The profile of the short chain fatty acids (SCFAs) produced by the microbiota was also investigated. The presence of tannin extracts in food promoted an increase of the relative abundance of the genus Akkermansia, recognized as a marker of a healthy gut, and of various members of the Lachnospiraceae and Ruminococcaceae families, involved in SCFA production. The enrichment of foods with tannin extracts had a booster effect on the production of SCFAs, without altering the profile given by the foods alone. These preliminary results suggest a positive modulation of the gut microbiota with potential benefits for human health through the enrichment of foods with tannin extracts.Food and food bioactive components are major drivers of modulation of the human gut microbiota. Tannin extracts consist of a mix of bioactive compounds, which are already exploited in the food industry for their chemical and sensorial properties. The aim of our study was to explore the viability of associations between tannin wood extracts of different origin and food as gut microbiota modulators. 16S rRNA amplicon next-generation sequencing (NGS) was used to test the effects on the gut microbiota of tannin extracts from quebracho, chestnut, and tara associated with commercial food products with different composition in macronutrients. The different tannin-enriched and non-enriched foods were submitted to  In the last decades, the human microbiota has been the focus of great attention. Considering the genome of the entire microbial ecosystem, we can count a 100-fold higher number of genes compared to the human genome . The micin vitro and in vivo for bioactive effects similar to those of dietary fiber  are the two main categories . These bry fiber .The interaction of tannins with food has been well-described in relation with several sensorial aspects, such as astringency and bitter taste . The strAs mentioned, another interesting property of tannins is related to their fiber-like behavior since they are not broken down during gastrointestinal digestion and, hence, they are not absorbed at the small intestine. Therefore, they reach the large intestine where they can be used as substrate by gut microbes, which could result in potential prebiotic properties .In light of this, we wanted to investigate if the association between different tannin extracts and a particular source of food could have modulatory effects on gut microbiota composition. We studied also the production of short chain fatty acids (SCFAs), which are good indicators of the effect of a foodstuff on the intestinal microbiota.in vitro digestion and fermentation were: potassium di-hydrogen phosphate, potassium chloride, magnesium chloride hexahydrate, sodium chloride, calcium chloride dihydrate, sodium mono-hydrogen carbonate, ammonium carbonate, and hydrochloric acid, all purchased from Sigma-Aldrich (Germany). The enzymes  and bile acids (porcine bile extract) were obtained from Sigma-Aldrich, and porcine pancreatin was from Alfa Aesar (United Kingdom). The fermentation reagents  were obtained from Sigma-Aldrich (Germany).The reagents used for the Short chain fatty acids standards  were purchased from Sigma-Aldrich (Germany).Three natural tannin extracts were chosen, which are representatives for the three main categories of tannins: quebracho wood extract , chestnut wood extract , and tara pods extract . The tannin content in the extracts, determined by the International Organization of Vine and Wine (OIV) method , was 80%Eight different food items, representing three types of products with different compositions in macronutrients were tested as potential tannin carriers: cereal-based foods , meat [meat (M) and meat with 30% fat (MF)], and dairy products . All commercial products were bought in local supermarkets . The food samples were ground using an Ultraturrax  at 13,000 rpm. Then, the products were supplemented or not with 0.6% w/w of different tannin extracts . This amount of tannin extract added to food was decided based on our previous studies (data not shown). Since tannins can exert antimicrobial activity, it was critical to find a concentration effective for our purposes but not high enough as to affect negatively the gut microbes. On the other hand, we should use an amount of extracts that does not alter the flavor or the structure of the food matrix.in vitro digestion and fermentation processes. The samples were aliquoted and stored at −80°C until the in vitro digested and fermented following the method described by 2 (0.3 M) to 5 g of food item alone or enriched with a tannin wood extract. The samples were then incubated for 2 min at 37°C. For the gastric phase, 10 ml of simulated gastric fluid with pepsin (2000 U/ml) and 5 μl of CaCl2 (0.3 M) were added and the pH was lowered to 3.0 by adding 1 N HCl. The mix was then incubated at 37°C for 2 h. Finally, 20 ml of simulated intestinal fluid with pancreatin (13.37 mg/ml), bile salts (10 mM), and 40 μl of CaCl2 (0.3 M) were added to the tube and the pH was raised to 7.0 with 1 N NaOH. The intestinal phase was followed by an incubation of the samples at 37°C for 2 h. A subsequent immersion of the tubes in iced water stopped the enzymatic reactions. The supernatants  were separated from the solid residue trough a centrifugation at 5000 rpm for 10 min at 4°C. To simulate the fraction that is not readily absorbed after digestion, 10% of the supernatant was added to the solid residue.Samples were The fermentation was performed by adding 500 mg of the digested wet-solid residues deriving from digestion to 7.5 ml of fermentation final solution (peptone water + resazurine) and 2 ml of inoculum . We used an oligotrophic fermentation medium so that the food/tannin combination to be tested would be the only source of energy and nutrients for the microbiota. The inoculum was obtained by mixing the feces of six selected healthy volunteers, adult individuals (men or women) with a body mass index within the range 18.5–25 . The selected people were not consuming any antibiotic or drug, and were following similar dietary patterns rich in vegetables, fruits, olive oil, and fish, typical of the Mediterranean diet.In the tubes, an anaerobic atmosphere was produced by bubbling nitrogen through the mix, followed by an incubation at 37°C for 20 h, under oscillation. Immediately afterward, the samples were immersed in ice, to stop microbial activity, and centrifuged at 5,000 rpm for 10 min. The supernatant was collected as a soluble fraction potentially absorbed after fermentation and stored at −80°C, until the SCFA analyses. The solid residue, representing the non-absorbed fraction after fermentation, was also stored in order to perform 16S rRNA amplicon sequencing analyses .Genomic DNA was extracted from the solid residues deriving from the fermentation process using the MagNA Pure LC JE379 platform (Roche) and DNA Isolation Kit III , following the manufacturer’s instructions, with a previous lysis with lysozyme at a final concentration of 0.1 mg/ml. DNA integrity was determined by agarose gel electrophoresis (0.8% w/v agarose in Tris-acetate-EDTA buffer) and DNA samples were quantified using a Qubit 3·0 Fluorometer (Invitrogen). All DNA samples were stored at −80°C until further processing.Total DNA (12 ng) was used as template for the amplification of the V3-V4 hypervariable region of the 16S rRNA gene. PCR primers were used as described by The sequence processing, assembly, amplicon sequence variants (ASVs) generation and annotation were performed in the DADA2 (v1.8.0) package from R v3.6.0; . The filShort chain fatty acids production was assessed by analyzing acetic, propionic, and butyric acids, according to the procedure described by p < 0.05) and linear discriminant analysis threshold (<2.0).Amplicon sequence variants with less than 10 counts in total were discarded. The ASV count table was normalized by total-sum scaling (TSS). Alpha and beta diversity measures were computed using various packages in the R platform. The Shannon diversity index, Chao1, and ACE richness estimators and Bray-Curtis dissimilarity index were obtained with the Vegan library v2.5-2; . Phylogen = 3) ± SD. One-way ANOVA with Bonferroni post-test correction was performed with the SPSS software  to determine significant differences among mean values on all the measured parameters.Results of SCFA production are expressed as mean values of triplicates , ellagitannins (CHE), and gallotannins (TE). We evaluated the effect on the gut microbiota by adding the extracts to eight different sources of food grouped in three food types: cereal-based foods , meat [meat (M) and meat with 30% fat (MF)], and dairy products . All the samples were subjected to an p = 0.035; Shannon: adjusted p = 0.023) and TE , and the larger variability observed with the addition of CHE.The addition of tannin to the different food matrices determined a general trend of increase of the sample richness and diversity, as evaluated by different estimators and indexes: the Chao1 and ACE richness estimators, Faith’s phylogenetic diversity (PD) and the Shannon diversity index that takes into account both richness and evenness . As an ein vitro fermentation of most samples was similar and dominated by Firmicutes and Bacteroidetes, followed by Proteobacteria, Verrucomicrobia and Actinobacteria, with some exceptions , while that of Bacteroidetes was lower  compared to meat samples not enriched with tannins.At the phylum level, the gut microbiota after ceptions . Indeed,Principal coordinate analyses based on the Bray-Curtis dissimilarity index and the weighted UniFrac distance were performed to establish whether samples separate into clusters. As seen in More in depth, the obtained pattern of sample clustering does not reflect exclusively the tannin or the associated food matrix, but is rather influenced by both. Among the evaluated tannin extracts, QUE clustered most homogeneously, with all samples present in a single cluster independently of the matrix to which QUE was associated. In contrast, for CHE and TE, microbial composition depended on the food matrix. In the case of CHE, although all samples separated well from non-enriched foods, dairy and meat samples clustered with the QUE samples, whereas cereal-based foods did not. In the case of TE, the yogurt and cereal-based samples did not separate from non-enriched foods, whereas the milk and meat samples were located in the cluster containing all the QUE samples and the dairy and meat CHE samples. This suggests that TE only has an effect on the gut microbiota when added to meat or milk.Bacteroides decreased  and Akkermansiaceae increased  with each of the tannins, although, in this case, only the differences with QUE and CHE were significant after adjustment for multiple comparisons. In addition, several abundance changes were significant only with QUE, including decreases of the Bacteroidales families Prevotellaceae (adjusted p = 0.031), Barnesiellaceae (adjusted p = 0.031), and Tannerellaceae (adjusted p = 0.031), as well as increases of the Rickenellaceae  and of several Clostridiales families . On the other hand, Peptostreptococcaceae  and the actinobacterial families Coriobacteriaceae (adjusted p = 0.048) and Bifidobacteriaceae (adjusted p = 0.048) augmented significantly only with CHE.To identify the bacteria most generally affected by the addition of each of the tannins, we applied Wilcoxon signed-rank tests to compare bacterial relative abundances in all samples enriched with a given tannin vs. all samples containing no tannins. These comparisons identified a large number of genera for which abundance after tannin addition differed