DICER1 syndrome is a rare genetic disorder that predisposes patients to the development of malignant and non-malignant diseases. Currently, DICER1 syndrome diagnosis still occurs late, usually following surgical operations, affecting patients’ outcomes, especially for further neoplasms, which are entailed in this syndrome. For this reason, herein we present a nationwide multicenter report of DICER1 syndrome in the pediatric population, with the prospective aim of enhancing post-surgical surveillance. Moreover, a comprehensive literature review of DICER1 cases, including case reports and multicenter studies published from 1996 to June 2022, was performed. Eventually, the retrieved data from the literature were compared with the data emerging from our cohort of patients. The early identification of patients affected by this mutation would allow a timely screening program, thus avoiding diagnostic delays.DICER1 syndrome is a rare genetic disorder that predisposes patients to the development of malignant and non-malignant diseases. Presently, DICER1 syndrome diagnosis still occurs late, usually following surgical operations, affecting patients’ outcomes, especially for further neoplasms, which are entailed in this syndrome. For this reason, herein we present a multicenter report of DICER1 syndrome, with the prospective aim of enhancing post-surgical surveillance. A cohort of seven patients was collected among the surgical registries of Pediatric Surgery at the University of Pisa with the General and Oncologic Surgery of Federico II, University of Naples, and the Pediatric Surgery, Regina Margherita Hospital, University of Turin. In each case, the following data were analyzed: sex, age at diagnosis, age at first surgery, clinical features, familial, genetic investigations, and follow-up. A comprehensive literature review of DICER1 cases, including case reports and multicenter studies published from 1996 to June 2022, was performed. Eventually, the retrieved data from the literature were compared with the data emerging from our cohort of patients. DICER1 syndrome, or “familial tumor predisposition syndrome of pleuropulmonary blastoma”, is a rare genetic disorder that predisposes patients to the development of malignant and non-malignant diseases . ChildreA cohort of seven patients was collected among the surgical registries of Pediatric Surgery at the University of Pisa with the General and Oncologic Surgery of Federico II, University of Naples, and the Pediatric Surgery, Regina Margherita Hospital, University of Turin. In each case, the following data were analyzed retrospectively: sex, age at diagnosis, age at first surgery, clinical features, familial, genetic investigations, and follow-up.The search for genetic variants in the coding regions of the causative genes of oncological predisposition syndromes was carried out by target-Next Generation Sequencing (tNGS) analysis of a multi-gene panel including 154 genes implicated in the onset of the syndrome. The filtering of the gene variants was carried out through a dedicated pipeline, considering the variants of the DICER1 gene. The data obtained by t-NGS were confirmed on the patient’s DNA by amplification with specially designed primers and subsequent Sanger sequencing .The follow-up program for patients who tested positive was set up as follows: a chest CT scan and renal ultrasound as a baseline, which was then repeated after 2.5 years; then a chest X-ray every 6 months until age 8 years; and then every 12 months until age 12 years. Starting from the age of 8 years, ultrasounds and blood tests for the thyroid gland were performed; however, if the patient had prior radiation therapy for PPB, ultrasound was performed every 6 months for at least 5 years. Pelvic ultrasound was performed every 1–2 years from infancy to adulthood [http://www.ncbi.nlm.nih.gov/PubMed (accessed on 5 July 2023)) offered by the National Library of Medicine, including case reports and multicenter studies published from 1996 to June 2022, was performed. “DICER1” “children” “surgery” “genetic” were used as Medical subject heading (Mesh) terms. Eventually, the retrieved data from the literature were compared with the data emerging from our cohort of patients. In this study, a comprehensive literature review of DICER1 cases using PubMed  frequency, and the continuous data were summarized by mean and range. To compare percentages and means, z-test for two proportions and t-test were performed, respectively. Significance was fixed at 0.05, and all analyses were carried out with SPSS v.28 technology.The results of our study are given in We analyzed seven patients, including three females and four males, with an average age of 6.6 years (range: 2–12 years). The average age at first surgery was 1.7 years (range: 40 days–3 years), while the average age at DICER1 syndrome diagnosis was 2 years (range: 3 months–4 years). We highlighted these two categories, namely the average age at DICER1 syndrome diagnosis and the age at first surgery, in order to highlight that this type of disease is often diagnosed following the first surgery. In our cohort of patients, DICER1 diagnosis occurred on average 5.4 months following the first operation, some of which led to the diagnosis of a second neoplasm. The PPB diagnosis occurred in four cases (57%) and was the most common neoplastic manifestation of the syndrome. All patients were treated with lobectomy via a thoracotomy and neoadjuvant/adjuvant chemotherapy; the average age at surgery was 1.6 years (range: 2 months–3 years). Only one case of PPB had already been diagnosed with DICER1 syndrome. Renal involvement was found in four cases (57%). Patients affected by cancer had an average age of 2.25 years (range: 1.5–3 years). Both cystic nephroblastoma (CN) and anaplastic renal sarcoma of the embryonic type were treated with nephrectomy and followed up. The other two cases involved one with asymmetrical kidneys at the age of 2 years and one with multiple bilateral renal cysts at the age of 3 months. None of the four cases had received a DICER1 syndrome diagnosis when renal involvement was detected.Thyroid nodules were present in two out of seven patients (28%); a thyroid adenoma (TA) and a DTC. The younger patient (4 years) underwent total thyroidectomy, which resulted in a DTC with capsular infiltration, whereas the older patient (11 years) underwent lobectomy. In such cases, DICER1 syndrome diagnosis had already been confirmed, and the follow-up allowed a timely diagnosis. Multinodular goiter (MNG) was diagnosed in one out of seven patients (14%), at the age of 4 years. Neurodevelopmental disorders were diagnosed in two cases, both at the age of 2 years. A patient was diagnosed with speech delay, while another was diagnosed with neuropsychiatric delay with a poorly organized motor pattern. Neither of them had previously been diagnosed with DICER1 syndrome. Central Nervous System (CNS) involvement was found in three patients (43%). The average age was 3 years (range: 2–4 years); two of these had already been diagnosed with DICER1 syndrome. In this case, the cerebral electrical activity on electroencephalogram (EEG) appeared diffusely slowed down and misconfigured, while on brain magnetic resonance imaging (MRI), the cerebrospinal fluid (CSF) spaces appeared diffusely prominent, with periventricular gliosis and megacisterna magna. In another case, a pineal cyst was found in brain MRI. No malignancies were documented in the latter two cases. The third case was diagnosed with left ocular malignant teratoid medulloepithelioma, which was surgically removed. Glow syndrome was diagnosed in a patient at the age of 2 years. The patient was reported to have asymmetrical lower limbs and a subleveled pelvis of about 5 mm on the left. A wrist X-ray showed bone age approximately 1 year and 1 month older than chronological age. Weight and head circumference were >97° pc, with dysmorphisms . This phenotype added to nephroblastoma has been identified as Glow syndrome with somatic DICER1 mutations. Embryonic rhabdomyosarcoma (ERMS) presented in a case at the age of 11 months (14.28%), localized on the left forefoot; the patient underwent surgical excision. The genetic diagnosis of DICER1 syndrome came two years after surgery. This patient developed multiple inguinocrural lymph nodes and bilateral lung metastases after two years after the first surgery and eventually died four years after the first operation. Taking familial factors into account, three out of seven patients (43%) had a positive family history of DICER1; in all cases, fathers were involved. More specifically, in the first case, namely Case 1, his father was diagnosed with glaucoma at the age of 18. During his second decade of life, he developed toxic MNG and hyperparathyroidism. Finally, he was diagnosed with non-small cell lung adenocarcinoma at the age of 44 years with a positive DICER1 test. In a second patient, namely Case 5, her father was diagnosed with MNG at the age of 9 years and was DICER1-positive. In the last case, namely Case 6, his father was documented positive for DICER1 syndrome during the screening test, although he never developed any symptoms. Siblings were involved in two cases: Case 1, a brother was diagnosed with cystic nephroma at the age of 1 year with DICER1 syndrome, while in Case 5, a one-year-older brother presented DICER1 syndrome with a single-loculated upper polar cyst of the right kidney, later defined as a simple dysplastic cyst. Mutations in DICER1 gene were assessed via genetic tests; blood sample were also retrieved on parents and siblings, as reported in The follow-up of our patients lasted 3.5 years (range: 1–8 years). To date, four patients are disease-free (57%), one developed a pineal cyst still under surveillance (14%), one patient submitted to surgery for PPB had a persistent lung cystic lesion under surveillance, whereas one patient with embryonal rhabdomiosarcoma (RMS) (14%), died after 2 years from surgery. As concerning the literature, most reviews are from the USA, Canada, and UK, with, respectively, 37, 36, and 22 reports. A minor contribution comes from Germany, Italy, China, Japan, Sweden, Spain, France, Turkey, Denmark and Thailand, while no reports are available from Russia, Australia or South America . The disIn the present paper, we report a multicenter study of DICER1 syndrome in the pediatric population, with the aim of increasing global awareness about this disease in order to improve clinical outcomes through the timely diagnosis of any neoplastic event. Approximately 87% of germline mutations have autosomal dominant inheritance with incomplete penetrance, while 13% are de novo mutations . As repoConcerning the epidemiological features of DICER1 syndrome, the sex distribution demonstrated, in accordance with our cohort, a male-to-female ratio favoring the female sex (62% versus 37%) ,73,74,75It could also be due to a more timely diagnosis, thanks to the genetic screening protocols more recently applied to subjects affected by PPB or multiple clinical manifestations related to DICER1 syndrome. PPB is confirmed as the most frequent clinical manifestation of the syndrome, as it accounts for about half of the cases both in our study and in the references (57% vs. 41%). As highlighted by Gonzàlez et al. ,77 as thA screening of DICER1 mutations in pediatric DTC as well as thyroid screening ultrasound is recommended for school children with DICER1, which may be followed up every five years or more frequently for those patients under chemotherapy, as children under high-dose chemotherapy for PPB are more prone to develop DTC ,78,81. TFamilial features were not found in 57% of our patients versus 29% of the literature. Germline mutations can occur anywhere in the DICER1 gene, causing loss of function; most carriers with a germline DICER1 variant may live a healthy life, although burdened with an increased risk of malignancy . DICER1 In our patients, Case 1, variant c.919_932 of the CGTGCCGTATTGGT (p.Arg307Serfs*9) of the DICER1 gene was found in heterozygosity: the subject was found to be a carrier of a germline mutation affecting the DICER1 gene, which consists in the deletion of 14 nucleotide bases in position 919_932 and which involves the sliding of the reading frame with the consequent introduction of a stop codon and interruption of the protein. This protein will be structurally shorter and functionally less active. This variant has not been found in the reviewed literature. According to the American College of Medical Genetics (ACMG) , the varOverall survival rate was 85.7% at a three-year follow-up from DICER1 diagnosis, versus 92.9% reported in the literature. Among our cases, only an infant affected by ERMS died at the age of five after a three-year follow-up, while seven out of the 132 patients (7%) died in previous reports: three for PPB2 ,28,86, oCurrently, DICER1 syndrome remains a diagnostic challenge because symptoms and signs can be unspecific and can have significant differences from one patient to another. Its manifestations can be of malignant or non-malignant nature and can occur exclusively or combined in each patient differently. However, it is important not to underestimate or overlook other atypical associated manifestations, as early identification of patients affected by this mutation would allow a timely screening program, thus avoiding diagnostic delays. Concerning genetic diagnosis, there are still gaps regarding the causative variants, as the same are not described in the reports. For such rare syndrome, an international database including both clinical and genetical details of these patients is still warranted.


