and permeate product concentrations and the respective removal rates are shown in rlapping ,54,55. Trlapping ,57. As sIn the previous section, the MCDI process was shown to have considerable ability to remove ions along with TOC and TMAH. However, RO and NF were operated at 90% process recovery, while MCDI recovery was only 48%. Since this is not a fair comparison, another set of MCDI tests were conducted with an increased recovery. In the case of MCDI Test #2, concentrate was returned to the feed stream (recycle mode), and process recovery was improved. As illustrated in +, Cl−, and TMA+ were not significantly affected by increasing recovery. However, the removals of divalent ions such as Ca2+ and SO42− were reduced by more than 11% with increasing recovery  and metal salts (coagulation) . Electro−) ions in high pH conditions, which are attracted to the electrode of positive charge. At the same time, TMA+ ions migrate to the CEM and the negatively charged electrodes of. Since the zeta potential across the CEM decreases at high pH, TMA+ ions can more easily pass through the CEM and be absorbed by the electrodes, resulting in their high removal. On the other hand, the competition of the electrosorption between TMA+ and H+ ions occurs in low and neutral pH conditions, as described in These results are attributed to the difference in the electrosorption in the electrodes in different pH conditions. As illustrated in The NF experimental test shows that it is inadequate to treat TMAH in the wastewater due to its limited molecular weight cut-off;The RO process effectively removed TDS ~23.9 mg/L and TMAH ~3.0 mg/L from the semiconductor wastewater. However, this process only accounted for 56% of the TOC removal from the wastewater;On the other hand, MCDI showed its sufficient ability to treat the semiconductor wastewater by its adequate removal efficiency of TDS, TOC, and TMAH;In addition, it was found that the MCDI process can remove the monovalent ions including TMA ions more effectively than the multivalent ions due to their inherent ionic hydrate radii;Furthermore, the TMAH removal capability of MCDI can be improved by pH adjustment. In particular, this improvement was more pronounced when the pH of the semiconductor wastewater was higher.The present study compares the removal of contaminants in the semiconductor wastewater containing TMAH by RO, NF, and MCDI processes. The major findings of this study can be summarized as follows:


Stereotactic radiosurgery (SRS), also known as gamma knife surgery (GKS), is a noninvasive procedure for treating tic douloureux (TD) or trigeminal neuralgia (TN). Due to a lack of sufficient evidence regarding the indication of SRS for the treatment of recurrent TD, the present scoping review was conducted to assess the effectiveness of repeated SRS procedures for managing recurrent TD. The literature search was performed from January 2012 to December 2022 on the PubMed, Scopus, and Web of Science databases. Of the 215 initial results obtained, 10 articles were finally selected for the review. Three studies used the SRS procedure for the third time in patients with recurrent TD. All studies were retrospective, with a mean maximal dose of 70-90 Gy and a cumulative dose of 120-180 Gy for two SRS treatments and 150-270 Gy for three SRS treatments. The target zone for irradiation was the retrogasserian zone (RGZ). Repeat SRS procedures led to pain relief in 80-90% of patients within one to four months and excellent pain relief in 50-90% of patients. Pain recurrence was noticed after one year in 20-40% of patients. Postoperative complications, such as trigeminal nerve deficits, facial numbness, and mild corneal dryness, were noted in the studies. The review concluded that repeat SRS is an effective and relatively safe procedure for pain management in patients with recurrent TD. Tic douloureux (TD), also referred to as trigeminal neuralgia (TN), is a condition characterized by chronic pain disorder of acute onset and severity that specifically targets the facial region. This condition fundamentally involves the trigeminal nerve, also known as the fifth cranial nerve, which is responsible for both sensation and neural communication throughout various regions of the cranium and face . The diaTN is classified into two types: classical trigeminal neuralgia (CTN), associated with an unknown etiology and often treated with neurovascular decompression, and secondary trigeminal neuralgia (STN), associated with multiple sclerosis . The firTN has a high recurrence rate of 6-41%. Previous studies demonstrated that the retreatment rate was 20% following MVD, 6% following GKS, and 57% following percutaneous radiofrequency rhizotomy [GKS, also known as stereotactic radiosurgery (SRS), is a commonly used treatment modality for refractory facial pain associated with TN that involves the trigeminal nerve. The concept of radiosurgery was first presented by Lars Leksell in 1951 . SRS useTo date, only one systematic review was conducted in 2014 to evaluate the effectiveness of the repeat SRS procedure in the treatment of recurrent TD . In lighMethodsThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines and Joanna Briggs Institute (JBI) protocol were followed in this review to provide a clear and transparent reporting of the outcomes. Ethical committee approval was not required as this review was conducted using an online database. Unlike systematic reviews, scoping reviews are not registered in the International Prospective Register of Systematic Reviews (PROSPERO).Study Selection and Search StrategyA systematic search of the English literature was conducted in the PubMed, Scopus, and Web of Science databases for articles published between January 1, 2012 and December 31, 2022, using Medical Subject Heading Terms (MeSH terms), as shown in Table The PRISMA-ScR flow diagram of the data search is shown in Figure The first author (MG) conducted a search of the databases using MeSH terms from January 2012 to December 2022, as mentioned in Table The patient/population, intervention, comparison and outcomes (PICOS) criteria for the search were as follows: P (population/patients), i.e., studies involving patients of any sex, and age, with recurrence of TD; I (intervention), i.e., using stereotactic radiosurgical procedure for treatment; C (comparator), i.e., comparison of the effectiveness of the SRS procedure, with initial treatments; O (outcome), i.e., the primary outcome was pain relief and the secondary outcome was post-SRS trigeminal dysfunction or facial numbness in the treatment of recurrent TD.Eligibility Criteria for the SearchInclusion criteria: All retrospective and prospective cohort studies, randomized control trials, studies between January 1, 2012 and December 31, 2022, studies where SRS has been used for initial and repeat treatments for recurrent type 1 TD cases, and primary studies in English were included.Exclusion criteria: Case series, conference papers, theses, letters to the editor, editorials, case reports or series, animal studies, systematic reviews, meta-analyses, studies published before January 2011 and after December 2022, studies conducted on TD or atypical facial pain arising from tumor or other intracranial lesions (type 2 TD), studies conducted on post-mortem data or non-humans, and studies published in any language other than English were excluded.Data ExtractionData were extracted according to the PICOS criteria. The information on authors’ name, year, and type of publication; details of demographic data, such as age, sex, number of subjects, type of initial method used for assessment, rate of follow-up after the initial and final treatments, methods used for the initial treatment, dose of SRS for the management of recurrent TD; and outcome of the intervention were extracted from the studies.ResultsThe initial database search resulted in 195 articles, and 20 additional records were identified through other sources. There was a perfect agreement between the two reviewers  in the initial screening of titles and abstracts. Disagreements were resolved by a third reviewer. A total of 26 full-text articles were assessed for their eligibility. Ten studies were finally included ,16,17,18Characteristics of the Included StudiesAll included studies were retrospective and were published in medical neurosurgery journals. The age range of the samples in the studies was 30-80 years, and both males and females were included in the studies, except for one study, in which the sample was not categorized . TN was Dose of IrradiationAll therapeutic procedures were performed