from that of non-enriched foods at nominal significance level, but only differences in QUE were still significant after adjusting for multiple comparisons . Remarkap < 0.05) in dairy sources and cereal-based foods enriched with the different tannin extracts, QUE, CHE, and TE. In most cases, genera increased rather than decreased with the addition of tannins, except in the case of CHE added to cereal-based foods, where several members of the Proteobacteria, Bacteroidetes, and Firmicutes were found to decrease, including various genera of the Ruminococcaceae and Lachnospiraceae families. Sutterella was the only genus that decreased in both food matrices with all of the tannins tested. No genus was overrepresented in both food matrices with all of the tannins, but Akkermansia, Intestinimonas, Phascolarctobacterium, and various unassigned Lachnospiraceae and Clostridiales Family XIII genera did increase in all cases except when cereal-based foods were enriched with CHE. It is interesting to note that several of the genera that decreased when CHE was added to carbohydrates actually increased when CHE was added to dairy .We also applied LEfSe analyses to identify the specific biomarkers that best characterize the microbiota changes generated by the addition of tannins within each of the three food groups . The only group where significant differences were not detected between tannin-enriched and non-enriched matrices was that of meats. Finally, the differences generated by the addition of each tannin extract to each individual food matrix are represented as fold changes in Short chain fatty acids are metabolites produced by gut microbial fermentation of carbohydrates, dietary fibers, proteins, and resistant starch. We focused on the release of the three principal subtypes: acetate, propionate, and butyrate. The PCA in p < 0.001, CHE: adjusted p < 0.001, and TE: adjusted p < 0.001) and MF . On the contrary, when added to M, none of the three tannin extracts produced a statistically significant increase of total SCFAs. However, the addition of QUE, CHE, or TE to M induced a significant increase in the production of acetic acid compared to M without tannins, suggesting that they were exerting a booster effect on specific acetate-producing bacteria  also determined a decrease of roidales . Bacteroigestion . Inhibitigestion .The interactions between tannins and food macromolecules may be different depending on the food matrices. Binding mechanisms between tannins and proteins or carbohydrates occur in a specific and selective way, mediated by hydrogen bonds and hydrophobic interactions . Some faFaecalibacterium, among others. In our analyses, Faecalibacterium rather decreased with addition of QUE and CHE to cereal-based and dairy products , reaching the colonic gut microbiota. Herein, these compounds could be used by microorganisms, resulting in metabolites with different bioavailability, activity, or functional effect compared to the parent molecule .in vitro digestion and fermentation of QUE and CHE  with tannin extracts  evidenced the potential to influence host physiology through the modulation of the composition and the functionality of symbiotic bacteria in the gut. Our findings are in line with the considerations of https://www.ebi.ac.uk/ena/browser/view/PRJEB41013).The sequence data are available in the European Nucleotide Archive (ENA) under accession number PRJEB14013 (SM, JAR-H, and MPF designed the research. SM, AL-A, and NJ-H conducted the experiments. SM and AL-A analyzed data and performed statistical analyses. AL-A conducted the bioinformatic analyses. SM and MPF wrote the manuscript. MJG, AL-A, and JAR-H provided significant advice and critically edited the manuscript. JAR-H obtained funding and coordinated the Stance4Health project. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Objective: The aim was to report 4 patients with intra-articular knee synovial haemangioma (KSH) and to perform a systematic review to describe the patient characteristics, patterns of tumor location, clinical presentation, usefulness of imaging examinations, pros and cons of arthroscopic vs. open resection, and follow-up in the literature.Design: From 1996 to 2016, four patients with KSH were retrospectively reviewed. A literature search was conducted in PubMed from 2000/01 to 2020/06 using the search terms “synovial haemangioma” and “knee.” Fifty full-text articles that included a total of 92 patients were included for further discussion.Results: Four adults (20–40 years) were diagnosed with KSH. Three lesions located in the suprapatellar pouch, two eroding the patella and one the supratrochlear bone, and one in the posterior compartment. Persistent anterior knee pain was the main complain. MRI revealed a benign tumor mass in all cases except one. Open excisional biopsy and regional synovectomy were performed in three patients, and by arthroscopy of the posterior compartment in the fourth. Histological type was arteriovenous in three cases and capillary in one. A pain-free knee without recurrence was achieve in all cases except one, which was successfully reoperated. Average follow-up time was 3.5 years. A literature review showed that KSH appears most frequently in children and teenagers (64.6%) and does not differ by gender. The suprapatellar and patella-femoral joint compartment was the most frequent location (47.9%). The bony tissue of the knee was rarely affected (13.5%). Pain, swelling and haemarthrosis were frequently reported . MRI was the most commonly used imaging test (98%). Treatment consisted of regional synovectomy by open surgery or arthroscopy in 66.7 and 15.6% of cases, respectively.Conclusions: KSH should be considered in the differential diagnosis of adult patients with chronic low-intensity knee pain. MRI is the most useful exam because it establishes the location, extent and benign characteristics of the tumor. Definitive diagnosis requires histological examination. We believe excisional biopsy and regional synovectomy by arthroscopy should be the treatments of choice for intra-articular tumors, but we recommend open surgery when the lesion extends to the tendons, muscle or bone. Synovial haemangioma (SH) is a rare benign tumor accounting for 0.07% of all soft tissue tumors and 0.78% of all excised haemangiomas . While tKnee synovial haemangioma (KSH) can present as diffuse or localized intra-articular, juxta-articular or intermediate (intra- and juxta-articular) synovial tissue masses , 5–7. ExMost are located in the anterior compartment of the knee , 12. OnlThe clinical presentation is non-specific, with symptom onset usually occurring in childhood and young adulthood, although it has been described at later ages, probably due to delayed diagnosis. Various imaging modalities have been used, but all are non-specific, and there is no clear diagnostic algorithm , 57, 58.Once a benign synovial lesion is suspected, it is unsettled if a biopsy is needed or if excisional biopsy and regional synovectomy with histological examination can confirm the diagnosis and simultaneously accomplish definitive treatment. Whether open , 38, 57 Further investigation is warranted, particularly because the existing information is scattered and based mostly on isolated clinical cases. An understanding of the differences in patient characteristics and clinical presentation, along with knowledge of the real value of imaging examinations and follow-up results after arthroscopic or open surgery, is important for making informed decisions on the need for invasive imaging examinations and on the differential effectiveness of open vs. arthroscopic treatment in light of the evidence.The aim of the study was to describe four patients with intra-articular KSH, two with the previously undescribed phenomenon of patellar bone erosion and one with an unusual tumor location in the posterior compartment, and to perform a systematic review of PubMed publications on KSH from 2000 to 2020 to describe the characteristics of the patients , the patterns of tumor location, the non-specific clinical presentation, the usefulness of imaging examinations, the pros and cons of arthroscopic vs. open resection, and the follow-up time and recurrence after treatment.Based on hospital records, we identified four patients with KSH who were seen between 1996 and 2016. Demographic data, symptoms, imaging tests, treatment and follow-up were retrospectively reviewed. All patients underwent surgical treatment by one surgeon (JHH). Written informed consent was obtained from the patients in all cases, and the retrospective study was approved by the hospital ethical committee . The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation  and with the Helsinki Declaration of 1975, as revised in 2000.A PubMed literature search was performed for full text publications between 2000/01 and 2020/06; these dates were selected because MRI was widely available in this period. The search terms were as follows:  AND (Knee) AND (2000/01:2020/06). Selection was restricted to single case reports or case series of KSH that described the diagnosis and at least four items in our study objectives. Only original reports or studies written in English, Spanish or French and available in full-text form were included.Each original manuscript was scrutinized, and search results on the number of cases described, the age and gender of the patients, the side of the affected knee, the tumor location, the history of previous trauma, the symptoms and signs, the presence of cutaneous haemangioma, the delay in diagnosis, the image examinations performed, the presence of bone involvement, the type of treatment, the histological type and the follow-up time were screened and collected in a database by two reviewers independently  to ensure accuracy and then stored on a Microsoft Excel spread sheet. Any discrepancy in the data collected was reviewed by both reviewers until an agreement was obtained. The review was limited to reporting variables that were obtained in each publication; when a variable was omitted, it was registered as not reported. The results are presented as the number of cases and the percentage with respect to the total number of cases, except for symptoms and signs and image examinations, which are presented as the number of manuscripts where they are reported and the percentage with respect to the total number of manuscripts reviewed. Age, delay in diagnosis and follow-up time are presented as the mean ± standard deviation of data available, and the percentage of cases not reporting those data was also specified. In order to avoid multiple reports of the same study, studies with the same authors were double-checked, and comparisons of case descriptions and treatments were performed. Neither of the review authors was blinded to the journal titles or the study authors or institutions.Results tabulated by age, gender, affected knee side, tumor location, history of previous trauma, clinical symptoms and signs, presence of cutaneous haemangioma, time in diagnosis delay, imaging test used, bone involvement, type of treatment, histology, follow-up time and recurrence are shown in A 20-year-old male suffering from sudden intense pain in the right knee with swelling presented to the emergency room. He had had occasional pain for 5 years, but never at that intensity. Palpation of the external aspect of the patella was painful. There was no patellar instability; meniscal, ligamentous and neurovascular examinations were normal.Plain radiographs were normal. Joint aspiration revealed a haemarthrosis. Anterior knee pain syndrome due to patella-femoral cartilage damage or synovial