Since the classification of processed meat as carcinogenic by the International Agency for Research on Cancer (IARC) in 2015, an increase in consumption of plant-based meat alternatives (PBMAs) has been observed worldwide. This occurs in a context characterized by concern for health, animal welfare, and sustainability; however, evidence of their nutritional quality is still limited. Therefore, our objective was to evaluate the nutritional profile and processing degree of PBMAs available in Spain. In 2020, products from seven Spanish supermarkets were analyzed for their nutritional content and ingredients. Of the 148 products, the majority were low in sugars but moderate in carbohydrates, total and saturated fat, and high in salt. The main vegetable protein sources were soy (91/148) and wheat gluten (42/148). Comparatively, 43/148 contained animal protein, the most common being egg. Overall, PBMAs had a long list of ingredients and additives, and they were classified as ultra-processed foods (UPFs) according to the NOVA system. This study shows that the PBMAs available in Spanish supermarkets have a variable nutritional composition within and between categories. Further research is needed to determine if replacing meat with these UPFs could be a good alternative towards healthier and more sustainable dietary patterns. In October 2015, the International Agency for Research on Cancer (IARC) released a report that classified unprocessed red meat as “probably carcinogenic” and processed meat as “carcinogenic” to humans based on the association between consumption of red and processed meat and colorectal cancer ,4. ConseCurrently, despite the nutritional information on PBMAs, there is need for a regulatory framework to allow the population to have better food choices . FurtherNOVA is a food classification system based on the degree of processing. In general, the classification criteria are based on the nature, extent, and purpose of industrial processing ,27.Thus, our aim was to evaluate the nutritional composition and processing degree and to perform a quantitative analysis of the ingredients of PBMA products currently available in Spanish supermarkets.Between September 2020 and December 2021, a sampling of PBMAs was conducted in seven of the most common supermarket chains in Spain, namely Alcampo, Aldi, Carrefour, Dia, El Corte Inglés, Lidl and Mercadona. These chains are well positioned throughout the country and were chosen to represent choices available to the majority of the Spanish population . For eacSpanish PBMAs were categorized into eight different food groups according to their format characteristics: (1) plant-based sausages, (2) plant-based nuggets and breaded food, (3) plant-based meatballs, (4) vegetarian cold cuts, (5) veggie patties, (6) “Beyond Meat-type” hamburger patties, (7) “Chicken-type” strips (vegan/vegetarian products made from soy), and (8) plant-based mince. Each item was classified into a single main group, based on the similarity to meat-based products and dishes. Products excluded from the study were those vegetarian foods not specifically created to mimic meat products, such as tofu, tempeh, seitan and falafel.In order to classify the products by their nutritional composition, we used nutritional claims from AESAN  Table 1Table 1. To classify the products according to the degree of processing, we used the NOVA system ,27 and t1. Unprocessed or minimally processed foods; 2. Foods with a simple or basic processing; 3. Moderately processed foods and 4. Ultra-processed foods.p < 0.05.Descriptive statistics  of energy and selected nutrients  were calculated per 100 g. As expected, there was missing information about dietary fiber and iron, unless specifically added to these products. Groups were assigned according to their main ingredients and similar characteristics to comparable processed meat products. The statistical analysis was performed using the statistical software Rstudio Desktop version 4.1.2, with the significance level set at n = 54), whereas the other supermarkets had lower quantities of products available . Overall, 176 plant-based meat alternatives were identified, but due to the repetition of some products in the different Spanish supermarkets, we analyzed a total of 148 individual products. Alcampo supermarket had the largest number of products on offer . Only 8/148 of the products contained olive oil exclusively in their formulation and 5/148 of the products had a combination of olive oil and sunflower or rapeseed oil. Egg yolk was present in 9/148 products, making them non-vegan. Considering carbohydrate sources, wheat flour was the most common ingredient, present in 64/148 of the products. Only 11/148 of the products were fortified with iron and 10/148 with vitamin B12. Overall, only 21/148 of the products were fortified.There was a diversity of the percentages of the products labeled as organic  in the dTotal carbohydrates ranged from 2.65 g to 17.9 g/100 g. Plant-based nuggets and breaded food (17.9 g/100 g), veggie patties (15.6 g/100 g) and plant-based mince (13.0 g/100 g) contained the highest amounts. Sugars were generally low (<5 g/100 g) and only plant-based mince had a moderate content (5.80 g/100 g). Almost all products can be considered a source of fiber (>3 g/100 g).In regard to total fat and saturated fat, the average values, 10.0 g/100 g and 1.30 g/100 g, respectively, can be considered moderate. Most products were upper-moderate to high in salt (>1 g/100 g), with vegetarian cold cuts having the highest content (2.00 g/100 g) and excepting the plant-based mince group, which presented the lowest (0.07 g/100 g) [According to the NOVA classification system, 93.9% of the products were categorized as ultra-processed food (Group 4) and the remaining 6.08% of PBMAs were categorized as processed food .According to recent studies, PBMA consumption is growing worldwide, reflecting a shift to a diet rich in vegetables and low in animal protein ,33. The Although more studies assessing the nutritional profile and healthiness of PBMAs are being published ,34,35, tOur results agree with other studies which examined the nutritional information of PBMAs, reporting similar energy values ,12. SimiThe total fat and saturated fat in PBMAs were moderate and varied substantially in all categories. The most common fat sources for the majority of products were sunflower oil and rapeseed oil. It has been shown that sunflower oil induced an increase of different proinflammatory markers  and thatRegarding proteins, the main protein sources in Spanish PBMAs were soy and gluten, which agrees with other studies done on products found in Germany or Brazil ,49. UnfoPBMAs showed variable content in carbohydrates and were low in sugars due to the presence of pulses in their ingredients. Pointke et al.  reportedSalt content was substantially high in most PBMAs. The WHO recommends consuming less than 5 g/day . ConsideIn addition to comparing the nutritional facts of PBMAs, they were also categorized using the NOVA classification. Results have shown that almost 94% of the products were classified as UPFs (4. Ultra-processed foods). The NOVA classification is one of the most referenced in the literature and it has been applied in several countries ; howeverThe present study is the first that describes the nutritional composition and processing degree of PMBAs available in Spanish supermarkets. In addition, it provides a quantitative analysis of the ingredients of Spanish PBMAs, allowing the comparison of the nutritional quality between and within the eight categories. However, some limitations should be mentioned. First of all, we did not include all supermarket chains in the study, nor all products that are exclusively found in vegan specialty stores. Further research is needed to identify some nutrition gaps, such as the micronutrient content and bioavailability, protein quality and digestibility, and dietary fiber type found in PBMAs.This study shows that a great number of plant-based meat alternative products available in Spanish supermarkets have a variable nutritional composition depending on the product category. There exists a false belief about the healthiness of these products because of their plant origin. Although PBMAs may show medium to high contents of vegetable protein and can be considered sources of dietary fiber, the majority of these products also meet the criteria of ultra-processed food, so their consumption should be sporadic within a plant-based diet with fresh vegetables, fruit and legumes. After a closer examination, both nutritional and quality information about PBMAs is needed to develop guidelines to counsel consumers about including these products in a healthy plant-based diet.To our awareness, the present study was the first one to focus on plant-based meat alternatives available in Spanish supermarkets, analyze the nutritional information, and estimate NOVA classifications for these products. Further research is needed to determine if replacing processed or unprocessed foods with plant-based meat alternatives in people’s diets can eventually lead to healthier dietary patterns.