using the Leksell Gamma Knife . The emission of radiation was administered toward a solitary isocenter, facilitated through the utilization of a 4 mm collimator. The placement of the isocenter was observed to be along the trigeminal nerve, which is dysfunctional, usually at the entrance into Meckel’s cave or in the prepontine cistern. All the studies used almost the same radiation dose for the initial and repeat SRS procedures, in the range of 70-90 Gy, except one study that used a low radiation dose in the range of 25-40 Gy . The radTreatment OutcomesPain response: Patient outcomes were evaluated using the Barrow Neurological Institute (BNI) pain scale . The claToxicity: New paresthesia after a repeat SRS procedure was noticed in 18-33% of patients. After the third SRS procedure, none of the patients developed paresthesia in two studies ,17, wherDiscussionAlthough SRS is an effective procedure for the management of pain in TD, 20-40% of patients suffer from recurrent pain, for which the second and third SRS procedures are being undertaken. Several studies have attempted to establish a correlation between the response to SRS retreatment of recurrent TD and various factors, including but not limited to age, sex, duration of symptoms, comorbidities, type of trigeminal pain, prior surgical treatment, time between SRS treatments, SRS dose and number of isocenters, treated nerve length, relationship between the nerve root entry zone and the isocenter, and response to the initial SRS treatment.Age, Gender, and DoseAge, sex, and duration of symptoms prior to initial SRS were found to have no statistically significant impact on outcomes. Most of the studies have used 70-90 Gy radiation doses and cumulative dose of 120-180 Gy for two SRS procedures and 150-270 Gy for three SRS procedures. Park et al. reported that initial doses less than 60 Gy and cumulative doses less than 150 Gy were less effective in pain control [TargetAll studies used a retrogasserian target for radiation. The use of a retrogasserian target confers a substantial advantage in minimizing the radiation dose to the brainstem, potentially mitigating complications that may arise from trigeminal sensory- and brainstem-related factors. It is recommended that brainstem doses be maintained below 12 Gy by utilizing target distances that exceed 5 mm from the surface of the brainstem to minimize side effects. Repeat SRS procedures with cumulative brainstem doses exceeding 12 Gy have been associated with postoperative toxicity, and 10 Gy has been suggested as a threshold for cranial nerve nuclei inside the brainstem ,16,17,18Outcome After Repeat SRSConsideration of the radiation target is of significant importance in relation to the initial cessation of pain and its potential side effects. The diverse range of radiation targets highlighted in existing publications creates challenges in establishing "optimal" targets. All studies reported pain relief (BNI I-IIIb) in 80-90% of cases within four months of treatment. A proportion of 30-40% patients reported excellent pain relief (BNI I). The pain cessation rates after repeat SRS were consistent with those after the first SRS. Raygor et al. reported pain relief in 100% patients, with excellent pain relief in 76% patients . The reaToxicityIt has been documented in the scientific literature that the likelihood of exhibiting symptoms associated with trigeminal nerve dysfunction is elevated subsequent to undergoing retreatment with SRS. New facial sensory symptoms caused by partial trigeminal nerve injury are the primary complications observed after repeat SRS. These symptoms are seen in 18-33% of patients. Other complications include corneal dryness, which can be mild to bothersome, alteration in taste sensation, jaw weakness, and anesthesia dolorosa . The reaThe predictive factors for new hypesthesia after the second SRS are isocenter placement , distance of isocenter from pons, cumulative radiation dose to pons, and cumulative radiation dose to REZ . No signLimitationsDue to the heterogeneity in the studies regarding the optimal dose and optimal target zone for the management of recurrent TD, the present review failed to address the two important research questions. All included studies were retrospective and did not mention the brainstem edge dose, which is a very important factor regarding post-SRS complications. Multicenter prospective studies with a long follow-up period are required in the future.Studies have indicated that the rates of pain control and recurrence after repeat SRS are similar to those of initial SRS. SRS is a relatively safe and noninvasive procedure that can be effectively used for pain management in type 1 TD. To scrutinize the safety and efficacy of this procedure, it is imperative to meticulously consider the individual patient characteristics at baseline and the technical intricacies, particularly the placement of the target and the amount of radiation dosage administered. Furthermore, it is crucial to consider the number of patients involved and the duration of follow-up, as these are important criteria for the evaluation of this treatment.


Numerous studies have shown that miRNAs play a crucial role in the investigation of complex human diseases. Identifying the connection between miRNAs and diseases is crucial for advancing the treatment of complex diseases. However, traditional methods are frequently constrained by the small sample size and high cost, so computational simulations are urgently required to rapidly and accurately forecast the potential correlation between miRNA and disease. In this paper, the DEJKMDR, a graph convolutional network (GCN)-based miRNA-disease association prediction model is proposed. The novelty of this model lies in the fact that DEJKMDR integrates biomolecular information on miRNA and illness, including functional miRNA similarity, disease semantic similarity, and miRNA and disease similarity, according to their Gaussian interaction attribute. In order to minimize overfitting, some edges are randomly destroyed during the training phase after DropEdge has been used to regularize the edges. JK-Net, meanwhile, is employed to combine various domain scopes through the adaptive learning of nodes in various placements. The experimental results demonstrate that this strategy has superior accuracy and dependability than previous algorithms in terms of predicting an unknown miRNA-disease relationship. In a 10-fold cross-validation, the average AUC of DEJKMDR is determined to be 0.9772. Numerous aspects of microRNAs are significant, including cellular biological processes, regulation of gene expression at the transcriptional and post-transcriptional levels, and others. Understanding could be increased and experimental costs reduced if we could identify the most probable potential miRNA-disease connections and prioritize their biological experimental validation.miRNA serve a crucial regulatory role in a variety of life processes within the human body and are tightly linked to the occurrence and development of cancer and other diseases. Methods of computational prediction have become an essential tool for discovering new disease-related miRNAs.On the molecular mechanisms and connections that exist between microRNAs and disease, genes and disease, etc., numerous studies have been undertaken.With regard to the connection between miRNAs and disease, Genome Tiling Arrays were suggested for universal detection of Human Transcribed Sequences by Bertone et al. . The relRegarding the relationship between chromosomes and diseases, a method investigating the role of miR-143, miR-145, and the MiR-143 host gene in cardiovascular development and illness was established by Vacante et al. . In addiGenomics and bioinformatics developments have assisted in the identification of microRNAs. It was additionally found that miRNAs bond with a variety of prescription drugs. For example, the SVMMDR, a prediction model of miRNAs-Drug resilience employing Support Vector Machines and Heterogeneous Network, was developed by Duan et al. . The SVMThere are multiple public databases that catalog the relationships between miRNAs and diseases. For example, the HMDD database was created by Huang et al.  to curatThere are currently studies predicting a possible link between miRNAs and disease. For example, an innovative miRNA-disease association forecasting framework applying dual walk randomization with relaunch and spatial projection pooled method was developed by Li et al. . A freshAlthough there are some instruments for forecasting the miRNA-disease association, these