derangement was suspected. Bone scintigraphy with 99mTc revealed an increase in uptake in the anterior portion of the knee. MR revealed a suprapatellar and supratrochlear synovial tumor extending medially and eroding the supratrochlear cortical bone; the tumor was characterized by hyperintensity on T2-weighted images and hypo-/isointensity to muscles on T1 sequences .A non-specific benign synovial knee tumor, either SH or localized pigmented villonodular synovitis (LPVNS), was suspected. An open excisional biopsy, partial synovectomy and curettage of bone were performed. Histological examination reported proliferation of arterial and venous vessels in a fibrous stroma, consistent with the diagnosis of arteriovenous-type SH .Recurrence of the tumor was observed on MRI follow-up 5 years later. MRI revealed diffuse involvement of the sub-quadriceps synovial lining and tendon . An openA 22-year-old male was referred to our hospital for persistent anterior right knee pain lasting 6 years. He had moderate pain that did not limit activities of daily living but prevented him from practicing sports. He had no history of prior trauma, although he had experienced minor impacts during sports. On physical examination, he had lower limb varus alignment, no muscle atrophy, no effusion, normal range of motion, a stable knee, and normal meniscal and neurovascular examinations.Radiographic images were normal. MRI was reportedly normal. Due to the persistence of symptoms despite analgesics and muscle strength exercises, diagnostic arthroscopy was performed. We detected no evidence of joint damage. Histological and microbiological tests of the synovial lining from various areas were normal.However, owing to worsening symptoms 2 years later, another MRI was performed, revealing a tumor in the synovial lining just over the proximal pole of the patella; the tumor was isointense on T1 and hyperintense on T2, with intra-osseous invasion of the upper pole of the patella , suggestUpon open surgery, the synovial lining above the upper pole of the patella was swollen and bluish brown, with poorly defined margins, and there was invasion of the quadriceps tendon and the superior pole of the patella. We resected the tumor and half of the quadriceps tendon to healthy margins and curetted the superior patellar bone lesions back to normal trabecular bone. Histological examination revealed blood vessels with multiple arterial and venous vessels in the stroma, confirming the diagnosis of arteriovenous SH.At the 6-week follow-up, the patient had a stiff knee with a range of motion of 0–30°. At 10 weeks, we performed arthroscopic arthrolysis and obtained new biopsy samples. Histological examination showed no evidence of a tumor. At the 5-year follow-up, the patient had a pain-free knee and a normal range of motion. A repeat MRI showed no evidence of recurrence.A 31-year-old man presented with an 8-year history of diffuse right knee pain, which persisted at rest and was aggravated with activity. The pain limited his participation in sports but not his activities of daily living. On physical examination, the knee was well-aligned but had mild swelling and tenderness adjacent to the medial patellar facet. There was no muscle atrophy or warmth. The range of motion and stability were normal, as were the meniscal and neurovascular examinations.Plain radiographs were normal. On aspiration, the joint fluid was clear, and the cell count was normal with no microcrystals. We suspected anterior knee pain syndrome due to patella-femoral osteoarthritis. MR revealed an intra-articular synovial mass located superior and medial to the patella that had eroded into the superior patellar cortex. Heterogeneous lower signal intensity on T1-weighted imaging and isointensity on T2-weighted imaging suggested LPVNS .Open excisional biopsy and partial synovectomy were performed. Two small intra-osseous cystic lesions in the medial and superior poles of the patella were curetted until healthy trabecular bone was observed. Histological exam showed synovial proliferation with subjacent capillaries, consistent with capillary-type SH .The patient had an uneventful postoperative recovery, with restoration of full range of motion and good muscle strength. He resumed amateur sports. Four years after surgery, he had a normal pain-free knee, and there was no evidence of tumor recurrence on MR.A 40-year-old male presented with a 10-year history of progressive anterior and posterior right knee pain with insidious onset. He had no history of trauma. Pain occurred when he performed maximum knee flexion or intense cycling but not during activities of daily life.On clinical examination, both lower limbs were aligned in varus. There was no muscular atrophy, swelling, tenderness or joint effusion. The range of motion of the knee was normal, but the patient reported discomfort at maximum flexion. The knee was stable, and the meniscal and neurovascular examinations were normal.Plain radiographs were normal. MRI showed a well-defined intra-articular synovial mass in the posterior compartment of the knee, behind the PCL. On T1-weighted sequences, the mass was isointense to the surrounding muscle signal with peripheral heterogeneous areas, and on T2-weighted imaging, it was hyperintense . A benigThe patient opted for observation and regular follow-up. Four years later, his pain had increased and was more frequently limiting his activities of daily living. Repeat MRI showed features similar to what had been observed previously, but the patient elected to proceed with surgery. On arthroscopy, we observed a 1 × 0.5 × 0.5 cm pale bluish vascular lesion in the synovial lining of the posterior capsule just behind the PCL . An exciThree months after surgery, the patient progressively resumed recreational sports. One year after surgery, the patient was asymptomatic, even when cycling. There was no evidence of recurrence on repeat MRI.We identified 75 abstracts from articles located through the literature search. Eight articles on KSH case descriptions were not reviewed because six were in other languages , one full-text article from an Indian journal was not available and one was an open radiology case. Four articles described SH in other joints, and 13 did not focus on KSH clinical cases or case series. Ultimately, we reviewed 50 full texts that focused on case or case series descriptions, including a total of 92 clinical cases. A flow chart of the literature search is shown in The literature review showed that KSH appears more frequently in children and teenagers (64.6% of cases). The average age of presentation was 21.7 ± 14.7 years, and the prevalence was not related to gender . The right knee was more frequently affected (39.6%).The tumor mass could appear anywhere in the joint, but an anterior knee location in the suprapatellar and patella-femoral (47.9%) joint space was the most frequent, followed by the infrapatellar (14.6%), posterior (9.4%) and medial compartment (7.3%) and the intercondylar notch (4.2%). Usually, there was no previous trauma (39.6%), or it was not reported (46.9%).Pain, swelling and haemarthrosis were the most frequently described clinical presentation form , although the symptoms and signs associated with KSH were multiple and non-specific see . CutaneoThe most commonly reported image tests were plain XR (86.3%) and MRI (98%) alone or enhanced with gadolinium (MRGd). Ultrasound (US), echo Doppler (ED), arteriography, computed tomography (CT) or scintigraphy (Sc) were used less frequently (9.8–5.9%) In rare cases (3.9–2%), venography, CT arthrography (CTArt), CT angiography (CTA), multi-detector computed tomography angiography (MDCTA), red blood cell scintigraphy (RBISc) or single-positron emission computed tomography (SPECT) were reported. Knee bone erosion was occasionally observed (13.5%) on image exams.Synovectomy was the treatment of choice and was more frequently performed by open surgery (66.7%) than by arthroscopy (15.6%). Treatment options such as observation, pharmacological treatment (corticosteroids and beta blockers), and TKA were rarely recommended . Biopsy prior to treatment was infrequent (9.4% of cases). The most frequent histologic type was the cavernous type (28.1%), followed by the venous vascular malformation, capillary, arteriovenous and cavernous-capillary types.The average follow-up time was 2.7 ± 2.2 years, but the follow-up time was unreported in 36% of cases. Reported recurrence was low (3.1%), as it was the persistence of symptoms (11.4%).Synovial haemangioma have been described in various joints, but the knee is the most common . Up to 2This is the first study that performs a detailed revision of a large number of KSH (96 cases) and describes its more frequent location and clinical presentation forms. The major finding of this study is that plain radiographs and MRI image studies appear to be enough for the differential diagnosis, that will be confirmed after histology exam. Being a tumor mass of benign characteristics on image studies rarely a biopsy is indicated previous to treatment, an excisional biopsy and regional synovectomy can be performed for diagnosis and treatment purposes before diagnostic confirmation. Although open surgery has been the treatment of choice, nowadays arthroscopy seems to offer advantages in the treatment of intraarticular KSH without bone, tendon or muscle involvement. Recurrence after surgery is low (3.1%) but persistence of symptoms is more frequent (11.4%), especially in diffuse forms.In the last 20 years, only nine cases (9.4%), including ours, had localized lesions in the posterior compartment of the knee. One was an intermediate tumor  that extOur other three cases were local sessile intra-articular SH located near the superior pole of the patella, by far the most frequent location in the anterior compartment of the knee , 53–57, KSH usually occurs in children and teenagers , 8, 12, All four of our patients were male, but we found no differences in sex distribution, and the exclusively male composition of our sample is probably merely a matter of sample size. The right knee is more frequently affected than the left knee. Previous trauma appears to be rare and is often not reported. Symptoms and signs associated with SH of the knee are non-specific. Low-intensity and long-duration pain is the most frequent symptom , but it No clinical test or imaging procedures provide a definitive diagnosis, nor is there a clear algorithm for diagnosis. Plain radiographs are typically normal , 55– 57,MRI appears to be the examination of choice , 53–57. Ultrasound may , 24, 46 Diagnostic arthroscopy may be useful in localizing a synovial tumor and ruling out unrelated intra-articular lesions , 45, 47.Histological examination is essential to establish a definitive diagnosis, although it was not reported in 8.3% of reviewed cases. Haemangiomata are tumors derived from endothelial cells, and four types have been described . AlthougWe advise treating these lesions because they can cause joint destruction either by direct invasion of the surrounding tissues or by repeated haemarthrosis , 10, 31.As KSH appears as a synovial tumor mass with benign characteristics in imaging studies, an excisional biopsy and regional synovectomy can be performed until free resection margins are obtained for diagnosis and treatment purposes before diagnostic confirmation. Biopsy prior to treatment is rarely reported 9.4%) but should be indicated if there is doubt regarding the benignity of the tumor based on imaging examinations. There is controversy as to whether open or arthroscopic surgery is better. Most patients have been treated by open