More than 80% of people diagnosed with cancer will require surgery. However, less than 5% have access to safe, affordable and timely surgery in low- and middle-income countries (LMICs) settings mostly due to the lack of trained workforce. Since its creation, virtual reality (VR) has been heralded as a viable adjunct to surgical training, but its adoption in surgical oncology to date is poorly understood. We undertook a systematic review to determine the application of VR across different surgical specialties, modalities and cancer pathway globally between January 2011 and 2021. We reviewed their characteristics and respective methods of validation of 24 articles. The results revealed gaps in application and accessibility of VR with a proclivity for high-income countries and high-risk, complex oncological surgeries. There is a lack of standardisation of clinical evaluation of VR, both in terms of clinical trials and implementation science. While all VR illustrated face and content validity, only around two-third exhibited construct validity and predictive validity was lacking overall. In conclusion, the asynchrony between VR development and actual global cancer surgery demand means the technology is not effectively, efficiently and equitably utilised to realise its surgical capacity-building potential. Future research should prioritise cost-effective VR technologies with predictive validity for high demand, open cancer surgeries required in LMICs. Of 15.2 million new patients diagnosed with cancer each year, more than 80% require surgery at least once during the course of their disease . HoweverVirtual reality (VR) is defined as a computer-generated simulation of an environment, where it interacts with users in a realistic way. In the past decades, the technology has evolved from a non-immersive, two-dimensional screen-based interaction into an immersive three-dimensional experience. In an immersive VR experience, one can interact with the virtual setting in a realistic manner through digital transposition of real objects and settings. With recent technology advancement in VR which improved user orientation and user sensory experience through haptic feedback, its application gained traction not only in surgical oncology where it is heralded as an effective adjunct to surgical training, but also in different fields of cancer management from radiotherapy through to rehabilitation.The advantages of VR simulation in surgical oncology training lie in its ability to allow trainees to learn, practice and master technical skills, clinical judgement, and the in-and-out of surgical procedures in a safe and controlled environment. This has become more important nowadays, as trainees face steeper learning curve to master increasingly complex surgical procedures with more restricted training hours and higher patient expectation. There is growing evidence behind how VR can be utilised to build surgical capacity and capability through reducing the time required of trainees to develop surgical proficiency in the operating room. Besides surgical training, VR also plays an increasingly important role in optimising operative planning through better illustration of individual anatomical structure, particularly in high-risk and complex procedures.In non-surgical oncology, VR has also grown into a new avenue to engage with cancer patients for patient education, rehabilitation and psychosocial support. The immersive experience provides a new avenue for patients to learn the complexity of their cancer treatment, such as radiotherapy, before they consent to the treatment and experience it in reality. During and after cancer treatment, patients also engage with immersive VR experience to rehabilitate physically and to process physical and psychological stress of the treatment itself.Given the burgeoning adoption of VR in various fields of oncology and promising early data in improving patient outcome especially for surgical oncology, an up-to-date, overarching analysis of VR technology and its application in surgical oncology will shed light on the strengths and opportunities. The primary rationale of this review is to understand how VR is being utilised in surgical oncology, situated within the wider context of VR in oncology. We identify trends across geographies, intervention, tumour type and cancer care pathway and to highlight gaps. This review also provides an in-depth analysis to identify ideal characteristics  of VR surgical simulation for clinical training and to inform method validation of VR-assisted surgical tools.We carried out a systematic review using the Web of Science following PRISMA guidance. We included papers (articles and reviews only) on VR and cancer. This process included papers published for 10 years between January 2011 and January 2021 and was done with a bibliometric filter in two parts. The first part involved the application of a pre-developed filter to identify papers on cancer research. The papers were then subsequently selected based on the application of VR if they had the words ‘virtual reality’ or ‘augmented intelligence’, or simply ‘VR’, in their titles. The full search strategy used is available in the supplementary data (Appendix A).Published full-text articles describing oncology and VR were considered for inclusion. Articles must have been published in English in a peer reviewed journal between the dates specified above.Any papers not related to cancer and VR were excluded . For exaRichard Sullivan (RS) carried out the initial search. Following which, Peng Yun Ng (PN) and RS selected articles meeting inclusion criteria from titles and abstracts for full text review. PN then reviewed full text articles to consider whether inclusion and/or exclusion criteria were met. Disagreement was discussed with Ajay Aggarwal (AA) to reach a consensus.PN extracted data from included studies, with consultation from RS and AA. Data extracted from all studies included:location of studycharacteristics of study part of cancer care pathway where VR was appliedpurpose of VRmodality of VRclinical specialitytumour siteuser of VRThe studies were categorised into surgical and non-surgical oncology. Studies related to surgical oncology were further compartmentalised based on the purpose of the VR, be it either for clinical training or operative planning.For studies focusing on the use of VR for clinical training, specific data extracted included:characteristics of VR-assisted training toolmethod validation of VR-assisted trainingThe characteristics of the VR-assisted surgical training tool were set out as follows. Fidelity is defined as the extent to which the simulator describes the realism or learning experience that the simulator provides. Generally, low fidelity refers to basic psychomotor tasks while high fidelity refers to full-length operations. User feasibility is more commonly known as user acceptance rate, a measure of whether something is capable of being done or carried out. Face validity is the extent to which the examination resembles real life situations. Content validity is the extent to which the domain that is being measured is measured by the assessment tool. Construct validity is the extent to which a test measures the trait it is designed to measure; sometimes inferred as the extent to which a test discriminates between various levels of expertise. Lastly, predictive validity is the ability of examination to predict future performance of the clinician.On the other hand, studies related to operative planning provided information on:pre/intra-operative use of VR-assisted toolsurgical complication rateduration of procedurebenefit of VR-assisted toolStudies related to non-surgical oncology were divided based on the modality of the VR into radiotherapy, rehabilitation and neuropsychiatric intervention. Data were extracted for cancer speciality, purpose of intervention and outcome.The initial search identified 95 papers. After a review of titles and abstracts, 77 articles were chosen for further review. Of these, 53 full-text articles were selected for data analysis. The study selection process followed the PRISMA guidance and is illustrated in A summary of the characteristics of all  includedn = 34, 64.2%) with surgical oncology dominating (n = 24) [n = 7, 13.2%) [n = 7, 13.2%) [n = 5, 9.4%) [Along the stages of the cancer care pathway, VR was applied predominantly in the delivery of cancer treatment n = 3, 64.2% w(n = 24) . Other c, 13.2%) –43, pall, 13.2%) –50, and 5, 9.4%) , 51–53  studied the use of VR in providing clinical training , 32, 54;2.% studin = 20, 37.8%) [n = 16, 30.2%) is the second most prolific continent [n = 11, 20.8%) [n = 3, 5.7%), [n = 2, 3.8%), [n = 2, 3.8%) [n = 11, 20.8%), [n = 9, 17.0%) [n = 6, 11.3%) [The majority of VR studies in oncology were from North America continent n = 20, .8% [37, , 37.8%) , 53–56. ontinent , 44, 47,, 5.7%), , 49, 52 , 3.8%), , 26 and 2, 3.8%) . This ge 20.8%), , 53–55 U, 17.0%) , 56, and, 11.3%) , 29, 44 n = 14, 58.3%), [n = 5, 20.8%) [n = 5, 20.8%) procedures [n = 13, 54.2%), followed by urology , and gynaecology , as illustrated in Of the 24 studies related to surgical oncology, 19 79.2%) focused on the use of VR in supporting surgical trainees with competencies, 9.2% focu, 54 and  58.3%), , 33, 54,, 20.8%) , 19, 22,ocedures , 25, 32.In terms of characteristics of VR-assisted surgical training tools, 11 57.9%) out of the 19 articles described VR-assisted tools which have high fidelity, meaning clinicians were able to practice through simulation of full length operations instead of abstract psychomotor tasks .9% out o, 26, 32.While all the VR-assisted surgical tool illustrated face and content validity, only 12 (63.2%) exhibited construct validity, thus discriminating clinicians of various levels of expertise , 32, 54.n =17, 89.5%) [n = 14, 73.7%) [In addition to the characteristics of VR-assisted surgical training tool shown in , 89.5%) , 32, 54 , 73.7%) , 32, 54., 73.7%) , 26, 32., 73.7%) .14 out of 19 studies 73.7%) recorded the time taken to complete the task, 3.7% reco, 26, 32 The application of VR in surgical oncology was not limited to surgical training, but also operative optimisation in clinical setting. Five out of 24 studies related to surgical oncology highlighted the use of VR in operative planning. Of the five studies, three (60%) were used in pre-operative setting , 30, 33 From a nascent technology reserved for experts from niche computer field, VR tool has matured and evolved into a popular technological gadget in the general consumer market as its creation fundamentally changes how one engages with virtuality for entertainment, education and communication.In particular, VR in medicine has emerged as an epiphenomenon of the rapid pace of its technological advancement as its potential was widely regarded as undertapped since an early stage. Nonetheless, our comprehensive search discovered surprisingly little literature related to its application in surgical oncology and, more widely, oncology. The literature reflects a widely disparate range of applications at different stages of cancer pathway and for different purposes, such as providing supportive and psychosocial care and facilitating rehabilitation. However, surgical oncology remains the main focus both for surgical training and operative planning.As a surgical oncology speciality, neuro-oncology led in the research and adoption of VR, primarily in surgical training. Most studies highlighted the benefit of VR simulation for neurosurgery trainees in gaining skill-based experience in common yet high-risk neurosurgeries, which are often heavily led by consultants in the operating theatre. Trainees were able to practice and receive feedback from senior colleagues on a wide range of surgical skills using VR simulation, without detriment to patients and with hope to translate acquired simulation-based skills to surgical proficiency. Their competencies were often subsequently tested through psychomotor tasks or OSATS to consolidate learning.Besides the high risk attribute of procedure, technically complex surgeries, such as those requiring endoscopic and robotic equipment, are also bona fide early adopters of VR simulation in surgical training. This is due to the fact that surgeons generally require more time and practice to acquire new skillsets required to use endoscopy or robot, which they often initially lack human intuition in without prior clinical exposure and experience. This review identified uro-oncology as the leading surgical specialty on this front, driven primarily by novel endoscopic and robotic approach to prostatectomy.This pattern of adoption of VR overshadows the larger potential of VR simulation as a platform to develop surgical training towards high demand, low-risk, open-approach cancer surgeries such as mastectomy and colectomy, that are sorely lacking in capacity in LMICs.There were very few studies of VR conducted by and for LMICs (except for China). This reflects a yawning socio-techncological gap between the direction of travel of VR in surgical oncology and the actual development need of VR to build surgical capacity and capability globally.Nonetheless, one study from Zambia  stood ouet al [Given the relative novelty of VR as a surgical training tool, there remains a dearth of evidence that actually showed VR simulation improves cancer surgical training, surgical quality and better patient outcomes. Evaluation gap is defined by the lack of standardisation of ideal qualities in VR-assisted surgical training tool, which make them user-friendly, realistic and effective in developing surgical skills. Based on definition set by Lewis et al , most VRSuch evaluation gap is thought to be tightly correlated to a lack of gold standard to validate VR-assisted surgical training tools, also known as method validation gap. This review identified heterogenous methods adopted to validate surgical training, most commonly through psychomotor tasks and OSATS that measure dexterity parameters, time taken to complete task and/or complication rate. Such practice is often enabled by the inbuilt features of the simulators but often lacks in inter-rater and test-retest reliability, which are crucial in distinguishing the level of proficiency of trainee through a peer-review process and in testing their future operative performance.Thus, to bridge these gaps, we recommend future studies related to VR-assisted surgical training to include a validation process, which requires more than one senior reviewer and to follow up on trainees’ surgical proficiency as well as patient outcome to establish test-retest reliability and predictive validity, respectively.Outside the scope of surgical oncology, the application of VR emerges in a myriad of other oncology fields- most prominently radiotherapy, neuropsychiatry and rehabilitation. These three modalities of treatment share the common feature of utilising the fully immersive experience of VR to engage with patients meaningfully for an extended period of time. To illustrate, half (three out of six) of the radiotherapy-related studies demonstrated how VR was adopted to help patients comprehend the intricate process of radiotherapy and vivaciously experience the treatment setting prior to starting, thus easing anxiety. On the other hand, 13 out of 15 studies which used VR as a neuropsychiatric intervention showed how VR could be effective in easing pain through distraction and alleviate patient mood. Creatively, mainstream VR consoles, such as Xbox 360 and Wii, have also over time adapted their games to help patients rehabilitate limb function and improve energy level after cancer treatment.The emergence of VR in medicine opens a window of opportunity to build capacity and capability in surgical oncology in a wide range of resource settings using low cost novel tools. However, current VR development is still overly focused on high-income settings, with complex procedures such as MIS and robotics, instead of open-approach procedures needed in many LMIC settings. The asynchrony between the development of VR in surgical oncology and the actual global cancer surgery demand means that the technology is not effectively, efficiently and equitably applied to realise its capacity-building potential. Future research should prioritise the use of affordable VR technology in high-demand surgical procedures and further explore its use in other common cancer domains such as breast, colorectal and lung cancer. This process can be accelerated with the adoption of a more standardised and complete method validation of VR-assisted surgical training tool, in a bid to make VR a real and effective digital adjunct to traditional, didactic surgical training.N/A.PN, RS and AA conceived, designed, and supervised the study. PN and RS searched, screened, and assessed the publications. PN extracted, analysed and visualised the data. PN and RS drafted the manuscript and interpreted the findings. EB, RS, AA, AC, BC, MM, MM and GP reviewed and edited drafts of the manuscript. RS accessed and verified the data. All authors read the manuscript, provided feedback, and approved the final version.