cannot optimally fuse heterogeneous information and strengthen the reliability of prediction by conducting adaptive learning. In addition, the accuracy and performance of these methods need to be improved. To solve the aforementioned problems, a miRNA-disease association prediction model, DEJKMDR, based on graph convolution is proposed in this paper. DEJKMDR incorporates biomolecular information of miR11NA and disease, such as the functional similarity of miRNA, the semantic similarity of disease, and the similarity of Gaussian interaction properties of miRNA and disease. The DEJKMDR is used to predict potential miRNAs-disease associations. Our method’s contribution consists primarily of the following elements:The DEJKMDR employs SNFS to incorporate various types of biomolecule data signatures.During training, the DEJKMDR deletes random edges of the adjacency matrix, increasing the diversity of input sample data and reducing overfitting.The DEJKMDR utilizes JK-Net to integrate the node representations of all previous layers into the final layer and to learn different order representations of various subgraph structures. By integrating all representations from previous layers, it eliminates the issue of graph convolution’s excessive smoothing.The DEJKMDR method boosts the accuracy of predictions and has the finest AUC values among the current ones.2.First, statistics regarding miRNA-disease associations are accessed from the HMDD v3.2 database . A totalmi linked with disease dj, A] = {d(i),T[d(i)], E[d(i)]}.Here, T[d(i)] represents the ancestor node set of disease d(i), and E[d(i)] represents the edge set from the ancestor node to disease d(i). This is shown in the following d(i) represents Breast Neoplasms, T[d(i)] are Breast Disease，Neoplasms by Site，Skin Disease，Neoplasms，and Skin and Connective Tissue Disease. From this, the contribution of disease d(n) to the lexical measurement of disease d(i) in DAG [d(i)] can be calculated, where n is the other diseases within T[d(i)].For example, a disease directed acyclic graph could be shown as DAG [d(i) is derived as follows:Where Δ symbolizes the contribution factor for semantics, which will be modified to 0.5. This is shown in reference 39. Consequently, the semantic value of disease d(i) and d(j) are computed:Finally, the semantic similarity scores between disease d(i). Based on this theory, the semantic value contribution of disease d(n) to d(i) is shown as follows:Secondly, to calculate semantic similarity between two diseases, it is also necessary to weigh the number of occurrences of the same disease in distinct DAGs. Since diseases in different layers of the same DAG also have different semantic contribution values of diseases, from this perspective, some specific diseases may contribute more to disease d(i) and the semantic similarity of disease d(i) and d(i) are obtained as follows:Then the logical rating of disease d(i) and d(i) is obtained by combining the two semantic similarity degrees:Finally, the semantic similarity matrix of 2.2.2.mi and miRNA mj are associated with m and n diseases, separately, the similarity between miRNA mi and miRNA mj could be determined by applying The computation of the functional similarities of miRNA is the same as in the previous investigation by Wang et al. , where ti. i. dm is the number of diseases in disease concentration, and m is the number of diseases in disease concentration. n is the number of diseases in the disease cluster. i for disease d. d1 indicates the diseases in which D1(mj) diseases are concentrated. 1 in disease set where 2.2.3.im, its IP(im) value is defined as row i of the miRNA-drug association matrix A, and the kernel similarity of Gaussian interaction attribute between every single pair of miRNA im and miRNA jm is calculated, as shown in Both miRNA and disease show Gaussian interaction attribute kernel similarity. The similarity of Gaussian interaction kernel of disease is calculated below. Initially, the adjacency matrix is established through the associated information of miRNA and disease. The columns of the matrix represent miRNAs while the rows indicate illnesses. Additionally, applying the Gaussian kernel Function of Radial Basis Function (RBF) to the adjacency matrix yields a similar matrix to the spectral kernel of the Gaussian interaction of the disease. The Gaussian interaction spectrum of miRNA uses the same nuclear similarity calculation approach as illness. The adjacency matrix is generated by applying the associated data between miRNA and disease. The columns of the matrix represent diseases while the rows indicate miRNAs. Then, the radial basis function Gaussian kernel function is implemented to the proximity matrix to acquire a similar matrix of miRNA Gaussian interaction spectrum kernel. The specific calculation process is as follows. For A miRNA im and miRNA jm. Where GSM represents the kernel similarity matrix of the Gaussian interaction attribute of miRNA. Element Likewise, based on the hypothesis that there is an association between functionally similar miRNAs and similar diseases, a Gaussian interaction attribute kernel similarity matrix GSD for diseases is constructed by using the identified miRNA-disease association network.i of miRNA-disease correlation matrix A. The kernel similarity of Gaussian interaction attributes between each pair of diseases is calculated, as shown in For a disease, its Where, GSD represents the kernel similarity matrix of the Gaussian connection attribute of disease.The element 2.3.Despite the fact that the disease semantic similarity matrix and the miRNA functional similarity network have been obtained through the aforementioned techniques, further research is warranted; owing to the paucity of valuable information, these similarity matrices are rare. In order to enrich the similarity matrix, the kernel likeness of the Gaussian interaction matrix of miRNA and the kernel resemblance of the disease engagement band are calculated according to the recognized connection between miRNA and disease. At the same time, similarity network fusion is employed for fusion. SNF is an effective method for fusion of different types of data features. SNF generates an equivalent system matrix for every possible similarity and employs the non-linear combination method relying on k-nearest neighbor to integrate two networks. For miRNA, functional similarity matrix FSM and Gaussian interaction spectrum kernel similarity matrix GSM have been obtained. First, the FSM and GSM lines are normalized to get RFSM and RGSM. After using KNN, KRFSM and KRGSM are obtained, as shown in the N(im) is the collection of K nearest neighbors of mi. Finally, multiple similar networks are fused using an iterative method.Where t is the number of iterations. t times, we get the final Where By means of the identical method, the disease integration similarity matrix DD is obtained.2.4.The miRNA similar network, disease similar network, and miRNA-disease association matrix obtained after fusion of similar networks were constructed into graph structure data and input into the JK-Net model for training to obtain a prediction model. In the training process, the random edge removal rate is set as 0.4. JK-Net uses multi-layer graph convolutional neural network for representation learning of nodes to aggregate node information in different fields and can adjust adaptively according to the position of nodes in the network and the topology structure of the graph to better represent both the local and broader traits of network nodes.3.3.1.Part of the experimental parameters in the DEJKMDR method will be introduced in this section, and part of the parameters used by DEJKMDR are displayed in 3.2.3.2.1.In the aim to appraise the effectiveness of DEJKMDR about predicting miRNA-disease association, this study employs 5-fold and 10-fold cross-validation techniques. ROC and PR curves are acquired, respectively. According to 3.2.2.p = 0, it means that the original adjacency is used as input for training. In p = 0, the AUC obtained is 0.869, and with a rise in loss rate p, the AUC also increases on a gradual basis. When p is 0.4, the ROC curve obtains the maximum AUC area and reaches a small vertex. When p continues to increase to 0.6 and 0.8, AUC gradually decreased, indicating that high edge loss rate would reduce model performance. Further, To investigate the effect of various edge loss rates on the efficacy of the DropEdge method model, several groups of comparative experiments are conducted, and the edge loss rates are set as 0, 0.2, 0.4, 0.6, and 0.8, respectively. The average AUC and