surgery because it has been argued that it allows a better view of the full extent of the lesion, mainly when it is located within the Hoffa fat pad, and therefore leads to a lower recurrence rate % but sho, 50, 55.Some authors recommend arthroscopic resection for localized intra-articular KSH , 59, 60.We note several limitations of our study. First, some clinical data were missing in our retrospective clinical review, although key data were available in the records. Second, the literature search was performed only in PubMed and was limited to English, French or Spanish; thus, there is likely additional literature on the subject. However, given the long period over which the papers were published and the large number of cases identified, the included studies are likely representative of the literature. We are unaware of any other such reviews at this level of detail.It is clinically relevant to know the frequent and unusual locations of KSH, its multiple clinical presentations, the real value of image examinations and the pros and cons of arthroscopic vs. open surgery to be able to make informed decisions on the need for invasive image examinations, previous biopsy or arthroscopic vs. open surgery in light of the evidence.In conclusion, KSH is a rare tumor. The superior pole of the patella is the most frequent location and only five intra-articular reported cases (including ours) in the posterior knee compartment. SH should be considered in the differential diagnosis of long-term knee pain in adults, particularly if there is no history of previous trauma. Plain radiography is usually normal. MRI is the imaging test of choice to localize a synovial mass, but the images are diagnostically inconclusive. MRA may be useful in diffuse or extended cases. The rare phenomenon of bone erosion, first time described in the patella, have to be bear in mind. Histological examination is necessary for definitive diagnosis. Biopsy prior to treatment should only be indicated if there is doubt regarding the benignity of the tumor. We believe arthroscopic resection should be the surgical technique of choice for treating localized intra-articular lesions or those in difficult areas such as the posterior compartment. We recommend open surgery for diffuse tumors and those that are localized in juxta-articular and intermediate regions with tendon, muscle or bone extension. Complete resection of the synovial lesion and the surrounding affected tissues is important to relieve symptoms and prevent recurrence.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.JH-H participated in the design of the study, participated in revision of clinical cases and search and revision of bibliography, and interpretation of the data and in drafting the manuscript. JM-B participated in revision of clinical cases and revision of bibliography. EG-O has participated in search and revision of bibliography. FC-S has been involved in search and revision of bibliography. SL-M has participated in search and revision of bibliography, interpretation of data, and drafting the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Reading List: Select Healthcare Transformation Library 2.0 represents a broad-based, annotated, general reading list for students of health care innovation. The books were drawn from the 5,000-book private home library of Ronald S. Weinstein, MD, President Emeritus of the American Telemedicine Association. Weinstein is a lifelong book collector with special interests in the history of medical innovation and poetry. A Massachusetts General Hospital-trained pathologist and inductee into the US Distance Learning Association's Hall of Fame, he is known as a pioneer in telemedicine and the “father of telepathology” for his invention, patenting, and commercialization of telepathology, a subspecialty of telemedicine that is a billion-dollar worldwide industry today. This Reading List: Select Healthcare Transformation Library 2.0 consists of 41 books divided into 10 sections: (1) Human Intelligence, Behavior, and Creativity; (2) Societal Revolutions; (3) Innovation; (4) Healthcare System Transformations; (5) Education; (6) Transformational Technologies—Part 1 ; (7) Transformational Technologies—Part 2 ; (8) Digital Medicine; (9) Healthcare Transformation Implementation; and (10) COVID-19 Pandemic as an Innovation Accelerator. The Select Healthcare Transformation Library 2.0 reading list was created to provide students, clinical investigators, and medical and nurse practitioners with a broad overview of the intellectual landscape in which health care transformation currently takes place and is well suited to serve as a course reading list for students of innovation, health care delivery systems, public health, and medical economics. The books included herein are all part of Dr. Weinstein's extensive personal home library, a collection of over 5,000 books.Dr. Weinstein's Select Healthcare Transformation Library 2.0 is divided into 10 sections: (1) Human Intelligence, Behavior, and Creativity; (2) Societal Revolutions; (3) Innovation; (4) Healthcare System Transformations; (5) Education; (6) Transformational Technologies—Part 1 ; (7) Transformational Technologies—Part 2 ; (8) Digital Medicine; (9) Healthcare Transformation Implementation; and (10) COVID-19 Pandemic as an Innovation Accelerator. These sections are starting points, not boundaries. Students of health care innovation are well advised to start their journey into the health care transformation literature by giving thought to (1) the topics of human creativity and ingenuity; (2) solutions for current challenges present throughout the health education continuum in the United States; and (3) uses of innovation accelerators to promote societal changes that favor the expansion of digital medicine in the 21st century.In each of the following 10 sections of books, we have listed 2–8 books that provide information that serves as a springboard for a deep dive into the core of the health care transformation literature and its related topics.Creativity: Flow and the Psychology of Discovery and Invention. HarperCollins Publishers, Inc., 1996, 456 pages.Csikszentmihalyi M. Thinking, Fast and Slow. Farrar, Straus and Giroux, New York, NY, 2011, 499 pages.Kahneman D. Behave: The Biology of Humans at Our Best and Worst. Penguin Press, New York, NY, 2017, 790 pages.Sapolsky RM. The Runaway Species: How Human Creativity Remakes the World. Catapult, New York, NY, 2017, 296 pages.Brandt A, Eagleman D. Creativity: Flow and the Psychology of Discovery and Invention,” is perhaps somewhat dated , but reading it is also a reminder that earlier scholarship often matters, especially when we think about creativity and the execution of transformative human activities. A masterpiece on human rationality and irrationality by Nobel laureate Daniel Kahneman, “Thinking, Fast and Slow” is a must-read for students of the human mind, written by one of the most influential psychologists in the world today. Robert M. Sapolsky's “Behave: The Biology of Humans at Our Best and Worst” is a landmark publication that probed the range of human behavior, from the good to the bad. Anthony Brandt and David Eagleman's popular book, “The Runaway Species: How Human Creativity Remakes the World,” ponders aspects of human creativity and genius from a historical perspective.Human behavior, intelligence, and creativity help set the stage for the world's great societal transformations. Successful societal health care system transformations will benefit diverse human populations. For an exploration of the creation process, the book by Mihaly Csikszentmihalyi, “Plagues and Peoples. Anchor Press, Garden City, New York, 1976, 329 pages.McNeill WH. The Structure of Scientific Revolutions. 3rd edition, University of Chicago Press, Chicago, IL, 1996, 212 pages.Kuhn TS. The Fourth Industrial Revolution. Crown Business, New York, NY, 2017.Schwab K. Plagues and Peoples,” describes how plagues may carry along health care transformations in their wake. McNeill, a distinguished University of Chicago historian, integrated ecology and demography with politics, culture, and the medical science of the day on a grand scale. At the time “Plagues and Peoples” was published, in 1976, it was regarded as a fresh look at history, from a unique perspective, by a leading historian.William McNeill's groundbreaking history book, “The Structure of Scientific Revolutions,” in 1996. This was just before his death and three decades after the publication of its first edition. Kuhn is famous for his recognition that the discovery of anomalies during scientific revolutions leads to new paradigms that ask new questions of old data. Kuhn's classic book had an influence far beyond its original intended audience. It provides one of the best explanations of the processes of discovery.Thomas S. Kuhn (1922–1996) was a professor emeritus of linguistics and philosophy at the Massachusetts Institute of Technology (MIT) when he published the third edition of his classic publication, “Fourth Industrial Revolution” are currently the rage among health care leaders who see the confluence of digital technologies, such as artificial intelligence (AI), automation, robotics, and telemedicine, as an innovation-rich river filled with opportunities that humans can harness to solve health care's biggest challenges and to advance us ever closer to the aspirational goal of providing world-class health care for everyone.Celebrations of Klaus Schwab's “Diffusion of Innovations. 5th edition. Free Press, New York, NY, 2003.Rogers EM. Crossing the Chasm. Marketing and Selling Disruptive Products to Mainstream Customers. HarperCollins Publishers, New York, NY, 2014, 288 pages.Moore GA. Seeing What's Next: Using the Theories of Innovation to Predict Industry Change. Harvard Business School Press, Boston, MA, 2004, 312 pages.Christensen CM, Anthony SD, Roth EA. The Innovator's Prescription: A Disruptive Solution for Health Care. McGraw Hill, New York, NY, 2008, 496 pages.Christensen CM, Grossman JH, Hwang J. The Innovator's DNA: Mastering the Five Skills of Disruptive Innovators. Harvard Business Review Press, Cambridge, MA, 2011, 272 pages.Dyer J, Gregersen H, Christensen C. The Innovator's Dilemma: When New Technologies Cause Great Firms to Fail. Harvard Business Review Press, Cambridge, MA, 2013, 256 pages.Christensen CM, Grossman JH, Hwang J. The Evolution of Everything: How New Ideas Emerge. HarperCollins, New York, NY, 2015, 360 pages.Ridley M. Rethink: The Surprising History of New Ideas. Scribner, New York, NY, 2016, 342 pages.Poole S. Diffusion of Innovations” is in its fifth edition. It describes what are now regarded as the five classic stages in the development and diffusion of innovations. Roger was an eminent American communication theorist and sociologist who originated the diffusion of innovations theory. He explained how innovations spread through populations in stages, along the line of a five-stage bell-shaped curve. His stages are (1) “Innovators”; (2) “Early Adopters”; (3) “Early Majority”; (4) “Late Majority”; and (5) “Laggards.” Geoffrey A. Moore's “Crossing the Chasm. Marketing and Selling Disruptive Products to Mainstream Customers” focuses on overcoming the chasm that may be encountered in the rollout of Christensen's disruptive innovations between the “Early Adopters” and “Early Majority” stages in Roger's bell-shaped curve in the technology adoption life cycle.Everett M. Roger's “The Innovator's Prescription: A Disruptive Solution for Health Care” describes a wellspring of ideas that add to our understanding of how successful products and services may evolve. In essence, it