Choosing which dairy cow mammary quarters to treat with antibiotics at dry off is difficult because current somatic cell count meters have not been tested and compared using the same data and metrics. The objective of this study is to compare predictions of somatic cell counts by current meters to a reference standard. The RT-10 meter best predicted individual quarter SCC ≤ 200,000 cells/mL followed by the DSCC which also best predicted BTM SCC ≤ 100,000 cells/mL. Using these meters to select which quarters to treat will help decrease antimicrobial use.2 = 0.86), lowest MSPE, and highest proportion of MSPE due to random variation (96%). Both the RT-10 and DSCC had the highest sensitivity and specificity for identifying quarter SCC above and below 200,000 cells/mL. For bulk-tank SCC, DSCC had the highest coefficient of determination (R2 = 0.45), lowest MSPE, and highest proportion of MSPE due to random variation (80%). The RT-10 and DSCC could be used to measure individual quarter SCC to determine which cows to treat at dry off potentially reducing antibiotic use.Intramammary infections, which cause mastitis, can increase treatment and labor costs, decrease milk production, and affect milk quality. Meters that measure quarter somatic cell count (SCC) could be used to make more informed dry cow therapy decisions. The objective of this study was to compare the RT-10 iPhone adapter , DeLaval Cell Counter , Porta Check Quick Test , California Mastitis Test , pH meter , electrical conductivity meter , and the dual laser infrared temperature thermometer  for measuring SCC in individual Holstein mammary quarters in comparison to a reference standard, the Fourier Transform Spectrometer 600 Combi System . Meters were evaluated using 658 individual cow quarter samples and 100 bulk-tank samples to measure SCC. Individual quarter milk samples from 160 cows from four commercial dairy herds were collected just before dry off and tested within 4 h of collection. To test bulk-tank SCC, 100 bulk-tank milk samples (25 mL) were collected from UC Davis Veterinary Medicine Teaching and Research Milk Quality Lab. Meter SCC values were regressed on observed Combi SCC. Goodness of fit was then evaluated by partitioning the mean square predicted error (MSPE). For individual quarter SCC, RT-10 had the highest coefficient of determination (R Dairy producers have multiple treatment options at dry off to combat intramammary infections, such as the use of blanket and selective therapies. Blanket dry-cow therapy, the practice of treating every cow at dry-off with antibiotics, has been the most prominent dry-cow therapy used. In 2014, 80% of dairy herds (and 94.2% of large dairy operations) used this method . This stMonitoring both individual cow somatic cell counts (SCC) and bulk tank milk (BTM) can provide an opportunity for dairy producers to improve milk quality, production, cow health, and lower treatment costs ,7. CommeThe objective of this study was to compare and evaluate seven cow-side meters by using individual quarter milk samples obtained at dry-off and BTM samples in comparison to a reference standard, Combi. Milk samples from dry-off were chosen because antibiotic treatment decisions for selective or blanket therapies for the cow are made at this time.n = 658 quarters total) located in Tulare and Fresno County, California. Individual quarter milk samples were collected on the same day and just prior to drying off. Bulk-tank milk samples (n = 100) were provided by the UC Davis Veterinary Medicine Teaching and Research Center’s Milk Quality Laboratory. No knowledge of the cows, location of the dairy, or other management factors of these dairy herds were known, other than sample collection time (at AM or PM). Samples were collected between October 2020 and August 2021, and there were no exclusion criteria for individual or BTM samples.An observational study was conducted using 40 Holstein cows per dairy from 4 commercial dairy herds , and foremilk was discarded. Fifty mL of milk was hand collected into separate tubes for each quarter. Milk samples were then placed on ice and transported to the lab. Then, 25 mL of milk were separated into two different vials, with 5 mL for analysis by DHIA using the Combi system and the rest for bench top analyses.For BTM sampling, 50 mL of BTM milk were collected from the laboratory after bacteriological sampling had occurred. Twenty-five mL were aliquoted into separate vials, one for bench top analysis and the other for Tulare County Dairy Herd Improvement Association (DHIA). Only meters RT-10 adapter , DeLaval Cell Counter , PortaCheck Quick Test , electrical conductivity meter , and pH meter  were used for BTM analysis, as the samples were not obtained cow-side.All individual quarter and BTM samples were mixed gently prior to measurement of SCC. The Combi, which was designated as the reference standard test, was owned and operated by DHIA, and was a combination of two modules, a Fourier Transform Spectrometer and a Flow Cytometer, for the determination of SCC and milk composition. Cells within the milk sample were stained with a fluorescent dye and exposed to a laser beam, and then light was refracted in accordance with the amount of somatic cells.The DSCC was a portable machine that uses cassettes to predict SCC. The RT-10 for the iPhone 5/s used the same cassettes to predict SCC. The cassettes contained a fluorescent reagent (propidium iodide) to stain the cell’s nuclei. In the DSCC, the cassette’s counting window was exposed to a light emitting diode, a digital camera photographed a picture of the stained nuclei, and then the DSCC counted the nuclei. The DSCC had a measuring range of 10,000 to 4,000,000 somatic cells/mL. In the RT-10, the camera of the iPhone was used to count SCC. There can be a high rate of cartridge failure if the counting window was damaged or smudged when handled, which can affect the usefulness of the device.N-tosyl-lalanyloxy)-indol] (~80 µL) in the sample well, which caused a color change to blue, and represented the amount of esterase in the sample. A color chart was used to score SCC results in categories of ≤100,000; 250,000, 500,000, 750,000, 1,500,000, ≥3,000,000 cells/mL.The PC used test strips that estimated the number of somatic cells by measuring the esterase enzyme present within white blood cells. The test strip was mixed with milk and an activator solution [3- was a qualitative four-welled plastic paddle that can test a cow’s individual quarters for SCC. A reagent that broke down cell membranes and contained a pH indicator (bromocresol purple) caused the milk to gel in accordance with the concentration of SCC. Milk and reagent were added to the paddle and were rotated and tilted until the reaction was completed. Results were scored a Negative , Trace , +1 , +2 , or +3  according to the standards set by the manufacturer. The ECM used electrodes to measure the resistance or density of milk, which was electrically positive. This model had a range of 0.00–19.99 S/m, and an accuracy of ±2.5% fs.The HC used an electrode to measure the pH of milk. Changes in milk pH were due to compositional changes, such as extracellular fluid components and blood, which led to an increase in pH. This meter had a range of 0–14 pH, and an accuracy of ±0.05 pH.Individual quarter temperatures were taken 1 h after sampling using a dual infrared temperature thermometer . The device used dual laser beams as a focal point for the temperature sensor on the front part of the tool for individual quarter temperature determination. The emissivity level was set to 0.98, the emissivity value used to measure the temperature of human skin . This meA common practice for dairies to decide which cows to treat at dry-off is the previous month’s SCC (PSCC)  by usingThe minimum number of samples for regression was 8 . This stThe unit of interest in this study was mammary gland individual quarter and BTM sample SCC. We defined cell counts ≥ 200,000 SCC cells/mL as an intramammary infection based on . PositivTo determine how well meters were able to predict individual quarter SCC measured by the Combi, SCC predicted by each meter was regressed on Combi SCC using general linear models . The indDairy 1 was the only dairy that tested all cows using DHIA each month. So, to evaluate the practice of using previous test date SCC (PSCC), Combi SCC were regressed on DSLT and PSCC using Dairy 1 data only using general linear models . Combi STo evaluate how well meters predicted BTM SCC, the SCC estimated by the meters RT-10, DSCC, ECM, and HC were each regressed on Combi SCC using general linear models . The dep2), mean bias (MB%), error due to mean absolute error (MAE), and partitioning of the mean square predictive error (MSPE) due to central tendency (CT%), unequal variation (UEV%), error due to random variation (RV%), and error due to slope ≠ 1 (%) were evaluated [For individual quarter and BTM meter predictions of SCC, tests for goodness of fit, and the coefficient of determination , specificity (SP), prevalence, accuracy, likelihood ratios positive (LR+), negative (LR−), and predictive values positive (PPV) and negative (NPV) for each meter for both individual quarter and bulk-tank milk samples was completed using a diagnostic test evaluation calculator . DiseaseDetection of high SCC is needed to improve milk production, cow health, and, ultimately, reduce the use of antibiotics at dry-off. To reduce intramammary infections in herds, dairy producers can employ different meters that assess the amount of SCC in individual cow quarter and bulk-tank milk. This study compares the performance of several common SCC meters and PSCC to predict SCC at dry-off. The four dairies represented different herd management practices, with different herd sizes, milk yields, and milk components . For exaThe RT-10 meter best predicted SCC in individual cow quarters compared to the other meters . The regThe RT-10 and DSCC had similar SE , and com2 = 0.44). This implies that the difference between the performance of the two meters is due to a better camera in the iPhone as the DSCC may lose some resolution of SCC with more lactose in the milk. The DSCC meter and RT-10 meter used the same methods and cartridges to measure SCC. So, it would be expected that they would perform well. While the DSCC meter performed well in diagnostic measures, SE and SP, the regression of predicted DSCC on observed Combi quarter SCC had a larger intercept, much lower coefficient of determination, larger MSPE with a higher error due the slope not being equal to 1 . The DSCThe PC meter was the third best at predicting SCC. This meter is a colorimetric meter only able to predict a range of SCC within specified SCC categories. So, the interpretation of results is not as precise as other meters since it relies on the ability