other performance indicators are also verified using the 10-fold crossover, as shown in 3.2.3.In an effort to confirm the performance advantages of similar network fusion, random edging, and JK-Net in the model, several ablation experiments are carried out based on the proposed DEJKMDR, and several groups of comparison experiments are designed to evaluate the effectiveness of these strategies by changing the structure of the model. By means of these investigations, we can better understand the contribution and function of these methods in the model. The average AUC and other performance indexes are also obtained by using the 10-fold crossover. As shown in 3.2.4.Some studies have predicted the potential association between miRNAs and disease, comparing the DEJKMDR algorithm with existing methods for predicting the relationship between miRNAs and drug susceptibility. In the experiment, three methods are selected to compare with the proposed DEJKMDR method. They are NIMGSA , TCRWMDA3.2.4.1.NIMGSA is an end-to-end deep learning framework which integrates inductive matrix completion and tag propagation . It impl3.2.4.2.TCRWMDA is a three-layer heterogeneous network miRNA-disease association prediction algorithm combined with non-equilibrium random walk . TCRWMDA3.2.4.3.The GAEMDA model uses a graph-based neural network encoder consisting of a clustering operation and multi-layer perceptron, to aggregate the adjacent data from nodes, produce low-dimensional embedding of miRNA and disease nodes, and accomplish operational fusion of heterogeneous info, subsequently embedding microRNAs and disease node input bilinear decoders to identify potential connections between miRNAs and disease nodes .The reasons are as follows: first, DEJKMDR integrates several biomolecular data types using SNF; secondly, DropEdge randomly deletes some adjacency matrix edges during training, increasing input sample data diversity and reducing overfitting. Finally, JK-Net combines the node representations of all previous layers in the last layer to learn different order representations of different subgraph structures. By combining all representations from previous layers, the problem of over-smoothing graph convolution is alleviated. All of these enable DEJKMDR to achieve better performance.4.More and more studies have shown that the expression level of miRNAs is closely related to the occurrence and development of a variety of tumors. Predicting the association between miRNA-disease can help to identify early diagnosis protocols for the disease and prognostic observation of diseases. Therefore, in this paper, an outstanding durability technique based on heterogeneous networks for predicting the association between miRNAs and disease (DEJKMDR) is proposed. Firstly, DropEdge is used to regularize the edges in the original adjacency matrix and some edges are randomly deleted to reduce overfitting. At the same time, JK-Net is used to gather the domain information of nodes. The effect of DEJKMDR is demonstrated by 10-fold cross-validation. Compared with other current excellent prediction models, DEJKMDR is effective at predicting undocumented miRNA-disease associations because of its substantial enhancements in performance.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.SYG, ZFK, TD, and LD conceived this work and designed the experiments. Both SYG and ZFK conducted the experiments and gathered the data and performed the analysis. The article was composed, revised, and approved by SYG, ZFK, TD, and LD. All authors contributed to the article and approved the submitted version.This work was supported in part by the National Natural Science Foundation of China under Grants Nos. 62072477, 61309027, 61702562 and 61702561, the Hunan Provincial Natural Science Foundation of China under Grants No.2018JJ3888, the Hunan Key Laboratory of Intelligent Logistics Technology 2019TP1015.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Efficient health interventions in individual populations should be based on evidence-based data. Our study provides new insights on melanoma  mortality trends in European Union (EU) countries, as well as in three non-EU countries, from a wide-time perspective (1960–2020), by sex and age groups. To the best knowledge, our study is the most up-to-date and broad analysis of melanoma mortality in Europe. It can be used as a reference for public-health actions aiming at a national and international melanoma-mortality reduction. Investigated melanoma-mortality trends vary in individual countries and age groups; however, a highly concerning phenomenon—an increasing melanoma mortality in both sexes—was observed in the case of 7 countries for the younger age group and 26 countries for the older one. There is a need for coordinated systemic actions to address this issue.Background: In 2020, in 27 European Union (EU) Member States, melanoma accounted for 4% of all new cancer cases and 1.3% of all cancer deaths, making melanoma the fifth most common malignancy and placing it in the 15 most frequent causes of cancer deaths in the EU-27. The main aim of our study was to investigate melanoma mortality trends in 25 EU Member States and three non-EU countries  in a broad time perspective (1960–2020) in a younger (45–74 years old) vs. older age group (75+). Methods: We identified melanoma deaths defined by ICD-10 codes C-43 for individuals aged 45–74 and 75+ years old between 1960–2020 in 25 EU Member States  and in 3 non-EU countries—Norway, Russia, and Switzerland. Age-standardized melanoma mortality rates (ASR) were computed using the direct age-standardization for Segi’s World Standard Population. To determine melanoma-mortality trends with 95% confidence intervals (CI), Joinpoint regression was applied. Our analysis used the Join-point Regression Program, version 4.3.1.0 . Results: Regardless of the considered age groups, in all investigated countries, in general, melanoma standardized mortality rates were higher for men than women. Considering the age group 45–74, the highest number of countries was characterized by decreasing melanoma-mortality trends in both sexes—14 countries. Contrarily, the highest representation of countries in the age group 75+ was connected with increasing melanoma-mortality trends in both sexes—26 countries. Moreover, considering the older age group—75+—there was no country with a decreasing melanoma mortality in both sexes. Conclusions: Investigated melanoma-mortality trends vary in individual countries and age groups; however, a highly concerning phenomenon—increasing melanoma-mortality rates in both sexes—was observed in 7 countries for the younger age group and in as many as 26 countries for the older age group. There is a need for coordinated public-health actions to address this issue. The incidence of melanoma is driven mainly by overexposure to a well-known single risk factor, ultraviolet radiation (UV), emitted naturally by the sun and artificially by sunbeds and other tanning devices. Even though knowledge of UV-preventive measures seems to be expected, in the past decades, the global melanoma incidence has been increasing . AccordiOur study aimed to investigate melanoma-mortality trends in 25 EU Member States and three non-EU countries  in a broad time perspective (1960–2020) among a younger vs. older age group. We also attempted to identify the patterns and regularities in the melanoma-mortality trends and presented melanoma-mortality rates in the investigated countries.To the best of our knowledge, our study is the most up-to-date and broad analysis of melanoma mortality in Europe.The analyzed mortality and population data were obtained from the World Health Organization (WHO) Mortality Database  and EuroAge-standardized melanoma-mortality rates (ASR) were computed using the direct age-standardization for Segi’s World Standard Population . We usedTaking into consideration the long period of the observation (60 years), some of the data (mainly from the earliest years) may not fully reflect the total size of the investigated phenomenon, as the process of data collection and its standardization has been improved over the years and is, in the case of some countries, still ongoing.Regardless of the considered age groups, in all investigated countries, melanoma standardized mortality rates were in general higher for men than women.Considering the age group 45–74, the highest number of countries was characterized by decreasing melanoma-mortality trends in both sexes—14 countries. Contrarily, the highest representation of countries in the age group 75+ was connected with increasing