provides a roadmap for reinventing health care delivery systems in the United States. Christensen's “The Innovators DNA: Mastering the Five Skills of Disruptive Innovators” coaches innovators on what it takes to succeed in making their enterprises work. His “The Innovator's Dilemma: When New Technologies Cause Great Firms to Fail” describes strategies for maintaining a competitive edge at companies. The fifth Christensen book selection is listed in “Section 5. Education.”Clayton M. Christensen, a Harvard Business School distinguished professor, was a thought leader in innovation science for many years. Five of Christensen's books are included in this 41-book Select Healthcare Transformation Library. His “The Evolution of Everything: How New Ideas Emerge” and Steven Poole's “Rethink: The Surprising History of New Ideas” are interesting reads that highlight the broad range of sources of new ideas, including the recycling of older ideas, which pop up as newer innovations within a later time frame.Matt Ridley's “The Heart of Power: Health and Politics in the Oval Office. University of California Press, Berkeley, CA, 2009, 484 pages.Blumenthal D, Morone JA. Reinventing American Health Care: How the Affordable Care Act Will Improve our Terribly Complex, Blatantly Unjust, Outrageously Expensive, Grossly Inefficient, Error Prone System. Public Affairs, New York, NY, 2014, 380 pages.Emanuel EJ. World Class: A Story of Adversity, Transformation, and Success at NYU Langone Health. Fast Company Press, New York, NY, 2019, 340 pages.Haseltine WA. The Heart of Power: Health and Politics in the Oval Office” is a presidential history book that takes the reader through the evolution of health care policy during 11 US presidencies, starting with Franklin D. Roosevelt and continuing through George W. Bush's presidency. It shows the centricity of the US president in the decision-making that affects the health care of large swaths of the US population.David Blumenthal and James A. Morone's “Reinventing American Health Care: How the Affordable Care Act Will Improve our Terribly Complex, Blatantly Unjust, Outrageously Expensive, Grossly Inefficient, Error Prone System” is recommended for readers interested in understanding how the US health care system functions and wishing to tackle transforming our byzantine US health care system into something new that functions well and fairly for all Americans. It is a detailed case study of how a brilliantly conceived health care policy, and its enabling legislation, can accomplish health care transformation even within a highly fragmented health care delivery system. It gave reason for hope for the continuing of US health care system transformation processes in positive directions. On the other hand, it turns out that this hope may have been premature.Ezekiel J. Emanuel's “World Class: A Story of Adversity, Transformation, and Success at NYU Langone Health,” is an inspiring account of the recent bailout and so-called transformation of a large university health care system in New York City. The rehabilitation process at New York University Langone was led by a visionary, arguably a one-of-a kind, New York City billionaire, who achieved total personal immersion in his mission to make New York University Langone the best-of-breed health care system in the New York City area. He succeeded according to a number of measures of excellence. This remarkable, academic, health care system rehabilitation story deserves special mention in the hopes that it will inspire other philanthropists to make comparable investments in our future. As this was happening, New York City emerged as a significant player in the development of leading-edge telemedicine-enabled reorganizations of vast, regional, health care delivery systems. That spirit of change spread to nearby Philadelphia, especially at Jefferson University, in even more recent times.William A. Hazeltine's book, entitled “Disrupting Class: How Disruptive Innovation Will Change the Way the World Learns. McGraw Hill, New York, NY, 2008, 238 pages.Christensen CM, Horn MB, Johnson CW. Crossing the Finish Line: Completing College at America's Public Universities. Princeton University Press, Princeton, NJ, 2009, 389 pages.Bowen WG, Chingos MM, McPherson MS. Who You Know: Unlocking Innovations that Expand Students' Networks. Jossey-Bass, San Francisco, CA, 2018, 180 pages.Fisher JF, Fisher D. Disruptive Class: How Disruptive Innovation Will Change the Way the World Learns,” take Christensen's earlier ideas on business disruptive innovation and expand on them in the context of education reform. Christensen, a brilliant teacher at Harvard Business School, along with a pair of coauthors, takes a stab at identifying ways to improve education research. Giving Schools the Right Structure to Innovate, the last chapter in the book, needs updating, especially in light of the explosive growth of distance learning in response to the COVID-19 pandemic early in 2020. Currently, the world seems overwhelmed with mandates to teach K-12 students at home in front of computer screens and make that equivalent to the traditional in-classroom experience. It is a time when we need our great thinkers hard at work to create education schemas that employ novel methods and leverage communication technologies to overcome physical location and bring students together in ways that improve their educational experience and outcomes. Sadly, Harvard Business School Professor Clayton Christensen died on January 23, 2020, at age 67. He will be missed as one of original thinkers in the business innovation arena, and beyond.Clayton M. Christensen, Michael B. Horn, and Curtis W. Johnson, in “Crossing the Finish Line: Completing College at America's Public Universities” is a sobering discussion of the challenges facing state universities in the United States. The ambivalence of state legislatures toward funding their state universities is a significant societal challenge.William G. Bowen, Matthew M. Chingos, and Michael S. McPherson's “Who You Know: Unlocking Innovations that Expand Students' Networks,” authored by Julia F. Fisher with Daniel Fisher, highlights the importance of engagement and networking in many human activities. The 16-page introduction to the book was authored by Clayton Christensen. The critical student needs for learning, referred to as soft skills, including networking skills, are becoming targets of interest and concern among educators. Are networking skills sacrificed in distance learning activities? Should explicit training in soft skills be added to the curriculums of health profession schools? Is it important to learn how to network with influential people? At what grade levels in the education curriculum should attention be directed at teaching of networking skills? Are teachers in the current workforce prepared and up to the task?Finally, the book, “They Made America: From the Steam Engine to the Search Engine: Two Centuries of Innovators. Little, Brown and Company, New York, NY, 2004, 496 pages.Evans H. Rise of the Robots: Technology and the Threat of a Jobless Future. Basic Books, New York, NY, 2015, 334 pages.Ford M. Our Robots, Ourselves: Robotics and the Myths of Autonomy. Viking, New York, NY, 2015, 360 pages.Mindell DA. Deep Medicine: How Artificial Intelligence Can Make Healthcare Human Again. Basic Books, New York, NY, 2019, 378 pages.Topol E. Human Compatible: Artificial Intelligence and the Problem of Control. Viking Press, New York, NY, 2019, 336 pages.Russell S. Rise of Robots: Technology and the Threat of a Jobless Future” provides a vision of what impact robots could have on the job market. David A. Mindell's “Our Robots, Ourselves: Robotics and the Myths of Autonomy” questions the impact of robots on society in the future. Eric Topol's “Deep Medicine” pictures health care systems becoming highly influenced by the intrusion of AI and deep learning, even overarching influences on health care delivery sometime in the future. Stuart Russell's “Human Compatible: Artificial intelligence and the Problem of Control” explains the risks to humanity of increasingly powerful AI programs over time. Is there a point at which AI becomes the master of us all?Harold Evans's highly readable anthology shows how emerging technologies can drive the creation of new industrial revolutions and their social transformations. Currently, we are witnessing astonishing advances in computer science, robotics, AI, and automation as major drivers of transformation in society across many business sectors. Martin Ford's “Deep Medicine” provides an enlightened description of Topol's personal, virtual multiyear tour of the AI and deep learning industries. He has a keen eye for detail and succeeds in weaving together a coherent picture of a future health care industry emerging from the integration of hundreds of AI-enabled apps that are under construction today. The final chapter, entitled “Deep Empathy,” seems heartfelt and highly personal. It is inspiring to have a practicing doctor this engaged in computer-based medicine while, apparently, retaining loyalty to his roots as a traditional hands-on physician. Dr. Topol remembers where he came from.“Deep Medicine” describes how medical care could positively develop in a technology-enabled world, as seen through the eyes of an optimist. Topol describes his transformative vision for the medical practice environment of the future, one in which doctors are freed up from their back-office menial tasks  and personally return to pure caring for patients. Hopefully, medical science and medical humanities would undergo what sounds a lot like what is called convergent evolution. There, different species begin to look alike from their cohabitation in a shared environment.The final chapter in “Deep Medicine” (Chapter 13), entitled “Deep Empathy,” first. We would like medical students to have empathy foremost in their minds as they do a deep dive into AI. In Dr. Topol's last chapter, he describes what medical practice could look like when the thousands of computer-enabled individual components of the health care delivery system become interconnected into a single, interconnected digital landscape that would free up doctors' time and become an enabler for the practice of truly patient-centric health care once again. Hopefully, some of that happens!Dr. Topol is eminently qualified as a candidate for the title of “Modern-day Sir William Osler,” as both an empathic physician and an accomplished medical scientist. We recommend that medical students read Dr. Topol's last chapter in “Five Patients: The Hospital Explained. Alfred A. Knopf, New York, NY, 1970, 239 pages.Crichton M. History of Telemedicine: Evolution, Context, and Transformation. Mary Ann Liebert, Inc., Publishers, New Rochelle, NY, 2009, 415 pages.Bashshur RL, Shannon GW. A Century of Telemedicine. Jordanova Publisher, Donetsk, Ukraine, 2016, 341 pages.Vladzymyrskyy A, Jordanova M, Lievens F. Atlas of the Telemedicine History. Jordanova Publisher, Donetsk, Ukraine, 2013, 72 pages.Dumanskyy YV, Vladzymyrskyy A, Lobas VM, Lievens F. Introduction to Telemedicine, 2nd edition, CRC Press, Boca Raton, FL, 2017, 197 pages.Wootton R, Craig J, Patterson V. Understanding Telehealth. McGraw-Hill, New York, NY, 2018, 305 pages.Rheuban KS, Krupinski EA. Telepsychiatry and Health Technologies: A Guide for Mental Health Professionals. American Psychiatric Association Publishing, Arlington, VA, 2018, 381 pages.Yellowlees P, Shore JH. Five Patients: The Hospital Explained” is the book in which HMS senior student Crichton tracked five patients he encountered at the MGH, including one telemedicine patient. The