of the user to match a color chart that designates a range of SCC values. The PC meter classifies SCC within these ordinal categories: ≤100,000, 250,000, 500,000, 750,000, 1,500,000, and ≥3,000,000 cells/mL. The predicted SCC by the PC meter vs. observed Combi SCC regression slope was further from unity than the RT-10 and DSCC and had a higher coefficient of determination and lower MSPE than the DSCC, while more of the proportion of error was due to random variation in the data . The PC Because many dairies use PSCC at the most recent DHIA test to identify cows to treat at dry-off, one more method of predicting SCC was evaluated. Since the Combi SCC was only measured on individual quarters, SCC from each quarter were averaged to estimate Combi SCC and compare to PSCC. The regression of PSCC on observed SCC from Combi had a low coefficient of determination and low MSPE but most of the error was due to a poor model fit, with high error due to slope not equaling 1 and bias in the predictions . The preThe SE, SP, and accuracy of PSCC were also low compared to the other meters . CompareThe meters RT-10, DSCC, PC, ECM, and HC were chosen for BTM analysis as these meters did not need to be used on fresh milk samples or in the presence of the cow. The DSCC meter and RT-10 meters best predicted BTM SCC with the highest coefficients of determination, lowest MSPE, and highest proportion of MSPE due to random variation . Both thThe RT-10, PC, and DSCC meters were the best in their ability to predict SCC. The DSCC meter is large and heavy, costs $1960.22 more than the RT-10, and analyzes samples 10 s faster than the RT-10 . The DSCThe PC test strip is available in different versions, one being a 45 min version and the other being a 5 min version, with both being able to be used on-farm. The 5 min version was used in this study because 45 min was too long to wait for results. There could be missed treatments in the dry-off period as the threshold for the detection of SCC is <150,000 cells/mL for this meter, and it did not perform as well as SCC increased. The test kit includes 20 pouches with two test strips in each pouch, 10 pipettes, activator solution, and instructions on how to perform the test, which cost $1.01 per sample, with all four quarters testing for about $4.04. While this test can be used cow-side, it is more feasible to perform this test on a lab benchtop. Results from  were simThe meters CMT, ECM, HC, and IR5 performed poorly on the analysis of individual quarter and BTM samples compare to the RT-10, DSCC, and PC. While the CMT can be used as an indicator for high SCC, this meter had very low SP for high SCC in this study. There is also an element of human error with the CMT, as not every person will read the results in the same way . The ECMMeters that can accurately measure individual mammary quarter SCC have the potential to reduce antibiotic treatment of non-infected quarters and to decrease treatment costs associated with dry-cow therapies. The RT-10 meter best predicted individual quarter SCC ≤ 200,000 cells/mL followed by the DSCC which also best predicted BTM SCC ≤ 100,000 cells/mL. It may be beneficial for dairies to use these cow-side meters instead of PSCC. As PSCC increases, predictability and the bias of prediction to underpredict SCC increases.


CaSR) gene, encoding a G-Protein-coupled cell membrane sensor of extracellular calcium concentration mainly expressed by parathyroid glands, renal tubules, and the brain. ADH1 has been linked to 113 unique germline mutations, of which nearly 96% are missense mutations. There is often a lack of a clear genotype/phenotype correlation in the reported literature. Here, we described a case series of 6 unrelated ADH1 probands, each one bearing a gain-of-function CaSR mutation, and two children of one of these cases, matching our identified mutations to the same ones previously reported in the literature, and comparing the clinical and biochemical characteristics, as well as the complication profile. As a result of these genetic and clinical comparisons, we propose that a genotype/phenotype correlation may exist because our cases showed similar presentation, characteristics, and severity, with respect to published cases with the same or similar mutations. We also contend that the severity of the presentation is highly influenced by the specific CaSR variant. These findings, however, require further evaluation and assessment with a systematic review.Autosomal dominant hypocalcemia (ADH1) is a genetic disorder characterized by low serum calcium and low or inappropriately normal levels of parathyroid hormone. The disease is caused by a heterozygous activating mutation of the calcium-sensing receptor ( It is c13.3–q21 . The encal range –12. In Asorption , causingutations .CaSR gene have been described in association with ADH1 , 25 hydroxyvitamin D [25(OH)D3], parathyroid hormone (PTH), and alkaline phosphatase (ALP). For the conversion of Calcium, PTH and 25(OH)D+2) is 8.6 to 10.3 mg/dL D3 is 30-50 ng/mL (To convert 25(OH)D50 ng/mL .Data of retrospective laboratory parameters were retrieved from the electronic medical records (EMR).2.3Images to assess for long-term complications of hypoparathyroidism consisted of renal ultrasound (US) and computed tomography scan (CT) of the brain were both retrieved from the EMR. For most of our cases, these investigations were done as part of their routine clinical care.2.4Genomic DNA was extracted by peripheral blood leukocytes, enriched for targeted gene regions using a hybridization-based protocol, and, then, analyzed by Next Generation Sequencing (NGS) technologies to cover the coding regions of the targeted genes plus 10 bases of non-coding DNA flanking each exon, using Illumina’s Reversible Dye Terminator (RDT) platform NovaSeq 6000 with 150 by 150 bp paired-end reads . Regions with insufficient coverage by NGS were covered by Sanger sequencing. Sanger sequencing was performed following Polymerase Chain Reaction (PCR) amplifications of coding exons and flanking splicing sequences. After purification of the PCR products, cycle sequencing was carried out using the Applied Biosystems incorporated (ABI) Big Dye Terminator v.3.1 kit. Genome build hg19, GRCh37 (Feb 2009) was used as a reference for all cases.2.5CaSR gene, hypercalciuric hypocalcemia, ADH1, to find published cases reporting the same CaSR variants we identified in our ADH1 cases.We searched PubMed, Google Scholar, and MEDLINE from 1994 to November 2022 using the following keywords: Hypoparathyroidism, autosomal dominant hypocalcemia, gain of function mutation, We also searched some of the most common databases of human gene variants, including OMIM, ClinVar, Human Gene Mutation Database (HGMD), and GnomAD to look for the same variants identified in our ADH1 cases.3de novo mutation due to a lack of family history of hypocalcemia or parathyroid disorder (cases 4 and 5). The remaining 37.5% are cases with a strong family history of hypocalcemia/hypoparathyroidism but with no confirmed molecular diagnosis, which we can infer are familial, making 75% of our cases familial. The lack of molecular diagnosis in family members of our cohort is multifactorial and predominantly related to access issues or living in a different part of the world. All of our mutation variants are heterozygous. CaSR variants, and their comparison with previously published cases.The clinical presentations and characteristics of our ADH1 patients are summarized in Our six unrelated ADH1 probands showed distinct clinical presentations, while the three ADH1 cases within the same pedigree  shared similar presentation and clinical characteristics, see 3.1CaSR gene . Replacement with calcium and active vitamin D was initiated at the time of diagnosis with the goal of maintaining the serum-corrected calcium in the low or just below the normal reference range. Her father had severe hypocalcemia and hypomagnesemia, as well as Fahr disease, and suffered from cognitive deterioration over time, necessitating institutionalization. Fahr disease, also known as familial idiopathic basal ganglia calcification, is a rare inherited neurological disorder that is characterized by abnormal deposition of calcium in the basal ganglia, thalamus, and cerebral cortex and was first described by Karl Theodor Fahr in Germany in 1930 , with hyperphosphatemia, hypercalciuria, and multiple hospitalizations for hypocalcemia. On this basis, our patient was offered PTH therapy on several occasions, however, this was deferred due to family planning. She has currently completed her family and is being considered for calcilytix therapy. Her most recent treatment regimen consisted of calcitriol 1.50 mcg twice daily, calcium carbonate 3000 mg twice daily, magnesium oxide 1500 mg twice daily, and cholecalciferol 2000 IU daily. The biochemical profile is summarized in A 25-year-old woman with ADH1, diagnosed at the age of 17 months after presenting with grand mal seizure and found to have hypocalcemia. She has an activating mutation of the  in 1930 , 41. She3.1.1nd trimester in both pregnancies with subsequent declines in the requirements during lactation. Both of her babies were born preterm at 37- and 34-weeks’ gestation, respectively; and required NICU admission for 2 weeks for the management of hypocalcemia. Both children have ADH1 and bear the same mutation variant as the mother, c.2363T>G; p.Phe788Cys. Child 1 is currently 5 years old, has normal milestones to date, and is maintained on calcium carbonate (500 mg three times daily), calcitriol (1.6 mcg twice daily), magnesium glucoheptonate (400 mg three times daily), potassium citrate (25 mg daily), as well as hydrochlorothiazide (5 mg twice daily). With regards to complications, nephrocalcinosis, nephrolithiasis, and recurrent urinary tract infection are present. Child 2 is 14 months old. The mother had a late preterm birth via emergency c-section due to decreased fetal movements and a low biophysical profile (BPP) of 2/8. She also had mild polyhydramnios. Following birth, the infant received APGAR scores of 3, 7, and 8, necessitating suctioning and subsequent continuous positive airway pressure therapy (CPAP). Alongside these challenges, an atrial septal defect (ASD) was detected. The infant also experienced hypocalcemic seizures and underwent treatment involving calcium carbonate , calcitriol (1 mcg twice daily), magnesium glucoheptonate (880 mg 6 times daily), and hydrochlorothiazide (5 mg twice daily). Notably, initial imaging did not reveal renal calcifications, however, repeated renal ultrasound has shown evidence of bilateral nephrocalcinosis. Nephrolithiasis, and basal ganglia calcifications have not been documented.This patient had 2 pregnancies, and, in both pregnancies, she required multiple hospital admissions due to hypocalcemia and non-adherence