melanoma-mortality trends in both sexes—26 countries. Moreover, considering the older age group—75+—there was no country with a decreasing melanoma mortality in both sexes .In the considered age group, seven investigated countries were characterized by an increasing melanoma mortality, with the highest age-standardized mortality rates in Slovenia for both men, and women. In the case of Greece and Lithuania, we observed a constant and stable increase in melanoma-mortality trends, which was, however, more dynamic in women in Greece and men in Lithuania. When discussing other countries, we investigated breakthrough years where the pace of increase in melanoma mortality slowed down—in 1982 in Italy (in both sexes) and Ireland (in women); in 1986 in Slovenia (in both sexes); in 1994 and 1997, respectively, for men and women in Portugal and in 2001 in Slovakia (in men) .In the analyzed age group, the highest proportion of countries (15) showed decreasing melanoma-mortality trends in both sexes. Among those countries, the breakthrough years, when melanoma-mortality trends started to decline, varied from the early 1980s through the early and late 1990s to the second decade of the 21st century, when the highest proportion of countries was noted to have a melanoma-mortality decrease. Moreover, in the vast majority of the analyzed countries, a melanoma-mortality decrease occurred earlier in the case of women compared to men, except for the Czech Republic, Germany, Norway, Russia, and Spain .In the analyzed age group, we also investigated two countries (Bulgaria and France) with a melanoma-mortality increase in women and a decrease. In the case of women, we observed a stable increase in Bulgaria. In France, the pace of growth slowed down in 1984 . In bothThe last group of countries underwent a decrease in melanoma mortality in women and an increase in men. In the case of Croatia and Finland, we observed the breakthrough years in men, respectively, to be in 2001 and 1970, when the pace of melanoma mortality decreased. In other countries, the increase in men was stable. We also observed that the decrease in melanoma mortality in Finish women started much earlier—in the early 1970s—compared to other countries from this group .In In general, the values of the current age-standardized melanoma-mortality rates are higher in men than women. The values of melanoma rates varied from 3.0 in Spain to 8.6 in Croatia. The highest proportions of countries were characterized by a subsequent range of melanoma-mortality rate values: 3.0–3.8 (6 countries); 4.0–4.8 (7 countries); 5.1–5.6 (7 countries). Contrary to women, only one Scandinavian country—Norway (7.7)—was among those with the highest melanoma mortality. The three lowest rates were linked to Spain, Greece, and Portugal, with rate values of, respectively, 3.0, 3.5, and 3.6.As much as 26 of 28 investigated countries noted increasing melanoma-mortality trends in men and women in the age group of 75 years old and older. Contrary to the youngest age group (45–74), the pace of the melanoma-mortality increase—particularly among men—was much more dynamic, reaching exceptionally high values of melanoma-mortality standardized rates in a relatively short time in Estonia, Ireland, Norway, and Slovenia . On the In The results of our study confirmed a general regularity in cancer-mortality increases connected with aging. So far, many studies have described increasing age as one of cancer patients’ most substantial prognostic factors . AdditioFurther, our study results showed that the highest melanoma mortality is more characteristic for Nordic countries, such as Norway, Sweden, Netherlands, and Denmark, irrespective of the age group and gender. Similar to our results, Robsahm et al.  investigEuromelanoma campaign data analysis [On the other hand, Nordic countries have the lowest annual sunlight hours; for example: Denmark—1618 h/year; Norway—1645 h/year; and Sweden—1981 h/year. Meanwhile, these numbers in Spain, Greece, and Portugal are, respectively, at 2435 h/year, 2804 h/year, and 3044 h/year. Paradoxically, sunnier countries generally demonstrated a lower melanoma mortality in both investigated age groups. In their study, Shipman et al. [analysis . MoreoveEuromelanoma data on sunbed-use prevalence in 30 European countries, only 6% of Slovenians use these devices . Additionally, Slovenia can be considered a southern country. Therefore, Slovenian inhabitants should demonstrate an individually lower sun sensitivity. Moreover, in 2016, in Slovenia, almost all innovative medicines for metastatic melanoma were available—registered and reimbursed (except for Nivolumab—lack of reimbursement) [Interestingly, Slovenia has the highest melanoma-mortality rates among all European women in both age groups and the second highest among men aged 75+. Considering rsement) . Despitersement) ,22. Evenrsement) .Moreover, data published by the European Observatory on Health Systems and Policies  showed tApart from Slovenia, in the younger age group of 45–74 years old, we investigated the melanoma-mortality increase in both sexes in six other countries: Greece, Ireland, Italy, Lithuania, Portugal, and Slovakia . Older aOn the other hand, Italy was second among the countries with the highest value of current healthcare expenditure on preventive care (after the UK). Similarly, Slovenia was among the countries above the EU average, which could translate into lower and decreasing melanoma incidence and mortality rates in these countries . HoweverFinally, access to innovative treatment options is often perceived as the most vital factor impacting cancer-survival rates and melanoma. According to a study by Kandolf et al. , in the Investigated melanoma-mortality trends vary in individual countries and age groups; however, a highly concerning phenomenon—increasing melanoma-mortality rates in both sexes—was observed in 7 countries for the younger age group and in as much as 26 countries for the older age group. Undoubtedly, a higher cancer mortality is related to older age. However, this phenomenon raises a question regarding cancer care that is available for older people, which should be a subject of further research.As in most countries, melanoma-mortality-rate values are higher for men, and the pace of increase is much more rapid for men; one should consider putting more emphasis on gender-tailored preventive actions. Likewise, in the case of age groups, melanoma mortality increases with age.The results of our study suggest that there is not only one universal factor affecting melanoma mortality for all investigated European countries. Rather, we should define a mixture of the most significant factors that substantially impact individual European populations with different intensities. We assume that the most substantial factors are (starting with the most important) aging, the efficiency of healthcare systems, good access to innovative treatment options, and UV overexposure (mainly caused by sunbeds).Despite the high availability of innovative treatment options for melanoma cancer patients , not all of these countries have undergone decreasing melanoma trends. Moreover, some of them have the highest current melanoma-mortality-rate values. This phenomenon could be possibly explained by a period that is too short since the given treatment options have been available or/and a worse efficiency of cancer care and the healthcare system in individual countries. Moreover, an assurance of innovative medicines is insufficient for a melanoma-mortality decrease during the staff shortages, underfinancing, or organizational difficulties in healthcare that many investigated countries have faced for decades. However, these hypotheses should be the subject of further studies.Considering the obtained results, primary and secondary actions aiming for the prevention and early detection of melanoma seem to be notably underestimated by policymakers and not effectively performed in many investigated countries—in most cases, primarily the fact that the early symptoms of melanoma can be easily recognized.There is a need to strengthen the efforts of medical societies to promote education on melanoma prevention, as health professionals have reliable knowledge and the highest trust among patients. We can assume that, as in the case of other highly preventable cancers , mortality reduction demands much broader coordinated public-health actions than primary prevention alone. The effectiveness of these systemic and individual actions will determine the success of such strategic initiatives as Europe’s Beating Cancer Plan.