book became a popular success and was an alternative book club selection. Crichton's book provides a rare first-person account of a Harvard medical student's initial exposure to several then-futuristic medical innovations, including computer-enabled, automated patient history taking and telemedicine , during his own medical school 4th-year clinical rotations. This was in the late 1960s, a half century ago. Crichton left medicine upon graduation from HMS. He never practiced medicine, but went on to become a famous science fiction writer and movie director. Nevertheless, Crichton retained his interest in progress in medical science throughout his life.In 1969, Michael Crichton, MD, the author of Andromeda Strain, and future author of Jurassic Park, was the first Harvard Medical School (HMS) medical student to rotate through the Logan International Airport–Massachusetts General Hospital (MGH) Medical Station telemedicine program and write a book chapter about it. His first nonfiction book “Five Patients: The Hospital Explained” book, Crichton recounts his telemedicine patient encounter with a Logan Airport traveler, as a medical student stationed 2.7 miles away in the MGH Telediagnosis Center on the first floor of the White Building on the MGH campus, in remarkable detail. Crichton's telemedicine patient, Mrs. Sylvia Thompson, was a passenger flying from Los Angeles to Boston when she developed chest pain while in the air over Ohio flying east. Upon landing, she walked to the Logan Airport MGH Medical Station walk-in clinic near Gate 23 and was examined in the Teleconsultation Room at the Medical Station by a telephysician located at the MGH 2.7 miles away. At the end of her telemedicine physical examination, Mrs. Thompson exclaimed, “My goodness. It was just like the real thing.” Her immortal words, uttered at the Logan Airport walk-in clinic, were likely repeated by millions of new telemedicine patients a half century later during the COVID-19 public health emergency as health care providers rushed to utilize telemedicine as a means to continue providing health care to their patients while leveraging telemedicine's inherent social distancing to mitigate the spread of COVID-19.In his “Following the rendering of her provisional diagnosis of pneumonia by a telephysician at the MGH in Boston, Mrs. Thompson was transported to the MGH for X-rays and treated for pneumonia following confirmation of her diagnosis by X-ray examination. It is interesting that television microscopy, the forerunner to modern telepathology, was available at the Logan Airport MGH Medical Station from the start of their telemedicine program in April 1968. Teleradiology became available at the MGH Medical Station over a year later. A decade of prior experience by television microscopy research investigators had validated the video microscopy technology. Television microscopy was ready for immediate implementation in clinical practice.Five Patients,” it is likely that Crichton, the soon-to-be best-selling science fiction writer Michael Crichton, had extracted nuggets of sophisticated information from a series of personal interviews with leading, senior faculty members at the MGH and at MIT across the Charles River from the MGH campus. It is likely that some of these high-profile interviews had been arranged by Dr. John H. Knowles, the General Director at the MGH. Crichton, already a legendary summa cum laude graduate from Harvard College, whose reputation as a brilliant undergraduate student preceded him at HMS, had the instincts of an investigative reporter, which he had acquired from his journalist father at a young age. The younger Crichton had published his first article, one on travel, in the New York Times at age 14, and as a physically imposing 26-year-old, Crichton cut an extraordinary figure.Crichton expands on his medical student telemedicine patient experience with a remarkably insightful consideration of a series of futuristic medical service innovations that would leverage leading-edge technologies, including private telecommunications networks, telemedicine, computers, and even AI. Based upon his acknowledgments in his book “As a footnote to history, Weinstein, the coauthor of this article, and Michael Crichton were contemporaries at the MGH during their training. Although Weinstein was four academic grades ahead of Crichton, they were MGH trainees at overlapping periods of time in the late 1960s (1968–1969). Weinstein vividly remembers seeing the towering, 6-foot 9-inch Michael Crichton strolling through the MGH corridors accompanied by a relatively young, and equally charismatic, 5-foot 8-inch MGH General Director, John H. Knowles, MD. Dr. Knowles was an early proponent for telemedicine. Crichton and Knowles were seen either walking together or having lunch in the MGH employee cafeteria many times. Weinstein recalls seeing them engrossed in serious discussions: an HMS medical student and the youthful hospital director, Crichton and Knowles, a Socratic pairing always acting out in public, face-to-face, despite their striking differences in physical stature. They were a memorable pair to observe in person, even at a distance. High energy appeared to flow naturally between the two of them.History of Telemedicine” is the product of meticulous scholarship by a pair of accomplished historians who display a special talent for explaining the complex interrelationships between people, events, and technologies. Bashshur is more than a historian. He has been professionally immersed in telemedicine since the 1960s, arguably longer than almost anyone else alive today. He has chronicled major events in the field in real-time, up close and personal, while authoring a significant part of the analytical literature on many facets of this complex health care delivery field with a “who's who in the field” panel of collaborators. Bashshur and Shannon's particular interest in public policy is reflected in their insightful descriptions of societal influences on the jerky progression of the implementation of telemedicine, particularly in North America, over half a century. The recent surge in COVID-19 pandemic-related, telemedicine case activity becomes understandable in terms of the decades-long deadweight influences of policy on earlier efforts by an army of workers to implement telemedicine and take it to scale.Rashid L. Bashshur and Gary W. Shannon's “The first half of the book is a detailed recounting of the adaptations of groundbreaking technical innovations for uses of telemedicine in health care, dating back literally to the Trojan War. Much of the more recent history is told against the backdrop of the birth and expansion of a new nation. The descriptions of innumerable events and activities are often riveting and even majestic. There is great precision to the story telling, which adds to its credibility. Bashshur and Shannon shift gears in the second half of the book by focusing the second half of the book on the modern era of telemedicine in the United States (1950–2009) and, to a greater extent than in the first half of their book, on the influences of public policy on telemedicine adoption and expansion. They carefully select model programs to illustrate specific points, such as roles for government in creating successful telemedicine programs.History of Telemedicine” is its under-reporting of telemedicine studies published in foreign language journals. Sponsorship of the book by the US National Library of Medicine may have played a role in limiting the scope of the book. It is noteworthy that there is a wealth of telemedicine and telehealth information in many foreign language journals. This is published in abundance in publications of the International Society of Telemedicine and Telehealth. Their publication reference citations and titles are dual published in the foreign language of origin and also in English translations.A limitation of Bashshur and Shannon's “A Century of Telemedicine: Curatio Sine Distantia et Tempora,” edited by Anton Vladzymyrskyy, Malina Jordanova, and Frank Lievens and published in 2016. This book is more of a survey than a history, and it is quite narrowly focused on technologies. The book's six chapters' titles include telecommunications, videoconferencing, telecardiology, biotelemetry, computational telediagnosis, and satellite technologies. Although titled in two languages, the detailed text is written entirely in English.For a greater international perspective on the development of telemedicine around the world, check out “Century of Telemedicine” is profusely illustrated. It is fun to see page after page of thumb-nail sized pictures illuminating many surprises, not the least of which is how many other countries have had telemedicine-related developments for decades. Unlike Bashshur and Shannon's “History of Telemedicine,” there is barely any description of national health care systems, societal priorities, or telemedicine applications that have gone mainstream. We now know that was by design since “Century of Telemedicine” has been followed up with a three-volume set of books specifically on over a dozen individual national telemedicine programs (see below). This tends to debunk the popular US notion that “telemedicine started here!”“Century of Telemedicine” also includes an extensive interesting Appendix  listing short bibliographies for historic participants in telemedicine programs. Included are descriptions and photographs for a large sampling of participants in telemedicine from the United States and Canada. Coverage is uneven and the criteria for inclusion are not stated. There are many obvious omissions.“Century of Telemedicine” is a product of the International Society for Telemedicine and Telehealth (ISfT). ISfT was officially founded in 1997 after several failed starts at several international meetings. The ISfT was officially registered in Basel, Switzerland, in 1997, with its Coordinating Office presently in Belgium.