concerns. Her requirements of calcium and active vitamin D tripled in pregnancy especially in the 23.2CaSR gene , and a variant of unknown significance (VUS) in the FAM111A gene . Mutation in the FAM111A gene has been linked to Kenny-Caffey syndrome (KCS), which is a genetic disorder characterized by short stature and impaired skeletal development as well as hypoparathyroidism . She also has a VUS mutation in the AIRE gene , a gene whose homozygous, compound heterozygous, or heterozygous mutations have been associated with APS1 with or without reversible metaphyseal dysplasia. She initially presented with numbness and tingling involving the face, hands and feet, leg cramps, and bronchospasm at the age of 34 years. There were no clinical or biochemical features to suggest APS1. She had a history of oral and vaginal candidiasis which has resolved, and the adrenal and gonadal functions have been normal. There was no evidence of basal ganglia calcifications, nephrocalcinosis, or nephrolithiasis on imaging. The patient’s father had a history of hypocalcemia and was on calcium supplements throughout his life; he also had chronic kidney disease. Similarly, both of her paternal uncles and three paternal cousins suffer from hypocalcemia. However, her two sisters remain healthy and have not experienced any episodes of hypocalcemia. Genetic testing is not available for her family members. On physical examination she has hypertension, and blood pressure is maintained on antihypertensive medications. There are no dysmorphic features. She is currently maintained on calcium carbonate 5000 mg daily with meals, calcitriol 0.5 mcg twice daily, and cholecalciferol 6000 IU daily. The biochemical profile is summarized in A 41-year-old woman has ADH1 with a confirmed activating mutation in the 3.3.1She was pregnant a total of 5 times, 2 of which resulted in miscarriages at 14 weeks gestation, and the remaining 3 pregnancies were complicated by preeclampsia, resulting in preterm delivery. She denied any seizure or muscle twitching in any of her children, none required ventilatory support and all children have normal milestones.3.4CaSR gene , he also has associated hypomagnesemia, hypokalemia, and hypercalciuria. He has a wide fluctuation in serum calcium with multiple hospital admissions with severe hypocalcemia complicated by seizures. He also has a history of recurrent kidney stones from the age of 8 years requiring lithotripsy, the last stone was passed at the age of 31 years. Moreover, he has chronic kidney disease stage 3. No family history of note, his mother has post-surgical hypoparathyroidism, and his father and sister have normal calcium levels. He has no dysmorphic features, and his other system examination is unremarkable. He is currently enrolled in phase 3 TransCon PTH (TC PTH) trial; TC PTH is a prodrug of PTH (1-34) that is transiently conjugated to polyethylene glycol resulting in stability of the PTH level . She also has a VUS mutation in the HADHA gene , a gene whose homozygous or compound heterozygous mutation has been associated with mitochondrial trifunctional protein deficiency (MTPD). Hypocalcemia was discovered in a the lab profile, along with hypocalcemic symptoms, predominantly paresthesia, for two years prior to presentation at the age of 37. This CaSR genetic variant is a novel mutation that has not previously been reported in the literature or mutation databases. The patient has not had previous history of radiation therapy to the neck, nor other syndromic features of inherited hypoparathyroidism disorders. She had one episode of seizure at the age of 30 years at which time the serum calcium level was not reported. She also had kidney stones, the last of which was passed at the age of 38 years. Renal ultrasound following the passage of the kidney stone showed preserved corticomedullary differentiation bilaterally. There were no basal ganglia calcifications on the brain CT scan. She has no family history of hypocalcemia in both of her parents and siblings. She has one aunt who had a seizure disorder, but the serum calcium level is unknown. The hypocalcemia in her case is mild and is managed with multivitamins , calcitriol 0.25 mcg 3x/week, and ergocalciferol 50,000 IU weekly. The lab profile is summarized in A 39-year-old woman has ADH1 with biochemical evidence of low serum calcium and inappropriately normal PTH level and a confirmed heterozygous VUS mutation of the 3.5.1She has one child, born at 40 weeks gestation and breastfed for 8 months with no issues, and has normal milestones to date. No miscarriages.3.6CaSR gene, c.1756G>A; p.Glu586Lys. She was first diagnosed with hypocalcemia at the age of 44 years after experiencing numbness and tingling in her face and hands. Her mother and maternal grandmother both had hypocalcemia but have not obtained a molecular diagnosis. Hypercalciuria is present, the renal ultrasound did not show evidence of kidney stones or nephrocalcinosis and the brain MRI did not show evidence of basal ganglia calcifications. She is currently maintained on calcium carbonate powder 600 mg daily, calcitriol 0.25 mcg daily, and cholecalciferol 1000 IU daily.A 47-year-old woman with a molecular diagnosis of ADH1. She has a VUS heterozygous mutation of the 4CaSR gene and the presence of hypocalcemia. However, the literature is lacking in identifying other clinical areas of phenotype-genotype correlation in ADH1 patients , seizures were described in two cases (66.7%), while basal ganglia calcifications were reported to date only in the 25-year-old mother.The search on the database of human mutations and Pubmed allowed us to identify a total of 10 published cases, in addition to our 3 cases, bearing the p.Phe788Cys mutation. This mutation is located in the fifth transmembrane (TM5) domain encoded by exon 7 of the revalent . Moreove+2. A previous report documented another mutation at the codon 788, the p.Phe788Leu, in two individuals who had ADH1 with basal ganglia calcifications and nephrocalcinosis (It was previously reported that activating mutations in the fifth transmembrane (TM5) domain of the CaSR protein cause severe familial hypoparathyroidism . This islcinosis . Both thlcinosis , 44.CaSR gene leading to the development of ADH1. Interestingly, our p.Thr828Pro-bearing patient (case 4) shared similar features to the three patients with the p.Phe788Cys variant , in which the disease presentation is early in life (10 days old), there are recurrent seizures and multiple hospital admissions with hypocalcemia, as well as the presence of nephrocalcinosis and renal insufficiency. Moreover, hypomagnesemia was present in all these four cases.We identified in one ADH1 case the p.Thr828Pro variant that has not previously been reported, despite the fact that three publications were listed on ClinVar, none of which reported this specific mutation in the manuscript , 23, 45.Time to ADH1 diagnosis was variable in our eight ADH1 cases, presumably reflecting the severity of the disease. Indeed, more severe cases tend to declare themselves early in life, as for our cases 1, 4, 7, and 8, while milder forms tend to present later in life with mild symptoms. Both the p.Phe788Cys and the p.Thr828Pro mutations are located in the exon 7-encoded TM5 domain of the CaSR protein. This suggests that the alteration of this domain could be causative for the shared clinical characteristics in our 4 ADH1 cases and for the earlier presentation of the clinical phenotype. In addition, another missense variant (p.Leu773Arg) located at the TM5 domain, was associated with an ADH1 clinical phenotype characterized by an early onset hypocalcemic seizure, hyperphosphatemia, and basal ganglia calcifications , strengtBy contrast, another novel missense mutation (p.Met734Thr) in the TM5 region was described, from a German survey, in an asymptomatic patient with hypocalcemia and low PTH level. However, this mutation lacked further familial and functional characterizations to be classified as “damaging or pathogenic” and was believed to be benign .Based on data from our patients and results from the published studies, we hypothesize that mutations affecting the TM5 domain of the CaSR protein could be responsible for a more severe form of the disease, and they may be associated with a higher rate of neurological manifestations, such as a history of hypocalcemic seizures and the presence of basal ganglia calcifications, as well as of renal involvement, including nephrocalcinosis, nephrolithiasis, and renal insufficiency.CaSR gene: c.2468T>A; p.Ile823Asn and c.1756G>A; p.Glu586Lys. Neither of these variants has been reported in ClinVar, Human Gene Mutation Database (HGMD), GnomAD, or PubMed. In silico analysis of these two missense mutations with PolyPhen-2  predicted the Ile to Asn substitution at position 823 as “probably damaging” with a score of 1.000  and the Glu to Lys substitution at position 586 as “benign” with a score of 0.095 . Interestingly, another CaSR variant affecting the same codon 586  has been previously reported, by a single entry on ClinVar, as a VUS variant for the familial hypocalciuric hypercalcemia type 1 (HHC1); a clinical phenotype, mirroring the ADH1, characterized by a lifelong elevation of serum calcium concentrations, an inappropriately low urinary calcium excretion and a normal or mildly elevated PTH, and caused by heterozygous loss-of-function mutations in the CaSR gene. However, there were no citations or functional evidence of this mutation.In this study, we also described two novel mutations of the In a recent systematic review, it was found that 93% of patients with ADH1 had an incomplete diagnosis of idiopathic hypoparathyroidism or hypocalcemia at the time of presentation, and 7% of the cases were misdiagnosed with seizures or respiratory/cardiovascular disorders . This isIn conclusion, our data and the comparison with previously published ADH1 cases suggested the existence of a genotype/phenotype correlation regarding the presence of specific ADH1-related clinical manifestations and the early onset and/or severity of the disease. These findings, however, require further evaluation and assessment with a systematic review.The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.Ethical review and approval was obtained. This study uses subjects enrolled to the CALIBRATE study: a Phase 3, Randomized, Open-Label Study that evaluated the efficacy and safety of Encaleret compared to the standard of care in participants with ADH1 (NCT05680818). Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.Design and conceptualization of the project: DA, AK, MB. Analysis and interpretation of patients’ clinical and biochemical data: DA, FM. Review/editing of the manuscript: DA, FM, FA, HA, AA, AK, MB. All authors contributed to the article and approved the submitted version.