BackgroundMany studies have been conducted to develop scoring systems for trauma patients, with the majority using logistic regression (LR) models. Neural networks (NN), which is a machine learning algorithm, has a potential to increase the performance of these models.ObjectivesThe aim of this study was to develop and validate two separate prediction models for 72-hour mortality of high-risk trauma patients using LR and NN and to compare the performances of these models in detail. We also aimed to share the SPSS calculators for our models.Materials and methodsThis is a retrospective, single-center study conducted using a benchmark dataset where the patients were retrospectively gathered from a level 1 trauma center. Patients older than 18 years of age, who had multiple injuries, and were treated at the University Hospital Zurich between January 1, 1996, and January 1, 2013, were included. Patients with a condition that may have an impact on the musculoskeletal system, with Injury Severity Score<16, and with missing outcome data were excluded.ResultsA total of 3,075 patients were included in the analysis. The area under the curve values of the LR and NN models for predicting 72-hour mortality in patients with high-risk trauma in the hold-out cohort were 0.859 (95% CI=0.836 to 0.883) and 0.856 (95% CI=0.831 to 0.880), respectively. There was no statistically significant difference in the performance of the models .ConclusionBoth of the models showed good discrimination. Our study suggests that the NN and LR models we developed hold promise as screening tools for predicting 72-hour mortality in high-risk trauma patients. These models were made available to clinicians as clinical prediction tools via SPSS calculators. However, further external validation studies in diverse populations are necessary to substantiate their clinical utility. Moreover, in subsequent studies, it would be beneficial to derive NN models with substantial events per predictor variable to attain more robust and greater predictive accuracy. If the dataset is relatively limited, using LR seems to be a viable alternative. Trauma is a significant cause of mortality worldwide, accounting for more than four million deaths each year . IdentifIn a 2019 meta-analysis comparing LR and NN models in predicting various outcomes in trauma patients, the area under the curve (AUC) of the NN model was calculated as 0.91 (95% CI = 0.89 to 0.93), and the AUC of the LR model was 0.89 (95% CI = 0.87 to 0.90) [The primary outcome of this study is to develop and validate two separate prediction models for 72-hour mortality of high-risk trauma patients using LR and NN and to compare and discuss the performances of these models in detail. We also aimed to share the SPSS calculators (available in the Appendix in xml format) for our models to allow researchers to perform future validation studies.We conducted this retrospective cohort study using the benchmark dataset accessed from the Dryad database ,10. DryaDefinitions and selection of the participantsWe defined “high-risk” trauma patients as having an Injury Severity Score (ISS) of 16 or greater according to the 2016 study of Newgard et al. [The original study where the benchmark dataset was obtained included trauma patients older than 18 years of age, who were treated at the University Hospital Zurich between January 1, 1996, and January 1, 2013. Patients with chronic illnesses and oncological conditions or genetic abnormalities that may have an impact on the musculoskeletal system were stated to be excluded .Since we conducted this study on high-risk trauma patients, we excluded patients who did not meet this definition (patients with ISS<16). Moreover, in accordance with a previous study using this benchmark dataset, we also excluded patients with missing outcome information or miscoded data .Study protocolFollowing the application of the inclusion and exclusion criteria, we performed a multiple imputation procedure to handle the missing data. The medians of the pre- and post-imputation datasets were summarized. The imputed dataset was subjected to univariate analysis in terms of 72-hour mortality. Following this analysis, the dataset was randomly divided into derivation and hold-out cohorts at a 3:1 ratio with the "random split-sample development and validation" method outlined in the TRIPOD statement . To accoMissing dataMissing data were imputed using “multiple imputations.” This process involves creating multiple plausible imputations for each missing value, which results in a more accurate estimate of the missing data and reduces bias in the analysis. Due to the high missing rate in the body mass index variable (47.4%), it was excluded from the imputation process. After the procedure, the analysis was performed on the complete dataset containing the imputed values.Sample size calculationThe estimated mortality prevalence of patients with polytrauma is reported to be 20% to 25% in the literature . Based oStatistical analysisData analysis and modeling were performed using IBM SPSS Statistics version 29 . Since none of the continuous data were distributed normally, median values with 25-75% quartile ranges were presented, and the Mann-Whitney U test was used to compare groups. Categorical data were presented as frequencies and percentages, and group comparisons were performed using the chi-square test. To evaluate the diagnostic performance of the models, we used receiver operating characteristics (ROC) and determined the optimal cut-off points with Youden’s index. For comparing two AUC values, we used DeLong’s test. We set the statistical significance level at p<0.05.We used variables that demonstrated a significant difference between mortality groups in the univariate analysis as predictors in both LR and NN models. We used binary logistics and forced-entry method to develop the LR model. We assessed the goodness of fit using the Hosmer-Lemeshow test and checked for multicollinearity by examining the correlation matrix for any strong correlations between the predictors. We examined Cook's distances for all outliers to determine their effect on the model. The overall performance of the model was evaluated using Nagelkerke R-squared. To identify the most valuable predictor for our model, we examined Wald statistics.For our NN model, we used a multilayer perceptron with two hidden layers. The first hidden layer had four neurons, and the second layer had three neurons. We used hyperbolic tangent as the activation function for the hidden layers, softmax as the activation function for the output layer, and cross-entropy as the output error function. Because Adam, which is the most commonly preferred optimization method, was not available in the SPSS, we used gradient descent as the optimization algorithm with a learning rate of 0.04 and momentum of 0.9.Outcome measuresThe primary outcome of this study is to develop and validate two separate prediction models for 72-hour mortality of high-risk trauma patients using LR and NN and to compare the performances of these models. We also aimed to share the SPSS calculators (available in the Appendix in xml format) for our models to allow researchers to perform future validation studies.Missing data, basic characteristics, and univariate analysisThe benchmark dataset contained 3,668 patients. We excluded 579 patients with ISS<16, 13 patients with missing outcome data, and one patient with invalid body mass index coding. After applying all the exclusion criteria, a total of 3,075 patients were enrolled in our study . Whereas, GCS, base excess, and pH were significantly lower . There was no significant difference between the mortality groups in terms of sex (p=0.084). The univariate analysis is summarized in Table Derivation and the internal validation of the final modelsThe dataset was divided randomly into a derivation cohort and a hold-out cohort using a 3:1 ratio, resulting in 2,050 patients in the derivation cohort and 1,025 patients in the hold-out cohort. The models were derived in the derivation cohort and then validated in the hold-out cohort , pH, base excess, lactate, and age as predictors. The assumption of goodness of fit was met , indicating that the model fit the data well. There were no strong correlations between the predictors; therefore, no multicollinearity was detected. The final LR model correctly classified 84% of the patients and explained 46.2% of the variance in the derivation cohort (Nagelkerke R-squared = 0.462). GCS, age, ISS, and lactate were identified as independent predictors of 72-hour mortality in patients with high-risk trauma . The most valuable predictor was GCS, with a Wald statistics of 175.2. Although there were 13 outlier patients, none of their Cook's distances exceeded 1, and they were not excluded from the model. Table For the NN model, multilayer perceptron was used, and ISS, GCS, pH, base excess, lactate, and age were included as the predictors. After the optimization with gradient descent, the final model was able to classify 84% of the patients correctly in the derivation cohort. The NN model was described, and the synaptic weights are shown in Figure The mean AUC of the LR and NN models in the derivation cohort were 0.873 (95% CI= 0.862 to 0.884) and 0.869 (95% CI= 0.858 to 0.880) respectively. In the validation cohort, the mean AUC for the LR and NN models were 0.868 (95% CI= 0.828 to 0.908) and 0.868 (95% CI= 0.837 to 0.900), respectively. Table External validation and the comparison of the performances of the modelsThe AUC values of the LR and NN models for predicting 72-hour mortality in patients with high-risk trauma in the hold-out cohort were 0.859 (95% CI: 0.836 to 0.883) and 0.856 (95% CI: 0.831 to 0.880), respectively Figure . There wOur LR and NN models demonstrated persistent results in the five-fold cross-validation. Furthermore, it is important to note that the NN model showed highly consistent results in the internal validation, with almost no performance degradation during the training and testing process. Therefore, we can safely assert that there was no significant risk of overfitting in either of the models.Upon evaluating the models' performances on the hold-out cohort, which they had not encountered before, we observed that both models exhibited good discrimination. There was no significant difference in the performances of the models on the hold-out cohort. The LR model demonstrated relatively higher sensitivity, whereas the NN had slightly higher specificity. The performance of both models is satisfactory for use as a screening tool for high-risk trauma patients to predict 72-hour mortality by using only six simple and easy-to-acquire variables.We observed that the order of importance of predictors differed between the models. However, the GCS remained the most valuable predictor in both models. Furthermore, the ISS was identified as the third most valuable predictor in both models.The GCS has been extensively studied as a predictor of mortality in trauma patients, irrespective of the presence of traumatic brain injury (TBI). A number of studies have demonstrated that lower GCS scores are strongly associated with an increased risk of mortality in trauma patients -5. HowevA higher ISS has been consistently associated with increased risk of mortality in trauma patients and is widely used as a tool for clinical decision-making in trauma centers and emergency departments . In addiTBI is a leading cause of morbidity and mortality in trauma patients, and accurate prediction of TBI-related mortality risk is crucial for guiding clinical decision-making. ISS may not accurately reflect the severity of TBI, as it does not take into account important factors .Hence, incorporating the GCS  along with the ISS appears to be a justifiable approach to enhance the performance of a trauma model for predicting mortality, as the limitations inherent in each predictor may be offset by the strengths of the other.LR has become the gold standard for developing clinical risk scoring systems. However, in recent years, ML algorithms, particularly NN, have gained significant popularity for binary classification problems and have been shown to yield consistent results . While tIn another systematic review that evaluated the data of 374,365 patients, the performance of LR and ML methods in predicting mortality and readmission rates in patients with myocardial infarction was compared. Although the ML methods were found to have higher AUC values than LR, it is reported that there were deficiencies in internal validation in ML studies. It was also emphasized that most of these studies also lacked external validation . SimilarLR is a theory-driven method that relies on several assumptions such as linearity, goodness of fit, and the absence of multicollinearity. The validity of these assumptions can and often should be positively influenced by the interventions of researchers during the modeling process . It has NN, on the other hand, is purely data-driven and performs many interventions, or penalizations, required in LR automatically. When the sample size is larger, it can handle greater numbers of predictors better than LR without overfitting the model . Thus, NHowever, ML algorithms such as NN have their unique limitations. For example, in an important study conducted in 2014, the optimism of the random forest (RF) algorithm was found to be quite high even at high EPVs (such as EPV=200), and it was reported that it usually generates worse results in the validation studies. In the same study, it was reported that LR has a reasonable optimism of around EPV=10 and even lower optimism when EPV=20-50. Therefore, it gives more robust results in studies where the dataset is relatively limited . RegardiFurthermore, unlike LR models that can be easily calculated using values such as β coefficients and intercept, NN models require a calculator for prediction. Furthermore, unlike LR models that can be easily calculated using values such as β coefficients and intercept, NN models require a calculator for prediction, as ML models usually produce complex algorithms with low interpretability and explainability . DespiteWhen designing this study, we followed the TRIPOD statement for both models and applied an internal validation technique in the NN model, as the TRIPOD statement suggested for LR. We reported the modeling steps in detail and shared our final models as a pragmatic SPSS calculator in the Appendix so that validation studies can be carried out. Moreover, in the derivation cohort of our study, the number of events was 458, and EPV was 76 for both models, and we observed that the models provided similar results. We believe that these aspects of our study do strongly address many of the limitations in the literature we discussed earlier.Our study has a number of limitations that should be acknowledged. First, the data were collected and reviewed retrospectively, which may raise concerns about data security. Second, the data were obtained from patients treated approximately over a decade ago, and advances in trauma management since then may have a negative impact on the generalizability of our findings. Furthermore, while our external validation showed no significant decrease in performance with EPV = 76, we acknowledge that better model performance and smaller optimism may have been achieved with EPV values in the range of 200 to 250 in the NN model.In conclusion, our study suggests that the NN and LR models we developed hold promise as screening tools for predicting 72-hour mortality in high-risk trauma patients. These models were made available to clinicians as clinical prediction tools via SPSS calculators. However, further external validation studies in diverse populations are necessary to substantiate their clinical utility. Moreover, in subsequent studies, it would be beneficial to derive NN models with substantial events per predictor variable and larger sample sizes to attain more robust and greater predictive accuracy. If the dataset is relatively limited, using LR seems to be a viable alternative.


Pemphigus vulgaris (PV) is a rare, potentially lethal blistering disease typically occurring in adulthood and characterized by autoantibodies directed against mucocutaneous desmosomal proteins. Clinically, flaccid vesicles, bullae and erosions after breakage are the main clinical features. According to the literature, the incidence of PV is rare in the pediatric population, ranging from 1 to 4% of reported cases. We describe an interesting case of a 12-year-old boy with severe PV that was referred to our university hospital for a mucocutaneous disease resistant to anti-infective therapy. Following the appearance of bullous lesions on the skin, antibody screening for autoimmune diseases showed positivity for PV and corticosteroid therapy was started. In view of the numerous adverse effects, we decided to set up biological therapy with rituximab, which was interrupted due to the onset of an urticarial reaction. Further second-line therapies were therefore attempted, with only a partial response. For this reason, a desensitizing therapy with rituximab was decided, thus allowing a clear improvement in the clinical picture and quality of life of the patient. To the best of our knowledge, this is the first report of a child with severe PV resistant to conventional therapies and with an urticarial reaction to rituximab. This case highlights that despite PV being extremely rare in the pediatric population, this diagnosis should not be entirely discounted. In case of severe clinical manifestations, rituximab represents a valid option in children and desensitization tests should be recommended in the presence of hypersensitivity to this drug. Pemphigus vulgaris (PV) is a very rare chronic bullous disease  which typically occurs in patients aged between 45 and 65 years, and it is characterized by the formation of autoantibodies, mainly of the IgG class, directed against desmoglein-1 and desmoglein-3 (Dsg1 and Dsg3 protein) ,3. OtherThe occurrence of PV is even rarer in the pediatric population, ranging from 1 to 4% of reported cases [We report the case of a 12-year-old boy who was admitted to our Pediatric Emergency Unit for severe gingivostomatitis and conjunctivitis present for 15 days and worsening despite oral treatment with amoxicillin–clavulanic acid and acyclovir.Vaccination calendar was sorted by age, and his personal and familial medical history was negative for dermatological and allergic diseases. The child appeared in good general clinical condition and hydration, was apyretic, had rosy skin and an absence of appreciable cutaneous lesions. He showed an intense non-secreting bilateral conjunctival hyperemia combined with multiple erosions and widespread de-epithelialization of the gingival mucosa, in particular at the vestibular level and hyperemic pharynx with aphthous lesions to the tonsillar pillars. He also reported pain during swallowing. A diagnosis of Steven–Johnson syndrome (SJS) was ruled out due to the clinical features of the manifestation, the patient’s generally good condition, and the fact that the time evolution in SJS is very rapid.The child was hospitalized, and tests were performed including blood chemistry, serology for viruses, gingival swab for herpes simplex and autoimmunity  tests as well as instrumental tests such as electrocardiography, echocardiography, chest X-ray and ultrasound of the abdomen with normal results except for a mild increase in the inflammatory marker (erythrocyte sedimentation rate (ESR) 37 mm/h). A multidisciplinary approach was undertaken including dermatological, ophthalmological and odontostomatological consultations. Due to suspicion of chronic bullous disease, a mucosal biopsy a, directFollowing the positive result for IgG antibodies BP 180  and anti-Dsg3 IgG autoantibodies  and negative result for anti-Dsg1 IgG autoantibodies and anti-epithelium antibodies (1:40), the diagnosis of PV was made .Furthermore, a biochip test was performed, showing positivity for anti-epithelium and anti-spiny cell desmosome antibodies. Nevertheless, the major four criteria for a PV diagnosis, including the coexistence of bullous pemphigoid and PV antibodies, were satisfied .During hospitalization, IV hydration and IV acyclovir (30 mg/kg/day) were administered. Moreover, after dermatological and ophthalmological consultation, steroid therapy with a fully oral dose of prednisone 75 mg/day  was started along with betamethasone and chloramphenicol ocular drops. A few days later, the boy resumed feeding with soft food. The patient was discharged home with steroid therapy until the next dermatological evaluation.After one month of follow-up, azathioprine 50 mg/day was added to prednisone 12.5 mg/day to obtain a steroid-sparing effect. After 6 months of immunosuppressive therapy along with supportive therapy in the form of regular nystatin prophylaxis, no improvement was shown in the oral cavity a, and thThe continuous relapsing and worsening trend of the disease required the use of R despite the poor data on its use in childhood. The boy was treated with IV R 1 g after IV premedication with methylprednisolone 60 mg + chlorpheniramine maleate 10 mg + paracetamol 1 g. The infusion had to be stopped after about 30 min due to the appearance of an urticarial reaction of the face and widespread erythema of the body with itching and referred difficulties in breathing . CardiacFollowing this event, prednisone 30 mg/day for 4 weeks with slow scaling was re-started, but the appearance of adverse effects deriving from chronic steroid intake, such as facies lunaris, striae rubrae, buffalo hump, gynecomastia and weight gain, required a reduction in the systemic dosage to 15 mg on alternate days and the evaluation of another treatment. Therefore, IV therapy with immunoglobulins  and seven courses of plasmapheresis once a week with 3 L of plasma with 5% albumin were attempted. Although these last treatments were well tolerated by the patient, with a reduction in antibody anti-DSG1 levels to 57.5 UR/mL, they showed only partial and temporary clinical benefit with, after only a few weeks, further extension of skin lesions, accompanied by subungual involvement, a marker of advanced pathology .To exclude paraneoplastic PV, also considering the positivity of autoantibodies BP-180, a lymph node station ultrasound and thoraco-abdominal computed tomography were performed, both of which were negative. As a last chance, methotrexate 20 mg/week plus folic acid 5 mg were added to prednisone 25 mg every 2 days for 6 months without a clinical satisfying result. New skin bullae and oral erosions were also present. For this reason, desensitizing therapy to R was considered.The desensitization was carried out at the hospital. A skin test with R was negative. The desensitization procedure was supervised by personnel  trained to treat severe hypersensitivity reactions. Rescue medications were readily available. Upon arrival of the fasting patient, two peripheral venous accesses were taken. Four desensitizations to R were performed. Premedications were administered one hour before starting each R desensitization. Chlorphenamine, methylprednisolone, paracetamol and omeprazole were administered IV. A 12-step desensitization protocol was planned. The first bag was prepared with an R concentration of 0.034 mg/mL, which was administered IV in the first hour at an increasing infusion rate. During the second hour, the bag with an R concentration of 0.340 mg/mL was administered at an increasing infusion rate. The protocol required that the infusion of the third bag with an R concentration of 3.377 mg/mL be carried out for the following 3 h and 50 min with an increasing infusion rate. However, during the administration of the third bag of R at an infusion rate of 40 mL/h, the patient presented facial erythema along with heat sensation and dyspnea. The infusion was interrupted. Nebulized salbutamol and beclomethasone as well as IV methylprednisolone were administered with rapid resolution of symptoms. A total of 65.798 mg of R was given. PV improved following R administration, but it relapsed after some weeks. So, one month later, the child underwent a second R desensitization using a different protocol. Three bags with drug concentrations of 0.02 mg/mL, 0.20 mg/mL and 2.0 mg/mL were consecutively infused at increasing infusion rates. Five hours after the third bag was started at an infusion rate of 20 mg/mL, the patient presented facial erythema along with heat sensation. A total of 208.88 mg of R was infused. Symptoms resolved after interruption of infusion and administration of IV chlorpheniramine and methylprednisolone. The next day, desensitization continued. After the first two bags, the infusion rate of the third bag was modified. R at the concentration of 2.0 mg/mL was infused at 10 mL/h for 15 min, and then at 15 mL/h for 4.5 h . A totalEven if the infusion of R was not at full dose, it allowed for a strong improvement in the disease in about 10 days with complete healing of cutaneous components and residual oral involvement, specifically of the hard palate and the gums a. After At 6 months, the oral mucosa was ameliorated, with a slight involvement of the inferior gum persisting without any symptoms. Furthermore, the therapy led to an important improvement in quality of life, considering even the psychological impact on a patient of such a critical age.PV is a life-threatening autoimmune bullous disease that generally affects adults between the fifth and seventh decades of life. It is extremely rare, and the incidence in the pediatric population is 1–4% with no predominance of gender . The patThe severity of the disease is due to skin and mucosal detachment that causes fluid and protein loss, exposing the patient to possible superinfections, the major cause of mortality . PediatrThe diagnosis of PV is based on four major criteria: clinical presentation, histopathology, DIF of a perilesional skin or mucosal biopsy and serological detection of autoantibodies against epithelial cell surface using indirect immunofluorescence (IIF) and/or enzyme-linked immunosorbent assay (ELISA Dsg1 and Dsg3) .The diagnosis of PV is not always simple, and differential diagnosis should include, even in children, other diseases characterized by dermo-epidermal detachment, such as bullous impetigo, staphylococcal scalded skin syndrome and Steven–Johnson syndrome/toxic epidermal necrolysis . AdditioLow-dose oral corticosteroids represent a mild form of therapy. In moderate-to-severe forms, the prednisone dosage must be increased to 1–1.5 mg/kg/day and possibly integrated with other immunosuppressive drugs (such as azathioprine and/or mycophenolate mofetil). R, a chimeric monoclonal antibody against CD20, represents today a first-line therapy in adulthood, with a therapeutic scheme of two infusions of 1 g two weeks apart with or without oral prednisone ,5.According to the literature, R appears to be well tolerated in children with PV, with the commonest adverse events being bacterial and viral infections and the rarest complications being B-cell depletion and hypogammaglobulinemia ,11. A reIn our case, we observed failure along with other immunosuppressive drugs, immunoglobulins and plasmapheresis. In comparison with a recent case treated with four cycles of plasmapheresis, during which 90% of the erosions healed, our patient underwent seven sessions without any resolution and even experienced skin and mucosal worsening .The management of our clinical case involved the use of all available treatments for PV, with the difficulty of adapting adult guidelines to the pediatric patient according to their needs. The first obstacle was the use of corticosteroids that were poorly tolerated by the child, who manifested significant adverse effects that also affected their psychological sphere. Moreover, nowadays we cannot exclude in our case a role of obesity in both pathogenesis and treatment failure. To date, there are only two reports in the literature showing a possible association between pemphigus and metabolic syndrome and its components. Further studies will be necessary to find a strong correlation between overweight/obesity and PV.To the best of our knowledge, this is the first report of a child with severe PV resistant to conventional therapies and with a hypersensitivity reaction to R. The desensitization test for R made it possible to find the right combination of infusion rate and dosage, leading to the remission of the clinical picture and an improvement in the patient’s quality of life, which was previously severely compromised even in basic activities of daily living.Despite the high cost of the molecule, its superior efficacy and durability may ultimately lead to lower overall system costs owing to more rapid recovery and fewer relapses.This case highlights that, despite PV being extremely rare in pediatric populations, this diagnosis should not be discounted in cases of unresponsive gingivostomatitis-like lesions, integrating clinical manifestations with laboratory findings. An early diagnosis can play a decisive role in treatment strategies and improving a patient’s quality of life. In cases of severe clinical manifestations with failure to first- and second-line therapies, R represents a valid option in pediatric ages, and desensitization tests should be recommended in the presence of allergy or hypersensitivity to this drug. A multidisciplinary approach is moreover mandatory to obtain better results for the patient. Further studies will be necessary to define treatment guidelines for children and adolescents, allowing for appropriate management of PV in pediatric ages.