“Dr. Weinstein, coauthor of this article, delivered the opening lecture at the “First International Conference on the Medical Aspects of Telemedicine,” held in Tromsø, Norway, in May 1993. This is where the seed was planted for ISfT. Dr. Weinstein gave the opening keynote address at the Tromsø Conference, on the topic, “Telemedicine in the United States.” The Conference Chair acknowledged Dr. Weinstein's invention of robotic telepathology in 1986 and its successful implementation in northern Norway, above the Arctic Circle, 3 years later. Because of this, Dr. Weinstein was well known in the European pathology community. His invention had been successfully implemented by Tromsø University Hospital pathologists as an enabling telemedicine technology that supported intraoperative frozen section diagnosis at Kirkenes Hospital, 400 km to the east. This was over a two-way E1 2 megabit per second landline, the European version of a US carrier T1 1.5 megabit per second landline.ISfT was renamed the International Society for Telemedicine and eHealth (ISfTeH) in 2005. Today, there are 90 countries participating in ISfTeH. The organization has robust education and publication programs. Its publications are authoritative and of generally high quality.A Century of Telemedicine” book now serves as an introductory book for a set of ISfTeH-endorsed books covering telemedicine programs in individual countries. The three books in this new series provide detailed descriptions of telemedicine programs in 16 countries: Book 1 ; Book 2 ; and Book 3 . The chapter on the United States in Book 2 is telenurse oriented and may disappoint physicians. Generally, comparisons of the telemedicine programs in individual countries, by the reader, might show how different national and cultural points of view influence countries' development and implementation of telemedicine and telehealth services. Each country has its own attitudes toward the well-being of its citizens. This can be reflected in the structures and functions of their telemedicine programs. However, such comparisons are somewhat complicated by the diversity of professions of the authors of the chapters . It would be helpful of ISfTeH to add a fourth book to the series, authored by a panel of experts assigned the task of analyzing the chapters describing telemedicine and telehealth in 16 individual countries and of identifying and discussing common threads. This ISfTeH global telemedicine book series calls out for analyses, and discussion, by authorities with a broad international perspective.In retrospect, the original “Atlas of the Telemedicine History,” published in 2013, contains many rare historical photos of early telemedicine pioneers and their programs from, literally, around the world. This is an outstanding, historical picture gallery.A fifth ISfTeH-endorsed telemedicine book is a special gem. This 72-page “1PDFs for these ISfTeH-promoted books are available, for free, at the ISfTeH webpage.Currently, there is a crescendo of interest in potential telemedicine and telehealth textbooks, worldwide. In the United States, schools, ranging from community and undergraduate colleges to a wide range of graduate schools, will be offering telehealth courses this year for the first time. The COVID-19 pandemic appears to be functioning as an innovation accelerator in the distance education industry.Due to the COVID-19 pandemic, in the United States, telemedicine caseloads in medical practices have increased at astronomical rates, not infrequently exceeding 3,000–6,000% for many medical practices in the United States. The vast majority of US practitioners had no telemedicine in their medical school training. Many office practices went from zero telemedicine cases to 1,000s of telemedicine cases per month in a matter of a month or two.The Association of American Medical Colleges, which oversees medical student education in the United States, has announced an urgent need to generate core competencies for medical students in virtual care, telemedicine, and telehealth. Other categories of health care profession schools have overlapping needs. A race is on to identify telehealth textbooks best suited to address trainees' needs. Potential contenders, already on the market, are worth mentioning.Introduction to Telemedicine” was published in 2017. The book's 17 contributors are drawn from five different countries on three continents. This reflects R. Wootton's extraordinary reach as an international authority on telemedicine. The second edition of Wootton's “Introduction to Telemedicine” lends itself to being a quick read for medical students or even practicing physicians who are exploring telemedicine for the first time. One drawback to using Wootton's “Introduction to Telemedicine” is that many of the pictures and figures are holdovers from the first edition and need updating.Richard Wootton, John Craig, and Victor Patterson's second edition of their “Introduction to Telemedicine,” published by RMS Press, was designed to serve as a general introduction for what became a seven-book series of specialty telemedicine books. His “Introduction to Telemedicine” can be used either as a stand-alone textbook for an introductory telemedicine course or in combination with Wootton's advanced topic textbooks for multisemester courses. The introductory medical specialty books in Wootton's seven-book collection cover specific telemedicine applications, including telepsychiatry, telepediatrics, teleneurology, and teledermatology, quite well, but need updating.Wootton's “Understanding Telehealth,” edited by Karen S. Rheuban and Elizabeth A. Krupinski, was a major event for the telemedicine and telehealth industry. For the sake of disclosure, Dr. Krupinski and Dr. Weinstein have been colleagues and close collaborators since 1992.The publication of “Understanding Telehealth” consists of 24 chapters, authored by 46 experts in the telemedicine field. Telehealth, per se, which is inclusive of telemedicine, is well represented. Chapter titles range from “Telehealth in Pediatric Cardiology” to “Legal and Regulatory Issues.” Despite their breadth of subject matter coverage, individual chapters are remarkably uniform with respect to the breadth of coverage of individual topics and their readability.That being said, Rheuban and Krupinski's book is brilliantly conceived and masterfully executed by any measure. “Understanding Telehealth” seamlessly kernels in what amounts to select up-to-date microreviews on a broad range of current topics of interest.In addition to providing essential foundational information for a broad swath of health care workers new to telemedicine, Rheuban and Krupinski's “Understanding Telehealth” is highly recommended for a broad spectrum of learners and professionals, including nonmedical staff, medical, nursing, and pharmacy students, residents, medical practitioners, public health officials, and C-suite health care executives, seeking updates on the issues of the day. “Understanding Telehealth” might not be a suitable textbook for a college Gen Ed course or an introductory course in an allied health profession curriculum.“Understanding Telehealth” is the telemedicine reference book of choice for our staff members at the Arizona Telemedicine Program. In addition, in our experience, some sophisticated patients and their advocates might find sections of the book worth reading. Finally, one can imagine that healthcare portfolio managers at financial institutions would be interested in diving into “Understanding Telehealth” with their eyes wide open. There is a great deal of information they will find worth mining in light of so many investment opportunities in telemedicine and telehealth these days! Outstanding nonfiction books such as this can generate large readerships.Currently, “Telepsychiatry and Health Technologies: A Guide for Mental Health Professionals.” Book collectors do get to fantasize and, occasionally, dreams do come true. Although marketed as a telepsychiatry book, which it is, much of the information in “Telepsychiatry and Health Technologies: A Guide for Mental Health Professionals” is not psychiatry specific and could be of value to students planning careers in nearly every sector of the health care industry. In general, according to our analysis of the book, nonpsychiatry information in the book could be carved out and repackaged as a general textbook on telemedicine and telehealth that could be outstanding. That might be of great immediate use to faculties at US medical schools, and undergraduate colleges, which are in urgent need of a high quality, US-centric, general telemedicine textbook because of the COVID-19 pandemic. We can see how a revised, generalized, and shortened version of “Telepsychiatry and Health Technologies: A Guide for Mental Health Professionals” could fit that bill.My ideal telemedicine and telehealth textbook for undergraduate college students remains to be written. Frankly, if I had access to a suggestion box, this textbook would be a generalized version of Peter Yellowlees and Jay H Shore's “It is noteworthy that Yellowlees and Shore's strategy of developing their model textbook is clearly stated on the first page of their preface. This could be replicated by others willing to take the time to do so. Instead of giving recruited authors free reign in selecting their designated chapter's subject matter and then simply assembling their chapters, as is often the case, Yellowlees and Shore “initially mapped out the book down to the section headings…and then selected colleagues to write the various sections of the book based on their individual expertise and knowledge.” There it is! That is the way to do it. Their product is an excellent textbook for a course on telemedicine, created by master educators and executed in partnership with a team of carefully selected high-quality scholar educators willing to follow their coeditor's directions. For the medical reader, telepsychiatry becomes a metaphor for a broad spectrum of medical specialties.The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Health Care. Basic Books, New York, NY, 2011, 320 pages.Topol E. The Patient Will See You Now: The Future of Medicine is in Your Hands. Basic Books, New York, NY, 2015, 374 pages.Topol E. The Digital Doctor: Hope, Hype, and Harm at the Dawn of Medicine's Computer Age. McGraw Hill, New York, NY, 2015, 330 pages.Wachter R. Digital Medicine. Springer International Publishing, New York, NY, 2018, 115 pages.André A. The Digital Doctor” discusses the possibilities for progress in a digital age from the perspective of a medical practice leader deeply embedded as a practicing physician in San Francisco. “Digital Medicine,” edited by Arthur André, gives a French-flavored update on digital medicine. Chapters focus on AI, big data applications, blockchain, regenerative medicine, and telemedicine. Dr. André is an enlightened neurosurgeon practicing in Paris, France.What is the future digital health care ecosystem once the current wave of innovations in digital technologies is in full blossom? What might the health care system look like? Where are we if, and when, the traditional doctor–patient relationship, which has provided the backbone for health care systems (as we knew them for past centuries), is a thing of the past? Robert Wachter's “Dissemination and Implementation Research in Health: Translating Science to Practice. Oxford University Press, New York, NY, 2018, 515 pages.Brownson RC, Colditz GA, Proctor EK. Advancing the Science of Implementation across the Cancer Continuum. Oxford University Press, New York, NY, 2019, 409 pages.Chambers DA, Vinson CA, Norton WE, eds. Dissemination and Implementation Research in Health” and David A. Chambers, Cynthia A. Vinson, and Wynne E. Norton's “Advancing the Science of Implementation across the Cancer Continuum” are two recently published books on dissemination and implementation research, both published by Oxford University Press. Brownson et al.'s book was the first of its kind: a practical textbook on dissemination and implementation research. Both books rapidly became required reading in the clinical dissemination and implementation of research in the health care field. These books are essential reading for clinical investigators and students interested in carrying out US federally funded intervention studies. They are also suitable for use as classroom textbooks on “how to do it.”Ross C. Brownson, Graham A. Colditz, and Enola K. Proctor's “Dissemination and Implementation Research in Health: Translating Science to Practice,” is inclusive and covers a broad spectrum of topics ranging from introductory terminology and the historical roots of dissemination and implementation research to dissemination and implementation research in a global context. There are 29 multiauthor chapters. Discussions of complex issues are presented in easy-to-understand language. This is noteworthy in light of the interdisciplinary nature of their target audiences.The book, “Advancing the Science of Implementation across the Cancer Continuum” can be viewed as an extension of Brownson et al.'s “Dissemination and Implementation Research in Health.” In addition to reiterating, and expanding on, introductory material in Brownson et al.'s “Dissemination and Implementation Research in Health” and expanding on certain topics, such as the history of NIH funding for dissemination and implementation research (see page 18), Chambers et al.'s book focuses on a single disease entity, cancer, and includes a series of chapters describing 19 highly informative case studies. These case studies will be of general interest.Chambers et al.'s “We hope that publication of this important pair of Oxford University Press books, by top authorities in the dissemination and implementation research fields, will increase the visibility of dissemination and implementation research and help catalyze a further expansion of funding for dissemination and implementation research by governmental agencies and foundations. Leaders in academic medicine would do well to read these books themselves and jump on board as advocates for this often undervalued component of health care transformation processes.The Great Influenza: The Story of the Deadliest Pandemic in History. Penguin Books, New York, NY, 2004, 546 pages.Barry JM. Deadliest Enemy: Our War Against Killer Germs. Little, Brown Spark, New York, NY, 2020, 314 pages.Osterholm MT, Olshaker M. The COVID-19 pandemic could turn out to be an innovation accelerator of historic proportions. Expect a flood of books on innovations resulting from the COVID-19 pandemic in the foreseeable future.The Great Influenza: The Story of the Deadliest Pandemic in History,” published in 2004, and Michael T. Osterholm and Mark Olshaker's “Deadliest Enemy: Our War Against Killer Germs,” published in 2017, with an updated foreword in 2020.To help prepare for reading the COVID-19 pandemic-related literature, two outstanding books are John M. Barry's “Deadliest Enemy: Our War Against Killer Germs,” Osterholm and Olshaker describe how nations can prepare for a pandemic and avert disastrous population outcomes by sticking to scientific-based reasoning. Their message is that health care catastrophes are preventable, but scientific discovery is an essential component of the process.Barry recounts the development of scientific theories and their importance in creating new diagnostic technologies and cures in the early 20th century. Newer scientific theories became foundational for the evolution of modern medicine. In “Ronald S. Weinstein, MD, FCAP, FATA, is an MGH-trained pathologist. He is the Founding Director of the Arizona Telemedicine Program and a President Emeritus of the American Telemedicine Association. He invented, patented, and commercialized telepathology and introduced the term “telepathology” into the English language.Mr. Michael Holcomb, BS, is the Associate Director for Information Technology in the statewide Arizona Telemedicine Program. He lectures on telemedicine technology and information security. Mr. Holcomb and Dr. Weinstein have coauthored dozens of articles together.


GCK) gene.To determine the pathogenic gene and explore the clinical characteristics of maturity-onset diabetes of the young type 2 (MODY2) pedigree caused by a mutation in the glucokinase (Using whole-exome sequencing (WES), the pathogenic gene was detected in the proband—a 20-year-old young man who was accidentally found with hyperglycemia, no ketosis tendency, and a family history of diabetes. The family members of the proband were examined. In addition, relevant clinical data were obtained and genomic DNA from peripheral blood was obtained. Pathologic variants of the candidate were verified by Sanger sequencing technology, and cosegregation tests were conducted among other family members and non-related healthy controls. After adjusting the treatment plan based on the results of genetic testing, changes in biochemical parameters, such as blood glucose levels and HAblc levels were determined.GCK gene (NM_000162) in exon 9, a heterozygous missense mutation c.1160C > T  was found in the proband, his father, uncle, and grandmother. Thus mutation, which was found to co-segregate with diabetes, was the first discovery of such a mutation in the Asian population. After stopping hypoglycemic drug treatment, good glycemic control was achieved with diet and exercise therapy.In the GCK gene mutation c.1160C > T  is the pathogenic gene in the GCK-MODY pedigree. Formulating an optimized and personalized treatment strategy can reduce unnecessary excessive medical treatment and adverse drug reactions, and maintain a good HbA1c compliance rate KCNJ11, ABCC8, INS, GCK, IPF1, PTF1A, GLIS3, FOX3, EIF2AK3, GLUT2, HNF1A, HNF1B, HNF4A, and PAX4  is a genetically heterogeneous type of monogenic diabetes mellitus that is characterized by autosomal dominant inheritance, an early age at onset, and pancreatic β-cell dysfunction . MODY isand PAX4 –9. AmongDY cases . Moreoveectively . In the GCK gene present with mild, stable hyperglycemia from birth, are mostly treated by diet alone and rarely suffer from diabetic complications  can improve molecular diagnostics of monogenic diabetes, thus genetic testing has important implications for MODY . In our All subjects completed questionnaires regarding medical and family history, and information was supplemented by information from medical records. Diagnosis and the classification of diabetes complied with the latest guidelines presented by the American Diabetes Association (ADA) . This stClinical data were obtained from all patients suspected of MODY, and 5ml of fasting blood was collected using EDTA for anticoagulation purposes. According to the manufacturer’s instructions, a DNA Extraction Kit  was used to isolate genomic DNA of peripheral blood obtained from the MODY family. For high-throughput sequencing, the SureSelect Human All Exon V5 kit  was used for sample preparation and pretreatment, and samples underwent WES using the Illumina HiSeq 2500 sequencing platform.The sequence was aligned with the human genome reference sequence , compared, and the SNPs (Single Nucleotide Polymorphism) and InDels (Insertion-Deletion) variants were obtained after alignment with publicly available databases , dbSNP, ESP (NHLBI Exome Sequencing Project), and gnomAD (Genome Aggregation Database)). For mutations that were not detected in the database, further analysis of the impact that mutation on changes in the genetic code is required to distinguish between synonymous mutations and missense mutations. Next, several silico prediction tools  were used to predict the influence of identified nonsynonymous mutations on protein structure and function.It is known that high-throughput sequencing has a certain rate of mismeasurement. Therefore, Sanger sequencing should be performed in the proband and his family to verify variants identified by next generation sequencing. Polymerase chain reaction (PCR) amplification of target gene fragments: Primer design: Based on the location of the mutation in the target gene, primers were designed at the genome-wide level. Primer synthesis: completed by Beijing Kinco Biotechnology Co., Ltd. Target gene amplification: the target gene was amplified using Golden Mix (green) Golden Star T6 Super PCR Mix (1.1×) from Beijing Kinco Biotechnology Co., Ltd. . Subsequently, the amplified product was subjected to agarose gel electrophoresis, and the target band as cut out of the gel and recovered using a DNA gel imager. The PCR product fragments were sequenced as follows: After the PCR product was tapped, recovered, and purified, the product was sequenced using an ABI3730XL Automatic Sequencer . The sequencing results were compared and analyzed with genome sequences that were downloaded from the Genebank database (using AutoAssembler 2.0 software).http://web.expasy.org/docs/swiss-prot_guideline.html) was used to simulate the three-dimensional (3D) structure of the protein sequence of the GCK gene bearing a missense mutation.The Swiss-Prot repository (via monitoring blood glucose levels of each subject (at least one blood glucose measurement per day) and by rechecking HbA1c levels.Based on the genetic testing results and related literature reports, the patient’s medication plan was adjusted in a timely manner. Glycemic control was assessed Baseline characteristics of the study subjects are displayed in Exome Capture Statistics are shown in GCK gene co-segregated with diabetes. The mutation was located on chromosome 7, position 44185189, c.1160C>T, NM_000162, p.Ala387Val, namely rs193921338. The p.Ala387Val mutation was analyzed for evolutionary conservation, which showed that the mutation was located in a highly conserved region among multiple animal species (http://exac.broadinstitute.org/), the variant was categorized as a rare change with a mutation frequency of 0.00001145. In addition, in this database, the mutation was classified as likely pathogenic. Therefore, based on the findings described above and the clinical condition of this family, this rare missense mutation was considered a disease-causing mutation.To identify key biological functions in the family of the proband, variants were filtered according to their genome site location, allele frequency, and functional consequences, excluding intronic and nonsense variants. Mutation sites are presented in Homology models of the tertiary protein structure of wild-type and p.Ala387Val GCK proteins were predicted by Swiss-Prot   . In the rvention , 32. Thirvention . In our GCK gene in a total of 1441 families . Data analysis showed that the mutation involved a rare change with a mutation frequency of 0.00001145 of which the variant was predicted to be likely pathogenic. Recent evidence has suggested that the coding region in which the mutation is located is a highly conserved region in many species. The mutation can cause changes in protein structure and affect protein stability, thereby affecting functional changes. Therefore, we have reason to believe that the GCK gene is the disease-causing gene in this diabetes family, and the pathogenic mutation site is rs193921338, which was first discovered in the Chinese population. For GCK-MODY, correct molecular genetic diagnosis is critical  or cardiovascular disease  later in life. Interestingly, these complications are relatively mild and did not significantly increase their mortality.So far, 620 types of mutations have been identified in the families , 35, andcritical . Young pe future . These f> T p.Ala7Val. DatGCK-MODY family with a mutation in exon 9 of the GCK gene c.1160C > T , which, according to our knowledge, was the first time to be detected in the Chinese population. For this GCK-MODY family, exercise and diet were sufficient as a therapeutic approach. The underlying molecular mechanism of action of GCK gene c.1160C > T  participation in diabetes remains to be elucidated and future prospective investigations are warranted.In conclusion, for patients with a high clinical suspicion of MODY, a definite diagnosis should be made through genetic testing. Correct diagnosis helps patients to choose a personal treatment plan and avoid overtreatment. In our study, we reported a The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: NCBI SRA: PRJNA744432.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.Conceived and designed the experiments: JL and HZ. Performed the experiments: JL, XW, AD, CW, JW, SJ, and HZ. Analyzed the data: JL and MS. Wrote the paper: MS and JL. JL and MS contributed equally. All authors contributed to the article and approved the submitted version.This study was supported by Grants from the National Natural Science Foundation of China , Grants from the Health and Family Planning Commission of Wuhan City (Grant Number WX18M02).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation with the authors at time of review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.