Pneumococcal disease is a major cause of morbidity/mortality worldwide, and vaccination is an important measure in its prevention. Despite European children being vaccinated with pneumococcal conjugate vaccines (PCVs), pneumococcal infections are still a major cause of morbidity/mortality in adults with risk conditions and their vaccination might be an important prevention strategy. New PCVs have been approved, but information is lacking on their potential impact in European adults. In our review, we searched PubMed, MEDLINE, and Embase for studies on the additional PCV20 serotypes  in European adults, between January 2010 and April 2022, having included 118 articles and data from 33 countries. We found that these serotypes have become more prevalent in both invasive and non-invasive pneumococcal disease (IPD and NIPD), representing a significant proportion of cases  and more serious disease and/or lethality , showing antimicrobial resistance , and/or affecting more vulnerable individuals such as the elderly, immunocompromised patients, and those with comorbidities . The relevance of pneumococcal adult carriers  was also identified. Altogether, our data showed an increase in the additional PCV20 serotypes’ prevalence, accounting for a proportion of approximately 60% of all pneumococcal isolates in IPD in European adults since 2018/2019. Data suggest that adults, as older and/or more vulnerable patients, would benefit from vaccination with higher-coverage PCVs, and that PCV20 may address an unmet medical need. Streptococcus pneumoniae (pneumococcus) causes severe bacterial infections in humans, manifesting either as invasive pneumococcal disease  or non-invasive pneumococcal disease  [eumonia) . Pneumoceumonia) . Diseaseeumonia) ) is greaeumonia) ,4,5.The capsular polysaccharide of the pneumococcus is its main virulence factor, and more than 90 different capsular serotypes exist. These serotypes differ not only in their structure but also in the disease severity and case fatality they are associated with, as well as their invasiveness, antimicrobial susceptibility, and geographical areas and age groups they affect ,7,8,9. TCurrently, two types of vaccines have been approved for the prevention of pneumococcal disease: a 23-valent pneumococcal polysaccharide vaccine (PPSV23) and pneumococcal conjugate vaccines (PCVs). The PPSV23 includes 23 purified capsular polysaccharide antigens  and was licensed in the United States of America (US) in 1983 . HoweverThe first PCV, PCV7 , was licensed in 2000–2001 and was integrated into the NIPs of many European countries between 2006 and 2008. Pediatric immunization with PCV7 prevented pneumococcal disease caused by the vaccinal serotypes as well as colonization and transmission to adults, leading to an overall reduction in disease burden in all ages . HoweverThe currently available PCV of highest valency, PCV20 , has been found to be safe and well tolerated, eliciting robust immunologic responses (including OPA—opsonophagocytic antibody responses) for its 20 serotypes one month after vaccination, in adults aged 18–49, 50–59, 60 years and above , and oveIn this review, we have focused on the evolution of the prevalence and impact  of each additional PCV20 serotype  in European adults. This review has focused on PCV20′s added serotypes’ clinical and epidemiological value to help support future decision making on adult pneumococcal vaccination policies.This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines .The PubMed and MEDLINE databases were searched for relevant studies published between January 2010 and April 2022. Only articles written in English and peer-reviewed studies from indexed journals were considered. Several searches were conducted in order to determine the best search strategy . The ultThis systematic review investigated the evolution of the prevalence and impact of serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F on pneumococcal disease, both invasive and non-invasive, in European adult populations (aged 18 to 64 years and aged 65 years and over). This review included studies published in the past decade (January 2010 to April 2022), including (but not limited to) observational studies, such as cross-sectional studies, prospective and retrospective comparative cohort studies, time-series studies, case–control studies, and randomized controlled trials. Reviews and systematic reviews that contained data from European national registries on pneumococcal disease were also included, provided their data did not overlap with other studies already included.Studies were excluded if at least one of the following was applicable: having no mention of at least one of the serotypes of interest ; not addressing epidemiological data on these serotypes ; being performed in non-European populations; focusing exclusively on children; or being published before 2010. Studies on mixed populations  were included, being signalized as such in the results.Study selection was performed by two different reviewers who screened the titles and abstracts from the retrieved articles. If an abstract or title did not contain sufficient information to determine eligibility, the full text was reviewed. The reviewers were not blinded to each other’s decisions. Disagreements were resolved by discussion or with the assistance of a third reviewer.The outcomes of this review included pneumococcal disease incidence, burden, and mortality associated with the additional PCV20 serotypes, as well as serotype prevalence, lethality, carriage and resistance to antimicrobials. The outcomes also corresponded to a certain time frame, which altogether was used to study the evolution of the additional PCV20 serotypes over time.The number of studies in each step of the process of study selection was represented in a PRISMA flow diagram . Full-teThese studies were also divided by timeframe according to the PCVs licensure dates and the PCV in use, in order to stratify collected data: pre-PCV7 . Most of the data described the incidence and/or prevalence and/or proportion of the different serotypes in IPD in different countries or regions, followed by information of the severity and lethality of each serotype and, to a lesser extent, data on the incidence and/or prevalence and/or proportion of each serotype in NIPD and antimicrobial resistance. Data from studies included in this systematic review are detailed in To enhance data visualization, we plotted the number of records in which each of the serotypes was found to be important  over the different PCV eras . Since tIPD incidence and prevalence for each serotype varied greatly across Europe and, at times, even regions within the same country, over time. Due to the extensive data set on IPD, only the overall European proportion of each serotype over time is stated below. Detailed information on each country and individual studies are presented in Serotype 8 displayed a 3–7% prevalence in IPD across Europe in the pre-PCV7 era . By the Serotype 10A was identified in approximately 1–2% of the IPD isolates in the pre-PCV7 era , varyingSerotype 12F was infrequently isolated in the pre-PCV7 era , much fewer records on NIPD (and carriage) were available in the literature. These were also more frequent in the late PCV eras  and for Serotype 11A was found frequently in carriage, identified in 6.4% of carriers in an European study with individuals of all ages (reaching approximately 11% in France and Sweden) , in 8.3%As for the other additional PCV20 serotypes, in the PCV10/13 and post-PCV10/13 eras, serotype 8 was sometimes found as one of the most prevalent serotypes in adults hospitalized with CAP, with prevalence rates approximately 7–8% ,60,61, aRegarding carriage, additional PCV20 serotypes were identified in a study involving several European countries with individuals of all ages . SerotypData on serotype associated disease severity and lethality were sometimes contradictory in the studies included in our review. When this was the case, the results we summarize aim at representing both perspectives, or, when several studies made the same claim, these results were considered instead. Detailed information on individual studies is presented in Serotypes 8 and 12F were less common in a high-risk group of patients , and morAs previously highlighted, serotype 8 was found to have enhanced propensity to cause invasive disease—OR 46.2 . On the Serotype 10A was found by multiple studies to be associated with a higher propensity for meningitis ,72,73 anSerotype 22F was also frequently associated with comorbidity prevalence (68.7%) as was serotype 33F 67.2%), both significantly higher than the other serotypes . Serotyp.2%, bothRegarding the lethality associated with each serotype, serotype 11A was the one most found to associate with higher risk of mortality and/or case fatality ratio (CFR) in IPD ,68,75,76Serotype 11A was the most associated with antimicrobial resistance. In the PCV7 era, it represented 14.3% of the IPD isolates resistant to erythromycin in Spain , while rSerotypes 15B and 33F were also often associated with antimicrobial resistance. Approximately 20% of the serotype 15B IPD isolates in Poland were found to show resistance to penicillin in the PCV7 era . In the Records of antimicrobial resistance in isolates from serotypes 8, 10A and 12F across Europe were uncommon throughout the past decade. Some studies in the PCV7 era found serotype 8 IPD isolates to show resistance to erythromycin , tetracyDetailed information on antimicrobial resistance is presented in Although pneumococcal disease burden in adults (particularly older adults) remains rather high, with pneumococcus leading to approximately 30% of adults’ hospitalizations due to CAP in Europe and 8–12% in the US , vaccinaIn this work, we found evidence showing a great increase in the prevalence of serotypes 8, 12F and 22F in IPD over the past decade in European adults. In the most recent epidemiological eras, serotype 8 showed an incidence of 15–30%, whereas serotypes 12F and 22F accounted for 7–10% each. These serotypes were also important contributors to the burden of CAP in several European countries ,64,65,75Serotypes 8 and 12F were more prevalent in younger versus older adults ,35,38,39Although some serotypes, particularly 8, show high propensity for causing invasive disease , others,Despite showing lower IPD incidence rates, serotypes 10A ,72,73 anAltogether, over the past decade, the additional PCV20 serotypes have shown an increase in prevalence, being associated with more serious disease, lethality, antimicrobial resistance, and/or more vulnerable individuals  in European adults. The emergence of PCV20 serotypes over the last decade is displayed in Streptococcus pneumoniae having indeed been detected in 60–90% of children, depending on geographic location [In our review, we found several studies showing carriage of the additional PCV20 serotypes in adults, namely 11A, 15B, 22F, and 8 ,51,52, dlocation ,88. Nonelocation ,89, namelocation ,13,86. TStreptococcus pneumoniae was caused by 34.9% of the PCV13 serotypes, 36.1% of the PCV15 serotypes and 79.5% of the PCV20 serotypes in adults aged 18–64 years old, and 40.2%, 46.4% and 66% for those aged 65 years and up, respectively [Altogether, our data showed an increase in the additional PCV20 serotypes’ prevalence in European adults in the past decade. In terms of vaccinal coverage, a European study on adults found that in 2018, the serotypes included in PCV15 represented one-third of the IPD cases, whereas serotypes included in PCV20 represented two-thirds of the IPD cases . This isectively .The US Advisory Committee on Immunization Practices (ACIP) has, since October 2021, recommended the use of either PCV20 alone or PCV15 in series with PPSV23 for all adults aged ≥65 years, and for adults aged 19–64 years with certain underlying medical conditions or other risk factors who have not previously received a PCV or whose previous vaccination history is unknown . AlthougAltogether, these data suggest that the higher-coverage PCVs (namely PCV20) pose advantages over the PCV15, PPSV23 and PCV15+PPSV23 schemes, and that improved vaccination strategies should be considered in the future.Our study has some inherent limitations. Although we defined PCV eras in order to simplify the stratification of data , not all European countries implemented PCV7 and PCV10/13 simultaneously, the rates of pediatric vaccination vary greatly between countries and even regions, and PCV10/13 only became widespread by late PCV10/13 era in some countries, all of which might shift the results in some regions considered. Moreover, although we grouped PCV10 and PCV13 in the same era, it is known that the choice of vaccine influenced the evolution of serotype prevalence . MoreoveHowever, our study also has several strengths. It is an unbiased account of all the records from the past 10–12 years regarding the incidence, prevalence, severity, lethality, and antimicrobial resistance of all the additional PCV20 serotypes. It answers the need for an update on the changing epidemiology of invasive and non-invasive pneumococcal disease in Europe  and in In this systematic review, we found that the additional PCV20 serotypes have been emerging in adults across Europe over the past decade, representing a significant proportion of cases , more serious disease and/or lethality , showing antimicrobial resistance , and/or affecting more vulnerable individuals such as the elderly, immunocompromised patients, and patients with comorbidities . Importantly, out of these serotypes, only 22F and 33F are covered in the new PCV15, and PPSV23 has showed limitations in prevention of non-bacteremic pneumonia; therefore, PCV20 has the potential to address an unmet medical need. Altogether, our data suggest that older and/or more vulnerable patients  would benefit from vaccination with higher-coverage PCVs.


Amid chairside CAD/CAM materials, the use of lithium-based silicate glass–ceramics (LSGC) has been steadily increasing. This review aims to report on the translucency of these materials and the variables used to measure it. An electronic search was performed within the PubMed database within the period between 2 June 2011 and 11 September 2022. English-language papers investigating the translucency of IPS e.max CAD, Celtra Duo, Suprinity PC, Initial LiSi Block, Amber Mill, N!ce, and CEREC Tessera LSGC CAD/blocks were included in the search strategy. After an initial retrieval of 160 papers, the application of exclusion criteria, and the screening of abstracts and then of full texts, 33 papers were included in the study. The retrieved materials, with different degrees of translucency , were IPS e.max CAD (n = 33), Suprinity PC (n = 8), and Celtra Duo (n = 1). Concerning the examined colors, the most used was A2 (n = 20), followed by A1 (n = 8) and A3 (n = 2). The translucency parameter (TP) was the most used method (n = 30) with respect to the contrast ratio (CR) (n = 11) to assess translucency. Five papers measured both. Several specimens’ thicknesses (0.5–4 mm) were investigated, with 1 mm (n = 23) being the most frequently analyzed. While a general tendency could be identified, conflicting results among different papers were reported. Nowadays, the demand for optimum aesthetics has become a primary criterion for successful restorative treatments. This requires that the physical and optical properties of restorative materials match those of natural dentition ,2. RecenThe selection criteria can be challenging and are often based on mechanical and optical (aesthetic) characteristics. Generally speaking, there is an inverse relationship between these two properties. Materials with higher crystalline content are characterized by higher mechanical properties but higher opacity, while a higher glass content determines higher translucency but is characterized by lower mechanical performance . The gre2O as the main oxide next to SiO2. According to the prevalent phase in which materials are crystallized, a classification has been proposed: “lithium disilicate” for the ones mainly composed by an Li2Si2O5 phase, “lithium silicate” for the ones crystallizing mainly in the Li2SiO3 phase, and “lithium (di)silicate” for materials composed by significant fractions of both phases [Among chairside CAD/CAM materials, lithium-based silicate glass–ceramics (LSGC) use has been increasing over the last few years . LSGCs ah phases .In analyzing the components of the CAD/CAM systems available on the dental market, the following LSGCs have been identified: IPS e.max CAD , Suprinity PC , Celtra Duo , GC Initial LiSI Block , Amber Mill , Tessera , and N!ce . The materials and their chemical nature, retrieved from manufacturers’ technical datasheets, are listed in Some of the CAD/CAM LSGCs , to achieve final mechanical and optical properties, require a thermal treatment  that needs to be performed in a dental furnace , while oCAD/CAM LSGC blocks are generally available in various shades and translucencies, usually low translucency (LT) or high translucency (HT). The translucency of aesthetic materials can be measured in different ways. The two most common methods are the contrast ratio (CR) and the translucency parameter (TP) ,19,20. WAn electronic search of the literature was performed on PubMed on 11 September 2022. The survey covered the period from 2 June 2011 to 11 September 2022.As this literature review was mainly aimed at providing a reference for practical interest to the dental community, it was decided to formulate the query using commercial names. The search strategy was the following: ((e-max) OR (Celtra) OR (N!ce) OR (LiSi CAD) OR (Suprinity) OR  OR (Amber Mill) OR (Tessera)) AND (translucency).Full-text, English-language publications analyzing the translucency of CAD/CAM LSGC were included.Publications were excluded if the assessment of translucency was not performed following an instrumental CR (contrast ratio) or a TP (translucency parameter) assessment. Therefore, studies based on a visual assessment of translucency were excluded. Also, as the study addressed milled versions of LSGC, studies analyzing translucency on pressed versions of LSGC were excluded.A data collection form was created and used to assess the experimental variables to measure specimens’ translucency. Six variables were assessed for every paper: (1) material type, (2) material shade, (3) material translucency, (4) specimen thickness, (5) the method used for translucency measurement (CR or TP), and (6) translucency value. The variables were recorded and tabulated in Excel sheets. Studies in which data on a certain variable were lacking or could not be calculated were entered as “not reported” (n.r.) for the variable in question. The selected articles are included in the reference list. A further search of the reference lists of the selected articles was also performed to eventually identify other relevant papers.The electronic search retrieved 160 titles for possible inclusion in the review. After initial elimination based on the titles, 97 abstracts were retrieved. For the selection of studies, two authors (A.V. and Z.Z.) independently reviewed the titles of the studies, according to the inclusion criteria for abstract reading. The Kappa score for interexaminer agreement on the screened abstracts was 0.89. After abstract screening, the full text of 70 articles was obtained. A further search of the reference lists of the selected articles did not result in additional articles being added. After full-text reading, 33 studies were found to be qualified for inclusion in the review . Among tRegarding the optical appearance of dental restorations, a tooth-like translucency is required for the fabrication of aesthetically pleasant restorations ,51,52. STranslucency is usually measured with a contrast ratio (CR) ,51,55,56LSGC presents differences in composition that can affect mechanical and optical properties. Variability in the crystalline content may provide significant differences in strength and optical properties ,61.In the present review, an electronic search of the literature was performed to retrieve data on the translucency of contemporary LSGC: IPS e.max CAD, Celtra Duo, Suprinity PC, Initial LiSi Block, Amber Mill, N!ce, Obsidian, and CEREC Tessera. As a possible limitation of the study, there is a chance that materials could be on the market with limited territorial availability, depending on market strategies, making it difficult to identify all the materials available worldwide. Also linked to this aspect, the conventional use of text only in English might preclude the full retrieval of information.2 = 8–12%) (ZLS) with densely distributed round-shaped crystals. The ratio between the crystalline phase and glass phase in volume is 57.1%:42.9%. Like Suprinity PC, Celtra Duo is also a lithium (di)silicate ZLS. The Celtra Duo glass matrix contains 10% zirconia with smaller silicate crystals, and the ratio between the crystalline phase and glass phase in volume is 51%:49%. Data on the translucency of N!ce, Lisi CAD, Tessera, and Amber Mill were not available at the time the literature search was performed.Among the examined papers, data for only three of the materials were retrieved: IPS e.max CAD was investigated in all 33 papers, whereas Suprinity PC was investigated in 8, and only 1 study investigated Celtra Duo. According to the classification proposed by Lubauer et al. , IPS e.mFor CAD/CAM blocks, manufacturers offer formulations with a higher degree of translucency (HT) and formulations with a lower translucency (LT or T). HT blocks are generally characterized by a small number of larger crystals with respect to LT  that present a larger number of smaller crystals . As a coAmong the materials examined, Amber Mill has a noticeable peculiarity, which is that the translucency can be controlled by firing temperature ,75. AccoAs a probable result of the absence of ISO standards for the measurement of translucency in dentistry, the papers examined in the present review considered different thicknesses, even if most of them (23 out of 33) evaluated translucency with specimens of 1 mm thickness. As LSGC can be used in different thicknesses, ranging from very thin layers for veneers up to thicker ones for crowns, knowledge of the optical behavior of different thicknesses could be clinically relevant. As a commonly reported and quite obvious observation, at clinical thicknesses, the lower the thickness, the higher the translucency.Unfortunately, only 7 out of 33 papers reported more than one thickness. Vichi et al.  reportedSome of the investigated papers also tested the HT version of IPS e.max CAD. Translucency values were very consistent for several papers, in a range of 18–19 ,37,42,48As translucency is a function of thickness, 0.5 mm specimens’ values were highly different from those of 1 mm and less consistent: Skyllouriotis et al.  reportedIn the present review, eight papers analyzed differences in translucency between IPS e.max CAD and Suprinity PC. Of the papers, 50% ,21,29,46In the only paper investigating Celtra Duo, Alayad et al.  comparedAs a general remark, the correlation between material nominal translucency  and thickness is a quite complex subject not extensively investigated and with uncertain measurement methodology. These values are clinically relevant, especially when compared to natural tissue values, which are likewise scarcely investigated. The classical study of Yu et al.  reportedTP is the most used method for evaluating the translucency of LSGC;Most of the studies used a 1 mm specimen thickness;HT and LT (T) formulations were equally investigated; A2 was the most investigated color, followed by A1 and A3;Data are sufficiently available for e.max lithium disilicate but scarce for ZLS VITA Suprinity PC and Celtra Duo and not available for the other searched LDGCs ;TP was prevalently measured in the range of 16–18 for LT and in the range of 18–19 for HT;CR was prevalently measured in the range of 0.56–0.63 for LT and in the range of 0.48–0.58 for HT.Based on the present review, some conclusions can be drawn: