The purpose of this study was to evaluate the outcomes of bifocal bone transport in the treatment of femoral bone defects caused by infections.Clinical and radiographic data of patients with infected femoral nonunion treated by the bifocal bone transport at our hospital were analyzed retrospectively, from January 2008 to December 2019. Depending on the location of bone defects, the patients were divided into three groups . The Association for the Study and Application of the Method of Ilizarov (ASAMI) criteria was applied to assess the bone and functional outcomes. Postoperative complications of three groups were documented and compared.Seventy-six cases of infected femoral bone defects  were managed by bifocal bone transport successfully with a mean follow-up time of 30.8 months . There were 58 men (76.3%) and 18 women (23.6%), with a mean age of 38.8 years . The bone union was received in 76 cases with a mean of 6.9 months . Pin tract infection was observed in twenty-nine cases (38.1%), 7 cases (9.2%) of muscle contractures, 3 cases (7.9%) of joint stiffness, 13 cases (17.1%) of axial deviation, 2 cases (2.6%) of delayed union, one case (1.3%) of nonunion, and none (0%) of transport gap re-fracture. One patient (1.3%) was scheduled for knee arthroplasty when bone transport treatment ended.Bone transport using an external rail fixator was a practical method to treat the femoral bone defects, since the satisfactory rate of bone union and limb function recovery. Complications of distal femoral bone transport were more severe than the proximal and intermedia, but the rate of complication was the least of the three groups. Soft-tissue-related complications were more likely to occur in the intermediate bone transport. Femoral bone defects caused by the infection have still been a tricky problem for orthopedic surgeons, which is commonly brought out by open fracture and chronic osteomyelitis –5. Soft For above, the purpose of this study was to evaluate the efficacy of bifocal bone transport in the treatment of femoral defects caused by infection, and the complications of different locations’ bone transport were compared for avoiding the potential risks.After receiving the written informed consent from participants and approval from our hospital’s Ethics Committee, the medical records and radiographs were evaluated retrospectively of all patients whose infected femoral bone defect treated by single-level bone transport using a unilateral external rail fixator , from January 2008 to December 2019. Inclusion criteria were as follows: femoral bone defect caused by infection; sinus tract or abscess of affected limbs; positive intraoperative culture or histology supporting a deep infection; bifocal bone transport for the reconstruction of the bone defect. Patients were excluded for those younger than 18 years old, incomplete medical records, poor compliance, or follow-up time less than twenty months.The demographic data, initial injury, previous surgical and medical treatment, comorbidities, antimicrobial utilization, biopsy, or culture results of secretions were documented. In physical examinations, the range of motion (ROM) of the hip and knee and condition of soft tissues were evaluated. The index of inflammatory was recorded, such as C-reactive protein (CRP), white blood cell (WBC), procalcitonin, and erythrocyte sedimentation rate (ESR). Cierny and Mader’s (CM) classification evaluated the degree of bone infection. The sensitive antibiotics were given to all patients intravenously for 2 weeks depending on the bacteria isolated. If no bacteria were isolated, intravenous antibiotic prophylaxis with a second-generation cephalosporin  was given at least 6 weeks before surgery and 1 week after surgery.Patients were positioned supine on the radiolucent table, and spinal anesthesia was performed. Firstly, the affected limb’s necrotic bone and soft tissue were removed until the residual bone showed evidence of punctate cortical hemorrhage (paprika sign). The infected biopsies and cultures were collected during the surgical procedure. The surgical area was flushed with 0.9% saline under low pressure. The gloves of all participating surgeons and surgical instruments were replaced. Antibiotic-impregnated cement spacer  equal in length to the bone defect was then filled into the defect to receive a high level of local antibiotic concentrations. Afterward, External fixators were placed on the proximal and distal femur in an anterolateral position parallel to the respective joint. Three 4.5-mm-diameter Schanz screws were inserted at the fragment of the proximal and distal femur, and two same Schanz screws were inserted at the transport bone fragment under the guidance of the intraoperative radiography machine. Simultaneously, the desired femoral length and alignment were maintained. These screws were angled at right angles to the anatomical axis of the femur. After the external fixator sliding clamps were assembled and the external frame debugged to parallel to the axis of the femur, the minimally invasive osteotomy was performed by Gigli saw. Depending on the size of the skin loss, the direct suturing under appropriate tension, local propulsive skin flap, or vascularized free flap was utilized to cover it. Removal of the spacer was conducted when the infection was under control, which could be determined by laboratory parameters such as WBC, CRP, and ESR.Distraction osteogenesis was conducted under the guidance of a senior orthopaedic surgeon at the 6 postoperative days, with a velocity of 0.5 mm/12 h, twice per day. Weight-bearing walking was encouraged for patients throughout the stage of distraction. The pin tract care was instructed to the patients to prevent the pin tract infection, such as washing the pin tract daily using a swab with 0.9% saline. Subsequently, radiography, WBC, ESR, and CRP were examined at 1, 3, 6, 9, 12, 18, and 24 months after bone transport. Bone grafting at the docking site was recommended to prevent docking site nonunion when the distraction stage ended.Patients who met the inclusion criteria were followed by the postoperative questionnaires routinely using the smartphone after discharge. Artificially, the femur was divided into three parts equally according to the anatomical length of the femur, namely, the proximal, intermediate, and distal. The Association for the Study and Application of the Method of Ilizarov (ASAMI) criteria was applied to assess the bone and functional results. The incidence and distribution of complications in different locations’ femoral bone transport were compared.p < 0.05.Data were input in a Microsoft Excel spreadsheet , reported as frequencies and percentages, and then analyzed by the SPSS 20.0 software package . One-way ANOVA was used to compare quantitative variables of three groups . The chi-square test conducted comparisons of the excellent and good rate of bone and functional outcomes. Statistical significance was p = 0.105), gender (p = 0.647), obesity , smoking (p = 0.318), antibiotics utilization (p = 0.529), mode of fracture (p = 0.683), and duration of osteomyelitis (p = 0.298).Seventy-six patients who met the criteria were included in this study between January 2008 to December 2019. There were 58 men (76.3%) and 18 women (23.6%), with a mean age of 38.8 years . Seventy-six femoral defects  caused by infection were managed for bifocal bone transport using a unilateral external rail fixator, with a mean postoperative follow-up time of 30.8 months (23 to 41 months) (Table p = 0.002) and EFT (p < 0.001) in Table Infection was eradicated in all patients, and the total bone union was received in 76 of 76 cases 100%), with a mean bone union time (BUT) of 6.9 months . The mean external fixation time (EFT) was 11.8 months , and the external fixation index (EFI) was 1.71 months/cm . There was statistical significance among the BUT  and successfully treated by dressing change combined with culture-sensitive oral antibiotics. Besides, there were 7 cases (9.2%) of muscle contractures, 3 cases (7.9%) of joint stiffness, 13 cases (17.1%) of axial deviation, 2 cases 2.6%) of delayed union, one case (1.3%) of nonunion, and none (0%) of transport gap re-fracture Table . Axial d% of delaThis study aimed to collect and assess the postoperative results and distribution of complications related to bone transport using a unilateral external rail fixator in treating femoral bone defects caused by an infection in our hospital from January 2008 to December 2019. Radical debridement combined with antibiotic spacer was necessary to ensure an infection-free limb. Bone transport using an external rail fixator was a pragmatic method to reconstruct the femoral defects and resolve the limb deformity, such as shortening, angular, sclerosis, and muscle atrophy caused by the initial injury. In this study, the rate of total bone union was 100%, and the per-patient complication was 0.82. The excellent and good rate of bone and function of the proximal group was better than the others. Pin tract infection, muscle contracture, axial deviation, and soft tissue incarceration were more likely to occur in the intermediate group, and the distal group was at high risk of joint stiffness, delayed union, or nonunion.It’s generally recognized that the defect and deformity can be resolved simultaneously by the bone transport using an external fixator, allowing the patient to utilize the limb function earlier to prevent joint stiffness or arthritis –4, 17, HThe high density of muscles, blood vessels, and soft tissue are distributed around the femur, especially the proximal, which facilitates bone regeneration and mineralization , 3, 23. The autogenous bone grafting at the docking site was recommended to perform when the distraction stage finished , 25–27. Pin tract infection (38.1%) cannot be ignored, which occurred in the intermediate group and the proximal group mostly , 29, 30.Via published articles , 34, 35,Last, several limitations were in this study, which was associated with its retrospective and single-center design nature. First of all, there is no mature algorithm for the resolution of complications in different bone transport locations of the femur. In addition, prospective case series with infected femoral nonunion treated by bone transport were rare. Therefore, a prospective multi-center study of large samples is crucial for clinical guidance.Pin tract infection, axial deviation remains the most common complication using unilateral external fixation. Complications of the distal site in femoral bone transport were more critical than other sites, but the rate was the least. The incidence of complications in the proximal group was comparable to the intermediate group. Soft-tissue-related complications  were more likely to occur in the intermediate bone transport. The bone healing and functional outcomes were affected directly by these complications in the period of bone transport. It’s essential to understand the incidence and distribution of complications at femoral different locations to formulate targeted measures to deal with postoperative complications.


In vivo cis-trans isomerization reaction is catalyzed by Peptidyl-prolyl isomerase (PPIases), a category of proteins widely distributed among all the three domains of life. The present study is majorly focused on the distribution of different types of PPIases in the archaeal domain. All the three hitherto known families of PPIases  were studied to identify the evolutionary conservation across the phylum archaea. The basic function of cyclophilin, FKBP and parvulin has been conserved whereas the sequence alignment suggested variations in each clade. The conserved residues within the predicted motif of each family are unique. The available protein structures of different PPIase across various domains were aligned to ascertain the structural variation in the catalytic site. The structural alignment of native PPIase proteins among various groups suggested that the apo-protein may have variable conformations but when bound to their specific inhibitors, they attain similar active site configuration. This is the first study of its kind which explores the distribution of archaeal PPIases, along with detailed structural and functional analysis of each type of PPIase found in archaea.Cis-trans isomerization of the peptide bond prior to proline is an intrinsically slow process but plays an essential role in protein folding.  FKBP12 gene is induced in Polytrichastrum alpinum by heat ABA, drought and salt stress. Overexpression of PaFKBP12 in Arabidopsis increased the plant size, which induced the cell cycle and showed a better growth and survival as compared to wild type variety. Apart from role of PPIase in stress conditions of plants they also help in regulation of other cell process in various organisms. C. elegans is normally grown at temperatures between 16°C and 25°C. When the worms are exposed to a low temperature (10°C), the expression level of parvulin increases, the increased expression of Pin-4 indicates a possible role in the worm’s adaptation at lower temperature. Hence, PPIases are expected to play important role in and organisms adaptation to extreme conditions.Peptidyl-prolyl isomerase are known to be involved in protein folding Halobacterium cutirubrum cyclophilin was the only functionally characterized cyclophilin until recently. The biophysical and biochemical characterization of cyclophilin protein from archaeal organism Methanobrevibacter ruminantium was recently reported  and short-type FKBP from Methanococcus jannaschii (PDBID: 3PR9) was used as a seed sequence (Cenarchaeum symbiosum (PDBID: 2RQS) was used as a seed sequence  . MEGA 6.To predict the conservation of amino acid residues in each PPIase family, which may be functionally important MEME (Multiple Expectation-maximization for Motif Elicitation) server was used . This seAll the PDB structures and fasta sequences available for cyclophilin, FKBP and parvulin were retrieved from RCSB PDB. There is high redundancy in retrieved PDB entries so to filter out the data; CD-hit at 100% sequence identity was performed. After CD-hit, phylogenetic tree was constructed using MEGA 6.0 to analyze how native and substrate/inhibitor bound structures relate to each other in every group. From the phylogenetic tree, cluster which has native and substrate/inhibitor bound structure from same group were selected for the study as they could help in better decipherment of changes in native vs substrate or inhibitor bound structures.There is no significant report till now about the distribution of archaeal PPIases in the archaeal kingdom. In eukaryotes and bacterial organisms, multiple copies of cyclophilin are present but no such information is available for archaeal cyclophilin. In archaea, two types of FKBP’s are reported but their relative distribution among archaea from different phyla has not been studied. So, the current study focused on the distribution and occurrence of homologs of different PPIase families in archaea.Hundred ninety-six Genomes were selected for the current study. The 196 archaeal genomes were further classified into phylum, class and order .From the constructed database of predicted proteomes of 196 archaeal organisms a total of 122 cyclophilin homologs were identified. From the above sequences it was observed that some cyclophilins were present as multi domain protein and pro-isomerase superfamily domain was found at the N-terminus. After the data curation only 106 sequences of cyclophilin were included in further analysis. On classification of these sequences, it was observed that out of these 106 sequences 91 cyclophilin sequences are derived from 84 organisms of Euryarchaeota and 15 are derived from organism of Thaumarchaeota .Candidatus caldiarchaeum subterraneum organism of phylum Thaumarchaeota.Several orders of Euryarchaeota i.e., Aciduliprofundum, Archaeoglobales, Nanohaloarchaea, Methanopyrales, and Thermococcales completely lack the cyclophilin gene . All orgTotal of 325 archaeal FKBP sequences were extracted from 196 archaeal genomes. It was observed that phylum Euryarchaeota has maximum number of FKBP’s belonging to both long-type and short-type. In 136 genomes of phylum Euryarchaeota, there are about 10 classes and 15 orders, having 264 homologs of FKBP. Hence, it can be assumed that this phylum has maximum diversity in number of FKBP’s homologs present in each organism. It was observed that order Aciduliprofundum, Archaeoglobales, Methanomassiliicoccales, Thermoplasmatales, Methanobacteriales, Methanopyrales, Nanohaloarchaea has single copy of long-type FKBP with no short-type FKBP in their proteomes . Some ofPhylum Crenarchaeota constitutes 41 genomes distributed in class Thermoprotei with its five orders. These 41 genomes have single copy of long type FKBP and complete absence of short-type FKBP . Phylum Candidatus Methanomassiliicoccus intestinalis and Methanogenic archaeon ISO4-H5). This distribution shows that parvulin is absent in rest of the phyla.Total 30 parvulin homologs were found in 196 archaeal organisms . In phylFrom the phylogenetic tree of the 106 cyclophilin protein sequences, it was evident that the proteins are separated into two main branches. One branch forms the largest cluster which includes cyclophilin homologs from class Halobacteria and second branch has three sub clusters, one having cyclophilins from class Thermoplasmata along with homologs from class Methanomicrobia, second having cyclophilin members from class Methanococci along with homologs from phylum Thaumarchaeota. The third cluster of this branch contains the homologs from class Methanobacteria and Methanomicrobia . The booMethanothermococcus thermolithotrophicus (whole genome sequence is not annotated)], as it is the only biochemically and genetically characterized organism from archaea  lying in Thaumarchaeota clade  respectively, whereas the rest are for the native structure. On analyzing the distribution of cyclophilin among bacteria, mammals, plants, viruses, yeast, fungi, nematodes and protozoa it was found that total 14, 16, 6, 2, 1, 12, 11, and 20 structures are reported, respectively, from each group of organisms. Only a single structure is reported from archaea, as the hypothetical protein with cyclophilin like fold from DSM 4304 .Total of 294 structures of FKBP proteins from various organisms are deposited in RCSB PDB. Among them 124, 46, 18, 18, 13, 8, 5, 5, 1, and 56 structures belong to human, bacteria, fungi, protozoa, animal, plants, archaea, insects, and nematode, respectively, whereas structures of 56 Chimeric proteins are also included. Out of these available structures 119 are in native form, 3 and 89 are structures of FKBP protein bound to substrate and inhibitor, respectively .In parvulin, total 71 structures have been reported in RCBS PDB. Among them 54, 8, 5, 3, 1 belongs to human, bacteria, protozoa, archaea and plant, respectively. Parvulin is a class of PPIase which is inhibited by juglone. In human out of 54 structures, 9 are native, 29 and 1 are inhibitor and substrate bound, respectively, while 15 structures are reported with mutation. The parvulin structures belonging to bacteria, archaea, protozoa and plants are reported only in their native form with no inhibitor or substrate bound structures have been reported yet .45, F50, V51, and Q53 that are known to be a part of the active site region. Motif M3 “GXGGXGY” is observed in the mid-region of the sequence. The observed motif appears to be variable in archaeal cyclophilins with only the glycine amino acid is being highly conserved in all the archaeal organisms. Human cyclophilins isoforms had revealed that the substrate binding region of each protein has two pockets namely i.e., S1 and S2 pockets. S1 pocket is shown to be specific for recognizing the proline (P1) residue of the substrate, whereas the S2 pocket creates space for interactions with the substrate residues P2 or P3. Motif M4 contains two highly conserved residues, M87 and A88, latter being part of the S1 cavity. Motif M5 has the conserved C-terminal motif “GSQFFI” having F100, H108, L109 residues that are known to participate in the formation of S1 cavity of the protein  and a highly conserved mixture of hydrophobic, aromatic, and polar residues including Phe60, Met61, Gln63, Ala101, Phe113, Trp121, Leu122, and His126. The basic residues, R55 and H126, are clearly involved in catalytic acceleration. The structure of hCyPA bound to tetrapeptide  shows thOn comparing the active site residues of human cyclophilin with orthologs from other organisms, it was observed that orientation of arginine residue at position 55 varies in all the group. In case of cyclophilins from the nematode there is a slight variation at position 60 and 121 , 5.The effect of inhibitor binding on the cavity in each class was also studied. It was observed that there is no significant difference in the cavity region after binding with inhibitor , 7.15, F25, D26  it was observed that there is variation in orientation of following residues; Y57/Y135, F67/F146, D68/D146, V86/V171, Y113/Y99, while at F77 is replaced by a different residue L162 in FKBP25 , 10.On comparison of animal and plant with FKBP52, it was observed that there are orientation differences in two substrate binding sites; D37/D48 and E54/E65 (highly conserved residue). F46 in animal as compared to F77 in FKBP52 has different orientation in animal and in plants phenylalanine is replaced by leucine. The above observation shows that substrate binding sites residues are same but there is difference in the orientation of the amino acid residues.On comparison of human FKBP25 with bacteria and fungi, it was observed that there is a difference in orientation of many catalytic residues; Y135 FKBP25/Y13 bacteria/I60 fungi, D146 FKBP25/D123 bacteria/D41 fungi, I172 FKBP25/I37 bacteria/I60, A195 FKBP25/A62 bacteria/A96fungi and Y196 FKBP25/Y63 bacteria/Y97 fungi. When F145, V171 in FKBP25 is compared with fungi and bacteria it was observed that there is a difference in the orientation of amino acid residue at position F40, V59 in fungi while it is replaced by a different amino acid L15, L36, respectively, in bacteria. Tryptophan in FKBP25 (W175) is an important active site residue but in bacteria it is replaced by L40 while in rest of the domain this residue remains conserved .When inhibitor binds to its FKBP52 and 25, it was observed that there are no significant changes in the orientation of active sites residues. Comparison of orientation of active site residues after binding of inhibitor it was observed that all the domains attain an ordered conformation as FKBP52 and FKBP25 , 12.9, D41, M59, F63, F83, and H86  and parvulin-like human peptidyl-prolyl cis/trans isomerase (hPar). In Pin1, substrate binding pocket is hydrophobic in nature and mainly formed by F134, M130, L122 amino acid residues. It is reported that PPIase activity is majorly performed by following residues C113, H59, H157, S154 and basic amino acid residues  are responsible for catalytic selectivity of substrate and inhibitor binding  it was observed that same active site amino acid residues  have different orientation and this could be responsible for the catalytic selectivity of both the protein against substrate and inhibitor .The effect of inhibitor binding on the cavity in human Pin1 was also studied. It was observed that there is no significant difference in the cavity region after binding with inhibitor as compared to native Pin1 .E. coli are reported to exert their function mainly through chaperone like activity  can be found in the article/VK, Anchal, and MG planned the whole study, analyzed the data, and wrote the manuscript. VK and Anchal compiled the work. 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.


Genitourinary syndrome of menopause (GSM) involves vaginal dryness (VD), pain during sexual activity (SAPain), vaginal itching (VI), burning, pain, and symptoms in the urinary organs. Non-ablative radiofrequency (RF) is a type of current with electromagnetic waves with a thermal effect that generates an acute inflammatory process with consequent neocolagenesis and neoelastogenesis. We aimed to describe the clinical response to VD, SAPain, vaginal laxity (VL), VI, burning sensation, pain in the vaginal opening, urinary incontinence, sexual dysfunction, cytological changes, and adverse effects of non-ablative RF in patients with GSM.This single-arm pilot study included 11 women diagnosed with GSM with established menopause. Patients with hormone replacement initiation for six months, who used a pacemaker, or had metals in the pelvic region, were excluded. Subjective measures  and objective measures  were used. A Likert scale measures the degree of satisfaction with the treatment. Five sessions of monopolar non-ablative RF (41°C) were performed with an interval of one week between each application. The entire evaluation was performed before treatment (T0), one month (T1), and three months (T2) after treatment. Adverse effects were assessed during treatment and at T1 and T2.The symptoms and/or signs were reduced after treatment in most patients : VD 90.9%/81.8%, SAPain 83.3%/66.7, VL 100%/100%, VI 100%/100%, burning 75%/87.5%, pain 75%/75%, and VHI 90.9%/81.9%. Most patients did not show changes in VMI (54.5%) and pH (63.6%) at T1, but there was an improvement in VMI in most patients (54.5%) at T2. Nine patients were satisfied, and two were very satisfied at T1. The treatment was well tolerated, and no adverse effects were observed. There was an improvement in sexual function (72.7%) and urinary function (66.7% in T1 and 83.3% in T2).Intravaginal RF reduced the clinical symptoms of GSM in most patients, especially during T1, and women reported satisfaction with treatment. The technique showed no adverse effects, and there were positive effects on sexual and urinary function.Trial registration This research was registered at clinicaltrial.gov (NCT03506594) and complete registration date was posted on April 24, 2018. Genitourinary syndrome of menopause (GSM) is traditionally defined as a set of signs and symptoms due to altered estrogen production, both physiologically or as a result of a therapeutic approach. It involves physical and sensory changes in the external and internal genitalia and lower urinary tract region, such as loss of collagen and elastin, altered smooth muscle cell function, reduction in the number of blood vessels, and an increase in connective tissue, leading to epithelial thinning, decreased blood flow, and reduced elasticity . Women mGSM treatment aims to alleviate symptoms and reverse atrophic anatomical changes. Hormonal therapy is the current gold standard treatment that can be administered systemically or locally , 5, 6. HWith the contraindications and limitations of standard therapy for GSM, a search for new therapeutic options for GSM management is needed. Radiofrequency (RF), a new alternative technique for GSM , is a hiBased on the knowledge of the physiological responses of the tissues submitted to RF and on the results of its use on the treatment of genitourinary signs and symptoms related to GSM, this research aimed to describe the clinical response , vaginal itching (VI), burning sensation, pain in the vaginal opening, UI, and sexual dysfunction), cytological changes, and adverse effects of non-ablative RF in patients with GSM.This was a single-arm pilot study preceding a randomized controlled trial (RCT) in progress, followed the precepts of the Declaration of Helsinki, with the approval of the Ethics and Research Committee of the Bahiana School of Medicine and Health (EBMSP) with CAAE 72147317.9.0000.5544 on September 5, 2017, and registered at clinicaltrial.gov (NCT03506594) and complete registration date (first date posted) on April 24, 2018. Written informed consent was obtained from all patients.Adult women with established menopause  and who had complaints of at least one of the symptoms of GSM  participated in the study. The women were referred by gynecology services, and the service took place at the teaching outpatient clinic of the Physiotherapy Clinic at EBMSP. For inclusion in the study, they should have a vaginal pH of ≥ 5 and vaginal cytology from the last 12 months, or three previous normal tests, without any malignancy and/or atypia. We excluded patients with hormone replacement initiation for six months, who used a pacemaker, or had metals in the pelvic region, hemophiliacs, using vasodilators and/or anticoagulants, and those with chronic neurological degenerative diseases and/or diagnosis of current vaginal infection.Numeric Rating Scale (NRS), which consists of a scale from 0 to 10 points, with 0 indicating no symptoms and 10 indicating as many symptoms as possible.Initially, we administered a basic anamnesis questionnaire for collecting sociodemographic and clinical data. Each participant subjectively assessed their symptoms  using the vaginal health index (VHI), which consists of a graduated scale from 1 to 5 for each item . Vaginal elasticity varies between 1 (no elasticity) and 5 (excellent elasticity), assessed through mucosal distention upon palpation and in the placement of the speculum. Fluid volume, assessed at inspection, varies between 1 (no secretion) and 5  (white flocculent). Epithelium integrity varies between 1  and 5 . Moisture varies between 1 (no moisture detected in the inspection and presence of an inflamed mucosa) and up to 5 . The pH was quantified using a pH indicator strip between 0 and 14 (MColorpHast™—pH-indicator strips) which was placed directly on the right lateral vaginal wall for one minute, giving 1 point for the pH of 6.1, and 5 for the pH ≤ 4.6, in which the last one was considered normal. The sum of all items represents the vaginal health score, with 25 representing the best vaginal health [The physical examination was to assess the l health .Vaginal Maturation Index (VMI) was evaluated from a vaginal secretion collection, in the middle third of the vaginal canal, fixed in absolute alcohol and sent to a laboratory, in which a biomedical doctor performed the percentage counting of the parabasal (P), intermediate (I), and superficial (S) cells, characterizing the vaginal epithelium in hypotrophic (I > S), normotrophic (I = S), hypertrophic (I < S), mild atrophic (I > P), moderate atrophic (I >  = P) and marked atrophic (I < P). The sum of the three cell types totals 100% and is presented as follows: P/I/S [The s: P/I/S .Female Sexual Function Index (FSFI) [Sexual Quotient-Female Version (QS-F) assessed women’s sexual activity. This questionnaire was developed and validated in 2006, specifically for the Brazilian population [Participants answered the x (FSFI)  questionpulation . ThroughInternational Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) [To assess the impact of UI on quality of life and characterize urinary loss, we used the ICIQ-SF) , composeAt the end of the treatment, the participants were asked about their degree of satisfaction with the treatment using a five-point Likert scale, which classified the patient's level of satisfaction as 1 (very dissatisfied), 2 (dissatisfied), 3 (unchanged), 4 (satisfied), 5 (very satisfied) .To assess the clinical response, we considered an improvement when there was a decrease in values in self-reported symptoms, verified by the NRS; the increase in the value of the VHI; the decrease in parabasal cells (deep) and/or increase in superficial cells evaluated by VMI, a decrease in vaginal pH, an increase in FSFI and QS-F scores, a decrease in the sum of the ICIQ-SF questions, and improved satisfaction according to the five-point Likert scale.We used all outcome measures before, one month, and three months after the end of treatment, respectively, times T0, T1, and T2, performed by the same initial evaluators.To test safety, we considered existing adverse effects if they had erythema, ulcers, fistulas, burns, blisters, bleeding, and/or pain. They were evaluated during each application at T1, T2, or at any contact by the patients’ self-reports. We considered it to be at risk if it had one or more of these effects. If an adverse effect occurs, the patient was referred for evaluation and treatment by the team’s gynecologist. The RF treatment would be interrupted, and the data are presented in the results.RF was used in the form of capacitive electrical transfer, monopolar configuration , which has two electrodes: an intracavitary active electrode placed in the vagina with a non-lubricated condom and water-soluble gel and another electrode, dispersive, positioned in the lumbosacral region Fig. . For theFor the elaboration of the database, we used the software Statistical Package for Social Sciences (SPSS), version 14.0 for Windows. The results were reported descriptively in the text or through tables and graphs; categorical variables are expressed as absolute and percentage values—n (%), and continuous variables with normal distribution in mean and standard deviation (± SD), and those with asymmetric distribution in the median and interquartile range (IQ).The sample consisted of 11 patients with GSM, with an average age of 59.6 ± 3.93 years, with data collected from October 2017 to August 2018. Table We observed the clinical improvement of GSM in the NRS scores of the symptoms of VD, SAPain, VL, VI, burning, and vaginal pain, as shown in Table Ten patients (90.9%) showed an increase in the VHI score in T1, which represents an improvement, and one worsened (patient five). Regarding pre-treatment, in T2, nine patients (81.8%) had an increase in VHI, while two (18.2%) had a reduction in this index during the initial value Table .Table 3VIn T1, most patients 7–63.6%) did not change, three (27.3%) showed a decrease in pH, representing improvement, and one (9.1%) showed an increase. In T2, there was also a predominance of maintaining baseline values  remained unchanged in the cell count, and five (45.5%) showed an improvement in T1, with two patients of the latter changing their category from moderate or severe atrophic to mild atrophic. In T2, six patients (54.5%) showed improvement compared to the beginning, three 27.3%) remained at the beginning, and two (18.2%) worsened. One patient maintained the category of severe atrophy, and the other went from hypotrophic to severe atrophy  had sexual dysfunction at T0. Ten (90.9%) and seven (63.6%) patients improved their scores at T1 and T2 respectively, compared to the beginning. We observed worsening of the two periods evaluated in Patient 11  in T1, with three patients without sexual dysfunction. In T2, eight patients (72.7%) had improved compared to the beginning, but half had a decrease compared to T1, and two continued without sexual dysfunction. According to the atients 6.6% had sIn this study, six patients had pre-treatment urinary complaints. When assessing the impact of UI on quality of life (QoL) using the ICIQ-SF questionnaire, we found a decrease in the score in four patients (66.7%) in T1, one of whom had no symptoms; two 33.3%) increased the score and one who had no symptoms started to complain (patient nine). In T2, almost all patients (five—83.3%) had an improvement in the beginning, in which two had their symptoms disappeared, and two had a higher score than the initial one  reported being satisfied and two (18.2%) were very satisfied at T1. In T2, nine patients (81.8%) remained satisfied, one (9.1%) very satisfied, and one (9.1%) very dissatisfied Fig. . The patWe did not observe erythema, ulcers, fistulas, blisters, burns, bleeding, and/or pain at any time during treatment or follow-up. The treatment was well tolerated. One patient reported a little discomfort in the lower abdominal region during the first two sessions, which ceased in the third application.We found an improvement in genitourinary symptoms such as VD, SAPain, VL, VI, burning sensation, pain in the vaginal opening, UI, and sexual dysfunction in most patients, especially in T1, in this pilot study that used non-ablative RF in postmenopausal women with GSM. The application of RF was considered safe because only one light adverse effect in one patient was found up to T2. To our knowledge, this is the first study to assess symptoms of GSM associated with cytological analysis and patient satisfaction after using non-drug and non-ablative treatment with intracavitary monopolar RF.VD was the main symptom reported by patients in this study and showed an important improvement when assessed by both self-report and by VHI. Based on the histological changes observed in previous studies, the process of neocolagenesis and neoelastogenesis that occurs after exposure to controlled RF thermal energy in the vaginal tissue restores most vaginal functions such as secretion, absorption, elasticity, lubrication, and tissue consistency, which are decreased in GSM , 19, 20.VD can generate or contribute to SAPain, just as abstinence from intimate relationships is involved in the decline of lubrication, often forming a cycle. Vaginal trophism is fundamental for a comfortable sexual intercourse, which depends on the lubrication promoted by vasodilation of the lamina propria and the vaginal epithelium , 23. In Other studies have also found positive results for SAPain. Alinsod (2015) studied RF with controlled temperature (TTCRF) with intra- and extra-vaginal application in six menopausal women and 10 in the peri-menopausal period with SAPain symptoms, demonstrating the safety and beneficial effects of the treatment . An RCT RF has also been widely used to improve collagen levels. Its diathermic effects cause the collagen denaturation. As the temperature rises, some of the cross-links are broken, causing the triple helix to unwind. Thus, there is a consequent activation of fibroblasts, with subsequent neocolagenesis, neoelastogenesis, and tissue remodeling . Coad etPrevious studies have obtained positive results with the use of monopolar RF with cryogenic surface cooling in pre-menopausal women with a history of at least one vaginal delivery and complaints of vulvovaginal atrophy/symptoms of GSM or VL , 29. AliSymptoms such as VI, burning, and pain are common complaints in GSM. Hypoestrogenia results in reduced number of epithelial layers and vessels, thinning of smooth muscles , and an The analysis of vaginal cytology through the VMI and the measurement of pH are well-used measures to establish diagnostic parameters of GSM , 37, butTwo patients presented with worsening VMI, which may have happened at random, because it is a small sample or due to the aging process. This change could be better controlled by an RCT. In the literature, there is no evaluation made of the agreement between evaluators of the VMI, which is a dependent evaluation instrument.GSM has adverse effects on sexual function and general well-being. The FSFI is an instrument used worldwide to assess sexual function. In this study, it improved in most of the samples in T1 (81.8%) and T2 (72.7%). Patients were also evaluated using QS-F, a questionnaire specifically developed for the Brazilian population . In termRF is considered one of the most innovative non-surgical modalities for treating UI and VL . In addiTreatment satisfaction was assessed using a five-point Likert Scale, with most patients reporting satisfaction with treatment. This was reinforced by the decrease in symptoms recorded in that study. On the other hand, we observed that although most of the outcome measures have improved, the indication of patient satisfaction was greater, showing that the degree of satisfaction do not always correspond to the clinical results. Thus, satisfaction is not only linked to the therapeutic result, but also to the level of expectations of the people involved. It is important to consider the Hawthorne effect, which states that when individuals believe they are experiencing a form of treatment, they are more likely to respond and be satisfied with therapeutic responses . In thisOur safety analysis showed that the technique was well tolerated by patients and no side effects were observed or reported. In one patient, only mild discomfort was noted in the first two sessions. Also in the study by Lalij and Lozanova (2017), using intravaginal and extracavitary radiofrequency, no side effects were reported . In thisAlthough some of the patients continued to show improvement in their symptoms in T2, some symptoms were accentuated in that period. Studying the frequency of reapplication after the end of treatment to maintain clinical improvement is essential in future studies, especially since we already have evidence from histological studies  that show that the peak of RF action occurs within 21 days after its application .This is a pioneer research on the application of intracavitary non-ablative radiofrequency (RF), in women with Genitourinary Syndrome of Menopause (GSM). The study combines clinical symptoms of GSM, including sexual and urinary functions, with cytological results, patient satisfaction and treatment outcomes.As it is a non-medicated pharmacological approach, applied locally, it opens up a new field for the treatment of this syndrome. In addition to being a new field for physiotherapy professionals.As limitations of the study, we found a short follow-up time, the use of independent symptom outcome measures  for symptoms associated with a syndrome, the use of evaluator dependent indices (VHI and VMI) and a subjective index (VHI).Based on these limitations, we understand the need to create a specific rating scale for GSM symptoms, intra- and inter-rating comparisons for rater-dependent scales for longer follow-up period and, since intracavitary non-ablative RF has been proven safe, the realization of an RCT.The symptoms of VD, SAPain, VL, VI, burning sensation, pain in the vaginal opening, UI, and sexual dysfunction of GSM with non-ablative RF showed clinical improvement in most of the patients, with improvement in the self-report of the symptoms and the VHI, especially at T1. The cytological analysis, through the VMI, remained unchanged in most evaluations in T1, but there was a greater improvement in T2. There was no change in vaginal pH in most patients after RF treatment. There was no adverse effect in the 11 patients evaluated, which is considered a safe and well-tolerated technique, and patients reported satisfaction with treatment.


For patients with early gastric cancer (EGC), a good prognosis is achieved by conventional standard gastrectomy with radical lymphadenectomy. However, postgastrectomy syndrome is often inevitable and results in decreased quality of life (QOL). To improve patients’ QOL, proximal gastrectomy instead of total gastrectomy and pylorus-preserving gastrectomy instead of distal gastrectomy have been widely accepted as function-preserving gastrectomies. Recently, personalized, minimized gastrectomy with sentinel node navigation surgery has been developed and is expected to be an ideal treatment option for patients with EGC. Herein, we review the indications, surgical techniques, and postoperative outcomes of function-preserving gastrectomy.Recently, minimally invasive (endoscopic or laparoscopic) treatment for early gastric cancer (EGC) has been widely accepted. However, a standard gastrectomy with radical lymphadenectomy is generally performed in patients with EGC who have no indications for endoscopic resection, and postgastrectomy dysfunction is one of the problems of standard gastrectomy. Function-preserving gastrectomy, such as proximal gastrectomy and pylorus-preserving gastrectomy, can be considered when attempting to preserve the patient’s quality of life (QOL) postoperatively. In addition, sentinel node navigation surgery for EGC has been applied in clinical practice in several prospective studies on function-preserving personalized minimized gastrectomy. In the near future, the sentinel lymph node concept is expected to form the basis for establishing an ideal, personalized, minimally invasive function-preserving treatment for patients with EGC, which will improve their postoperative QOL without compromising their long-term survival. In this review article, we summarize the current status, surgical techniques, and postoperative outcomes of function-preserving gastrectomy for EGC. Recently, minimally invasive approaches, such as endoscopic treatment or laparoscopic gastrectomy (including robot-assisted surgery), for early gastric cancer (EGC) have gained wide application in clinical practice . HoweverA systematic literature search of the PubMed database was carried out until August 2021. The search was limited to studies published in English. The search terms were as follows: “gastric cancer or gastric neoplasm” and “pylorus-preserving or pylorus preserving” or “function-preserving or function preserving” or “proximal gastrectomy” or “sentinel node or sentinel lymph node” or “local resection or local gastrectomy.”The inclusion criteria for the evaluation of postoperative weight change were as follows: (1) studies of patients with pathologically confirmed gastric cancer, (2) comparisons of PG to TG, (3) comparisons of PPG to DG, (4) studies of patients who underwent local resection of the stomach, and (5) the revealed adequate data of postoperative weight changes. Exclusion criteria were as follows: (1) overlapping publications or duplicated data and (2) reviews, case reports, comments, and conference abstracts.The incidence of proximal gastric cancer has increased in recent years ,6. PreviPG is performed in patients diagnosed preoperatively with cT1N0M0 primary gastric cancer in the upper third of the stomach and whose remnant stomach is more than half the original size . This inPatients who underwent PG had a good prognosis with a 5-year overall survival rate of 94–97%, and some observational studies showed no difference in the recurrence and long-term survival rates associated with PG when compared with TG ,9. In paAlthough retrospective observational studies on PG for gastric cancer have been conducted, the level of evidence is generally not strong because there are no prospective randomized trials comparing the outcomes of PG with those of other surgical procedures involving TG ,13,14,15D1 lymph node dissection includes lymph node station Nos. 1, 2, 3a, 4sa, 4sb, and 7; station Nos. 8a, 9, and 11p are included in D1+ lymphadenectomy [In PG, the rate of complications, such as reflux esophagitis and anastomotic stenosis, was markedly higher compared with TG ,17,18,19EG is considered a simple, physiological reconstruction method because there is only one anastomotic site; however, the frequency of postoperative reflux esophagitis may be high. In recent years, good outcomes from novel reconstruction methods, such as EG with fundoplication ,16, the Reconstruction methods using the jejunum, such as JI and DT, are also used to reduce gastroesophageal reflux. JI is a more physiological reconstruction method that uses the jejunum in form; however, it is slightly complicated. In the era of laparoscopic surgery, the frequency of JI has decreased due to its complexity, and DT, which is easier to perform laparoscopically, has become more common ,29. DT iPG has several advantages over TG in patients with proximal EGC, including surgical outcomes and long-term nutritional status ,12,17,18The incidence of complications after PG, such as anastomotic leakage, bleeding, and pancreatic fistula, is considered the same as after TG, except for anastomotic stenosis and reflux esophagitis ,17,18,19A multicenter study using the Postgastrectomy Syndrome Assessment Scale-45 (PGSAS-45) to investigate postoperative long-term QOL, reported that PG was better than TG in terms of needing additional meals, experiencing diarrhea, and dumping symptoms .PPG is a surgical procedure for EGC located in the middle third of the stomach; it is generally thought to offer several advantages over DG with Billroth I reconstruction, especially in the incidence of dumping symptoms and bile reflux gastritis.PPG is a type of function-preserving gastrectomy for EGC (without lymph node metastasis) located in the middle third of the stomach when the distance between the distal tumor border and pylorus exceeds 4 cm ,38,39,40In PPG, there are concerns that in a bid to preserve the pyloric cuff, the dissection of lymph nodes in stations 5 and 6 is inadequate. However, it was reported that the possibility of micrometastasis to the lymph nodes in stations 5 and 6 might be negligible for EGC located in the middle portion of the stomach ,42. It wThe 5-year overall survival rate of PPG was reported to range from 96.3% to 98.0%. ,40,44. AAll studies comparing the outcomes of PPG to those of DG are observational, except for one multicenter prospective randomized trial with a small sample size , and theD1 lymph node dissection includes lymph node station Nos. 1, 3, 4sb, 4d, 6, and 7; station Nos. 8a and 9 are included in D1+ lymphadenectomy, according to the Japanese Gastric Cancer Treatment Guidelines , and theIn PPG, the length of the pyloric cuff is also important to prevent pyloric dysfunction. It was reported that preserving a 2.5 cm pyloric cuff was associated with a lower incidence of postoperative stasis than a 1.5 cm cuff, which might reduce gastric wall motility due to severe postoperative edema of the pyloric cuff . SeveralFor gastro-gastro anastomosis after PPG, hand-sewn anastomosis, especially layer-to-layer anastomosis, is the most widely used technique ,51. EvenPPG has several advantages over DG for patients with EGC in the middle third of the stomach, including surgical outcomes and long-term nutritional status ,51,54,55The cumulative incidence of gallstones was also reported to be lower in PPG than in DG . The preThe length of the pyloric cuff is as described in the previous section, but the size of the proximal remnant stomach affects the change in weight and postoperative QOL . This stp = 0.026) [On the other hand, PPG is associated with a long hospital stay, decreased lymph node collection, and delayed gastric emptying . In part= 0.026) . GastricThe SN is the first lymph node to receive lymphatic flow from the primary lesion and is regarded as the first possible node of metastasis . If the A meta-analysis of 2128 patients in 38 studies showed that the detection rate of the SN was 94%, and the accuracy of SN diagnosis was 92% . A prospRecently, the results of a multicenter retrospective cohort study of SN mapping in patients with EGC after ESD were reported . The feaAlthough there are only a few retrospective studies with small sample sizes, the prognosis of patients treated with SNNS has been reported to be good, with a 5-year overall survival rate of 98.0–98.5% ,70,71. SSNNS for patients with EGC is performed as a clinical trial rather than a standard treatment and, thus, is not mentioned in the Japanese Gastric Cancer Treatment Guidelines .The dual-tracer method using both radioactive colloids and blue or green dye is considered the standard procedure in SNNS for patients with EGC ,4. IsosuThe day before surgery, the radioactive colloid solution is endoscopically injected into the submucosal layer around the primary lesion using an endoscopic puncture needle. The ICG solution is also injected in the same manner into the submucosal layer surrounding the primary lesion to function as a tracer during surgery. The lymphatic vessels and lymph nodes are stained green and visualized within 15 min of the injection of the ICG solution. Simultaneously, ICG fluorescence imaging using near-infrared technology, such as VISERA ELITE II  and Firefly of the da Vinci Surgical System , enabled easy visualization . SubsequSN basin dissection is performed according to the results of SN mapping. The gastric lymphatic basin is divided into five directions along the main arteries as follows: the left gastric artery area, including lymph node station Nos. 1, 3a, and 7; the right gastric artery area, including station Nos. 3b, 5, and 8a; the right gastroepiploic artery area, including station Nos. 4d and 6; the left gastroepiploic artery, including station Nos. 4sa and 4sb; and the posterior gastric artery area, including station No. 11p . The harHowever, there are several issues with performing SNNS in clinical practice, including the learning curve, the need for radioisotope equipment and additional staff to identify sentinel nodes on the back table, and the extra load on laboratory technicians and pathologists. Therefore, currently, the implementation of SNNS would be limited to specialized facilities with well-trained surgeons.In cases of laparoscopic LR of the stomach, laparoscopic and endoscopic cooperative surgery (LECS) is useful . HoweverFew studies have assessed the QOL and nutritional status of patients following LR of the stomach with SNNS. According to an assessment using the PGSAS-45, patients who underwent CLEAN-NET with SNNS had better QOL than those who underwent laparoscopic distal gastrectomy (LDG) . It was Ongoing Japanese and Korean trials of SNNS are expected to verify whether limited gastrectomy with SN basin dissection achieves similar oncological outcomes and improves patients’ QOL compared to standard gastrectomy with radical lymphadenectomy for patients with EGC. In the near future, the SN concept is expected to form the basis for establishing an ideal, personalized, minimally invasive function-preserving treatment for patients with EGC that will improve the patients’ postoperative QOL without compromising long-term survival.Function-preserving gastrectomy for patients with EGC appears to help maintain postoperative gastric function and improve patients’ QOL. It is also considered feasible from the perspective of oncological safety. However, most reports that support function-preserving gastrectomy are retrospective cohort studies, and the evidence is insufficient. The indications for function-preserving gastrectomy should be carefully considered to avoid the possibility of inadequate treatment.


Background: Mesh is beneficial in the repair of umbilical hernias. But it may cause chronic pain due to inflammatory reactions, which may impair the patient's quality of life.Objectives: To assess and compare the quality of life of patients following umbilical hernia repair with and without mesh.Methods: During the study period, 45 patients underwent umbilical hernia repair. The study was conducted at King Abdul-Aziz University Hospital (KAUH), KSA. Data were collected using medical records, and each patient was contacted by telephone, to fill the “Carolina Comfort Scale (CCS)” survey. The survey assesses the grade of pain, sensation of mesh, and movement limitation in different situations.Results: A non-significant difference was found between mean quality of life (QOL) scores of mesh and non-mesh groups. The relationship between CCS and gender was not significant in both groups. However, males had significantly higher CCS scores in mesh-treated cases. There was no statistically significant relationship between CCS and comorbidity, nationality, or symptoms. The overall CCS score did not differ statistically between mesh-treated and non-mesh-treated cases. Conclusion: The CCS score did not differ between mesh-treated and non-mesh-treated cases. It is suggested that future multicentric studies with a larger sample size be conducted. An umbilical hernia is defined as a midline abdominal wall defect extending from 3 cm above to 3 cm below the umbilicus, and it is a common adult diagnosis, with a global prevalence of 2% . Hernia Pregnancy, weightlifting, constipation, weight gain, chronic cough, damage from an injury or surgery, and abdominal wall defects  may causMore than 20 million hernias are operated on around the world yearly , and umbThe World Health Organization (WHO) defines the quality of life (QOL) as an individual’s perception of their position in life in the context of the culture and value systems in which they live, in relation to their goals, expectations, standards, and concerns .The California Comfort Scale (CCS) is a 23-item questionnaire that quantifies the severity of pain, mesh sensation, and movement limitation from the hernia or surgical site during the following eight activities: lying down, bending over, sitting up, activities of daily living, coughing or deep breathing, walking, climbing stairs, and exercise ,11.A 1% recurrence rate of large umbilical hernia treated with mesh versus suture repair was found in two retrospective randomized control trials . UmbilicAs the postoperative QOL has become an important outcome measure following herniorrhaphy -11, thisThis cross-sectional study was completed from January 2019 to December 2020 at King Abdul-Aziz University Hospital (KAUH), Jeddah, Saudi Arabia. All adult patients who underwent umbilical hernia repair between January 1, 2019, and December 31, 2020, were included in the study.Ethical approval was obtained from the Unit of Biomedical Ethics Research Committee at King Abdul-Aziz University, Faculty of Medicine (reference no. 443-18). Data were collected using the hospital's electronic medical records, and each patient was contacted by telephone, and after his/her verbal consent, a phone interview was conducted to fill the “Carolina Comfort Scale” survey . The surStatistical analysisAfter checking the data for errors and completeness, all data were given input to SPSS version 24  for analysis. The analysis was performed at a 95% confidence interval. The categorical variables were presented as frequencies and percentages; continuous variables were presented as mean and standard deviation. The mean score for all CCS measuring items was presented. The mean total CCS score was calculated by adding individual CCS items. The mean total CCS was presented and compared between cases with mesh and without mesh, males and females, nationalities, and with comorbidity and without comorbidity groups by Mann-Whitney U test. A non-parametric test was done because the mean total CCS was non-normally distributed. Correlation between age, operation duration, blood loss, and total CCS was done by the Spearman Rank Correlation test. This retrospective chart review study involved a total of 45 cases; 29 (64.4%) were female, and 36 (80%) were Saudi. Of the cases, 40% practiced regular or consistent sports activity. Comorbidity was present in 42.2% of cases. The most common symptom was the feeling of a mass (55.6%). Only four (8.9%) of the cases were smokers. These socio-demographic characteristics for the mesh and non-mesh groups were presented in Table 2. The difference between the mesh group and the non-mesh group in terms of age and BMI was not statistically significantly different .The mean age and BMI of all cases were 49.33 + 13.15 years and 31.81 ± 7.44 kg/mRegarding the surgical procedure in cases with mesh n = 29), 25 (86.2%) had open surgery and elective operation. The commonest mesh used was Parietex composite ventral patch (44.8%), and for 20.7% of patients, the size of the mesh was 10 × 15. Most of the cases did not have any symptoms after one month of the operation (82.8%). In addition, 89.6% did not suffer from any complications  during the post-op follow-up visits. Only 69.0% of the patients suffered from constipation before the surgery, and six patients complained of recurrence 20.7% , respectively. The relationship between CCS and gender was not significant for all cases with and without mesh. But for the mesh group, males had significantly higher CCS of 10.91 ± 14.52 as opposed to females 7.56 ± 11.21 . Weak positive correlations were found between age and BMI (p=0.001), age and operation duration (p=0.022), and BMI and operation duration . This rate is lower than that found in a previous study of 300 patients from 12 Italian hospitals (76.3%) .In the mesh group, 86.2% of patients underwent open surgery and elective surgery. A previous study used the CCS to assess changes in health-related QoL overtime after different mesh hernia repair procedures yielded different results. In the former study, all umbilical hernia repairs were performed laparoscopically . In anotIn the present work, we mostly used absorbable mesh (44.8%). A randomized study was done to compare the effect of non-absorbable tackers (NAT) versus absorbable tackers for laparoscopic incisional and ventral hernia repair (LIVHR). The study discovered that NAT is a cost-effective method of mesh fixation in LIVHR patients, with comparable early and late postoperative outcomes in terms of pain, QOL, and patient satisfaction scores .In this study, we discovered that the majority of cases (79.1%) were repaired electively, while the remaining (20.9%) were repaired as emergency cases. In a previous Saudi study conducted at King Fahd Hospital (KFH), open surgery was used in 89.7% of cases and laparoscopy was used in 10.3%, while mesh was used in 46.3% of all cases . In the After one month of the operation, two patients (6.9%) complained of pain after one month of surgery, two patients (6.9%) complained of pain associated with discomfort, and one patient (3.4%) complained of pain associated with mass. Comparison between the occurrence of postoperative pain between mesh and suture repair during all-time points was done in a previous study. It was revealed that two weeks after the operation, 102 patients (74%) in the suture repair group and 111 patients (76%) in the mesh group were free of pain with no significant difference. After two years, 129 patients (93%) in the suture repair group and 138 patients (95%) in the mesh group were free of pain . AnotherIn terms of QOL among this study's patients, the mean difference between patients with and without mesh was not statistically significant. A different result was revealed in a Danish study, where the CCS scores changed significantly, indicating that health-related QoL gradually improved after four different types of mesh hernia repair over the first three months . AnotherAlthough the overall complication rate in the laparoscopic group is twice that of the open group, and the length of hospital stays and readmission tended to be higher after a laparoscopic repair, our data do not suggest a significant difference in outcome following laparoscopic rather than open repair, umbilical rather than epigastric hernia repair, mesh or no mesh repair. This agrees with the study done in Denmark, where no important difference was found in the outcome results regarding open umbilical and epigastric hernia repair, and mesh or no mesh . HoweverIn 2018, a study demonstrated that laparoscopic umbilical hernia repair results in less operative time, faster postoperative recovery, and a higher QOL than open umbilical hernia repair .The study's findings revealed that the relationship between CCS and gender was not significant for mesh and non-mesh cases. Males, on the other hand, had significantly higher CCS score in the mesh group. This coincides with our results, as looking at CCS, predictors of outcome, and recurrence and reoperation rates during the first postoperative year showed that an event-free recovery was associated with male sex and laparoscopic surgery .The relationship between CCS and the presence of comorbidity was not statistically significant in all cases in the current study, as well as in the mesh group versus the no mesh group. In terms of the recurrence component of QOL, a previous study discovered that BMI had no effect on the number of recurrences .Umbilical hernias have a higher morbidity and mortality rate than inguinal hernias due to the increased risk of incarceration and strangulation, which necessitate emergency repair . In the LimitationsThe cross-sectional design of the current study, which could reveal the association between variables but not the causal association, is an important limitation. As a result, future prospective studies are advised. Other limitations were the small sample size, the short follow-up period, being a single-center study, and the possibility of a recall bias.Our study found a non-statistical significant relationship between CCS scores and the presence of comorbidity or presenting symptoms. The overall CCS score did not differ statistically between the mesh and non-mesh groups, however, males of the mesh group had a better CCS score compared to the no mesh group. Multicentric studies with a larger sample size are recommended.


IL4RA gene polymorphism, which is related to type 2 inflammation, in these exacerbation-prone phenotypes.Chronic inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease (COPD), are complex syndromes with diverse clinical symptoms due to multiple pathophysiological conditions. In this study, using common and shared risk factors for the exacerbation of asthma and COPD, we sought to clarify the exacerbation-prone phenotypes beyond disease labels, and to specifically investigate the role of the IL4RA gene polymorphism rs8832 with each exacerbation-prone phenotype was evaluated by multinomial logistic analyses using non-asthma non-COPD healthy adults as controls . In addition, the genetic influence of rs8832 was also examined in asthma patients with allergic rhinitis and no history of exacerbation (n = 130).The study population comprised patients with asthma (n = 117), asthma-COPD overlap  or COPD (n = 48) and a history of exacerbation within the previous year. Cluster analyses were performed using factors associated with both asthma and COPD exacerbation. The association of the p = 0.013) and also for the type 2 exacerbation-prone phenotypes , p = 1.9 × 10−3).Two-step cluster analyses identified five clusters that did not necessarily correspond to the diagnostic disease labels. Cluster 1 was characterized by high eosinophil counts, cluster 2 was characterized by smokers with impaired lung function, cluster 3 was characterized by the presence of gastroesophageal reflux, cluster 4 was characterized by non-allergic females, and cluster 5 was characterized by allergic rhinitis and elevated total immunoglobulin E levels. A significant association with rs8832 was observed for cluster 5 , Our results indicated that the clinical heterogeneity of disease exacerbation may reflect the presence of common exacerbation-prone endotypes across asthma and COPD, and may support the use of the treatable traits approach for the prevention of exacerbations in patients with chronic inflammatory airway diseases. Chronic inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease (COPD), are complex syndromes with diverse clinical symptoms due to multiple pathophysiological conditions. Despite the fact that asthma and COPD share common mechanisms, the mainstream approach to treating chronic inflammatory airway diseases has been to name a diagnosis first, then to follow the clinical guidelines that correspond to that diagnosis. This approach, also known as one-size-fits-all medicine, has been reported to have limitations in providing appropriate treatment for a variety of conditions that vary from patient to patient . A newlyAcute exacerbations of asthma and COPD are common occurrences that are associated with an increased decline in lung function, poor quality of life and increased mortality. Asthma and COPD are chronic diseases with high morbidity worldwide, and their acute exacerbations, in particular, are a major socioeconomic burden , 4. PatiIL4RA gene expression in whole blood cells [The G allele at rs8832 is associated with upregulated od cells . Moreoveod cells , 11.IL4RA gene polymorphism, which is related to type 2 inflammation, in these exacerbation-prone phenotypes.In this study, using these common and shared risk factors for the exacerbation of asthma and COPD, we sought to clarify the exacerbation-prone phenotypes beyond disease labels, and also to investigate the role of the IL4RA on the exacerbation of chronic inflammatory pulmonary diseases in relation to the exacerbation phenotypes was evaluated.In this study, we focused on the exacerbation-prone phenotypes of chronic inflammatory pulmonary diseases  and conducted cluster analyses using patients with at least one exacerbation within the previous year despite being treated by pulmonologists. Multiple clinical features related to exacerbation were used to clarify the phenotypes of exacerbation that were independent of conventional diagnoses. Furthermore, the genetic effect of the functional single nucleotide polymorphism (SNP) of This study consecutively enrolled patients who had experienced at least one exacerbation within the past year, without matching of the number of patients per disease, within the study period of January 2017 to December 2017. The target population comprised patients with asthma (n = 117), ACO (N = 37) or COPD (n = 48) and a history of at least one exacerbation within the previous year who visited the University of Tsukuba Hospital and/or its affiliated hospitals. In all patients, the diagnosis of the disease was made by a pulmonologist. Patients with smoking COPD with features of asthma were defined as having ACO . PatientIn addition, asthma patients with allergic rhinitis who had not experienced an asthma exacerbation within the past year n = 130) were also recruited to investigate the genetic influence of rs8832 on the development, but not exacerbation, of allergic asthma with rhinitis. Healthy volunteers with the rs8832 genotype (n = 1529) were recruited from among the individuals who visited the Tsukuba Medical Center and the Health Center of Kamisu City for annual health checkups [0 were alSpirometry was performed at each participating site using an automated electronic spirometer with the patient in a sitting position. These tests were performed and evaluated by well-trained technicians as described in the ATS/ERS guidelines .9/L) were obtained from the automated laboratory test results from each participating site.The total serum immunoglobulin E (IgE) level was measured using a commercial fluorescence enzyme immunoassay . The specific serum IgE antibody was measured in both the healthy and asthmatic groups with the multiple allergen simultaneous test (MAST)-26 chemiluminescent assay systems  . We defiPatients’ health-related quality of life was assessed using the COPD assessment test (CAT), a self-administered questionnaire consisting of eight items that assess various manifestations of chronic airway disease . GastroeIL4RA, was performed using the Infinium Asian Screening Array  or the Illumina HumanHap 550v3/610-Quad BeadChip (Illumina) [Genomic DNA was extracted from peripheral blood samples using an automated DNA extraction system . The typing of rs8832, which is an expression quantitative trait locus and splicing quantitative trait locus of llumina) .One-way analyses of variance, Kruskal-Wallis tests and the chi-square test were used for comparisons among the exacerbation-prone phenotypes for parametric continuous, non-parametric continuous and categorical variables, respectively.For SNP data analysis, the genotype frequency in each exacerbation-prone phenotype was summarized and the odds ratios for risk genotypes were calculated by multinomial multiple logistic regression analyses using non-asthmatic non-COPD healthy volunteers as the control group with adjustments made for age, sex and smoking index .1)/forced vital capacity (FVC), body mass index (BMI), CAT score, FSSG score, peripheral blood eosinophil count and the number of exacerbations that required steroid administration within the previous year. The distribution of serum IgE was not normal, and the values were thus log-transformed (log IgE).For cluster analyses, two-step cluster analyses were performed using SPSS® Statistics V26 . The analysis used the following 12 variables, including factors associated with both asthma and COPD exacerbation: age, sex, smoking index, age at onset, total IgE, presence/absence of allergic rhinitis, forced expiratory volume in 1 s  and duration (years smoked), and was categorized into three groups: 0, >0 to <200, and >200 cigarette-years . A cutofWe validated the results of the two-step cluster analyses using the silhouette coefficient, which is a measure for the cohesion and separation of clusters . ObtaineThis study was approved by the institutional review board of the University of Tsukuba (IRB No. 136–4) and the University of Tsukuba Hospital (IRB No. H29-294). After verbally explaining the research to all target participants, the survey and analyses were conducted in accordance with the joint Ethical Guidelines for Human Genome/Gene Analysis Research and the principles of the Declaration of Helsinki after obtaining written consent from the patients.1/FVC, BMI, CAT score, FSSG score, peripheral blood eosinophil count and number of exacerbations in the previous year. Consequently, a total of 202 patients  who had information for all 12 items were included in the subsequent cluster analysis. The presence/absence of allergic rhinitis was judged mainly based on the typical symptoms, including sneezing or a runny/blocked nose, especially when the patients did not experience a cold or the flu within the past 12 months.A total of 225 patients were initially enrolled, including 127 with asthma, 41 with ACO and 57 with COPD. Patients with missing data for at least one of the following 12 items were excluded: age, sex, smoking index, age at onset, total IgE, presence/absence of allergic rhinitis, FEV2 for those with asthma, ACO and COPD, respectively. The mean FEV1/FVC was 74.1%, 54.4% and 44.4% among those with asthma, ACO and COPD, respectively. Furthermore, the percentage of patients with a peripheral blood eosinophil count ≥450 cells/μL was 18.8%, 21.6% and 10.4%  among those with asthma, ACO and COPD, respectively. The number of patients who experienced at least two exacerbations within the previous year was 66, 22 and 24  among those with asthma, ACO and COPD, respectively. The prevalence of allergic rhinitis, as determined by interviews, was 36.8%, 18.9% and 4.2% among those with asthma, ACO and COPD, respectively. The mean fractional exhaled nitric oxide  was 1.41, 1.51 and 1.29 ppb among those with asthma, ACO and COPD, respectively .Cluster 1  was a smoking male dominant group with a mean age of 72.8 years. The mean peripheral blood eosinophil count was 362.1 cells/μL, which was the highest among all clusters. The mean serum IgE level  was 2.23 IU/mL, which was the second highest after cluster 5. Together with an elevated level of exhaled NO  of 1.56 ppb, cluster 1 was considered to be an eosinophilic phenotype. The rate of complications of allergic rhinitis was 19.6%.1/FVC was 48.9%, which was the lowest among all clusters. The mean BMI was 22.2 kg/m2, which was also the lowest among all clusters. The mean peripheral blood eosinophil count was 160.2 cells/μL, and the rate of complications of allergic rhinitis was 2.8%.Cluster 2  was a group of symptomatic smokers with a mean age of 76.1 years. The mean FEV1/FVC was 57.3%.Cluster 3  was a group with a higher mean age of 75.5 years and a relatively high number of smokers. The FSSG score was 8 or more in all patients, indicating that this cluster was an exacerbation-prone phenotype characterized by the presence of GERD. The mean FEVCluster 4  was a group of non-smoking females with a mean age of 64.8 years. The mean serum IgE level  was 1.71 IU/mL, and the rate of complications of allergic rhinitis was 2.1%; these were the lowest among all clusters, indicating that this cluster was non-smoking females without a predisposition for allergies. The mean level of exhaled NO  was 1.31 ppb.In cluster 5 , all patients had allergic rhinitis. The proportion of females was as high as 82.4%. The mean age and age at onset were 58.4 and 36.0 years, respectively, both of which were the lowest among all clusters. This group also had the highest mean serum IgE level  at 2.35 IU/mL. The peripheral blood eosinophil count and exhaled NO level  were 272.4 cells/μL and 1.44 ppb, respectively.Exacerbations treated by steroids were most frequent in cluster 5, while exacerbations treated by antibiotics only were most frequent in clusters 2 and 3.p = 1.9 × 10−3). In contrast, non-type 2 exacerbation-prone phenotypes  were not associated with the SNP. We further examined the role of the IL4RA SNP in participants with increased eosinophil counts in the studied population .Genotyping for rs8832 was unsuccessful in some of the patients included in the cluster analysis . In addition, the same proinflammatory mediators are present in both the nasal and bronchial mucosa, including IL-4 and IL-13 . Thus, tIL4RA gene expression, was significantly associated with the high IgE allergic rhinitis group (cluster 5). When the effects of the G allele on the type 2 exacerbation-prone phenotypes (clusters 1 and 5 combined) were examined, the association became stronger, while the non-type 2 exacerbation-prone phenotypes  were not associated with the SNP. In addition, a significant association was found between the SNP and patients characterized by an increased number of blood eosinophils. Taken together, the functional SNP at IL4RA may have some role in the susceptibility to exacerbation, especially in patients with a type 2 phenotype. Among patients with asthma who had concomitant allergic rhinitis, but no history of exacerbation within the previous year, the frequency of the G allele did not differ significantly from that in the healthy volunteers; therefore, it seems that the functional allele might be primarily involved in the susceptibility to exacerbation itself rather than to the development of the type 2 phenotypes of asthma and/or COPD. A previous study revealed that SNPs in IL4RA were also associated with severe asthma exacerbations, lower lung function and increased mast cell-related tissue inflammation; the study suggested that the SNPs may modify the activation status of mast cells through a FceRI-dependent manner [The G allele at rs8832, which is associated with upregulated t manner . Given tt manner , rs8832 There are some limitations of this study. First, in the studied population, the causes of the exacerbations, which may include viral infection, environmental exposures, air pollution and/or psychological stress, were not confirmed. Second, the clinical variables used to search for exacerbation-prone phenotypes included variables that are subject to fluctuations . These clinical indicators may vary depending on the control status of the patients and the details of treatment, which may have affected the results of the cluster analyses. However, to minimize these changes as much as possible, data for clinical variables that were obtained during periods of stable disease were used. Third, no clear information on non-eosinophilic airway inflammation was available, which is considered to play a central role in airway inflammation in COPD and the neutrophilic phenotype is also present in asthma. However, to detect exacerbation phenotypes associated with non-type 2 inflammation, the indicators of a smoking history, GERD and BMI were used in our cluster analyses. Furthermore, the peripheral blood eosinophil count, total IgE, and presence or absence of allergic rhinitis were used as indicators for inferring non-eosinophil exacerbation phenotypes. Last, the number of patients evaluated in the present study was small; therefore, these findings are preliminary in nature and it is important to confirm the findings of the current study by performing a replication study in a larger population in the future.IL4RA was found to be particularly associated with the type 2 exacerbation-prone phenotypes. Therefore, our results indicated that the clinical heterogeneity of disease exacerbation may reflect the presence of common exacerbation-prone endotypes across asthma and COPD, and may support the use of the treatable traits approach for the treatment of exacerbations of chronic inflammatory airway diseases.In summary, five phenotypes associated with the exacerbation of chronic inflammatory airway diseases were identified across traditional diagnostic labels, including asthma, COPD and ACO. Furthermore, the functional SNP at S1 Data(XLSX)Click here for additional data file.S2 Data(XLSX)Click here for additional data file.S3 Data(XLSX)Click here for additional data file.


An H-section steel bar that had been set against the wall fell and hit the abdomen and then both legs of a 33-year-old Chinese man. As his vital signs were stable and his chief complaint was leg pain, he was transferred to a local medical facility. After the confirmation of gross hematuria by an indwelling a bladder catheter there, he was transported to our hospital. On arrival, his vital signs were stable. His main complaint was foot pain. He had a scabbing injury at the scrotum and bilateral foot joint deformity. Whole-body computed tomography (CT) from head to toe revealed trabecular formation in the bladder and slight fluid collection in the rectovesical pouch, as well as bilateral fracture-dislocations at the ankles. The urinary tract injury and the fluid collection in the rectovesical pouch were managed conservatively, and the lower limbs were treated tentatively. Follow-up CT on day 3 revealed multiple free air pockets in the intra-abdominal cavity, which was considered to indicate perforation of the duodenal ulcer and treated conservatively. However, he showed abdominal pain on day 7, and repeated CT revealed increased fluid in the intra-abdominal cavity. Urgent laparoscopy showed intact bowels and perforation of the bladder that was closed by suturing. He ultimately obtained a survival outcome. This is the first case of transient trabecular formation in the bladder and delayed free air due to traumatic intraperitoneal bladder rupture. This unique case adds another radiological finding to the list of documented etiologies of traumatic bladder perforation. Bladder rupture, a relatively rare condition, is most commonly due to abdominal and/or pelvic trauma, but it may be spontaneous or iatrogenic in association with surgical or endoscopic procedures -3. BladdWe herein report a case of free air due to traumatic intraperitoneal bladder rupture initially treated as duodenal perforation.An H-section steel bar that had been set against the wall fell and hit the abdomen and then both legs of a 33-year-old Chinese man. He was unable to stand due to his leg injuries and was transferred to a local medical facility. His vital signs were stable and his chief complaint was leg pain. After the confirmation of gross hematuria by indwelling a bladder catheter, he was transported to our hospital because there were no urologists at the local medical facility. He had no specific past or family history.4/μL, prothrombin time of 12.4 (11.7) seconds, activated partial thromboplastin time of 26.2 (26.7) seconds, fibrinogen of 185 mg/dL, and fibrin degradation product of 29.1 μg/mL. Whole-body CT from head to toe revealed trabecular formation in the bladder and slight fluid collection in the rectovesical pouch , respiratory rate of 20 breaths per minute, and percutaneous saturation of oxygen under room air of 97%. His main complaint was foot pain. He had a scabbing injury at the scrotum without abdominal signs and bilateral foot joint deformity. The results of a biochemical analysis of the blood were as follows: total protein of 6.2 g/dL, albumin of 4.0 g/dL, total bilirubin of 1.2 mg/dL, aspartate aminotransferase of 48 IU/L, alanine aminotransferase of 17 IU/L, lactate dehydrogenase of 294 IU, creatine phosphokinase of 2,374 IU/L, glucose of 110 mg/dL, HbA1C of 5.5%, blood urea nitrogen of 27.1 mg/dL, creatinine of 1.63 mg/dL, uremic acid of 6.5 mg/dL, sodium of 140 mEq/L, potassium of 4.2 mEq/L, calcium of 8.7 mg/dL, C-reactive protein of 0.02 mg/dL, white blood cell count of 23,600/μL, hemoglobin of 14.0 g/dL, platelet of 22.5×10Initially, he received a diagnosis of urinary tract injury and fracture-dislocations of the bilateral lower limbs.The urinary tract injury and fluid collection in the rectovesical pouch were managed conservatively with fasting based on the urologists’ decision without further examination, and the lower limbs were treated by external fixation and pinning. Ultrasound on day 2 also indicated trabecular formation in the bladder (Figure Follow-up CT on day 3 revealed multiple free air pockets in the intra-abdominal cavity and the disappearance of the fluid collection and trabecular formation in the bladder (Figure He underwent emergency gastroscopy, resulting in the discovery of a duodenal ulcer at the bulbus, and therefore the free air was considered to indicate perforation of the duodenal ulcer and was treated conservatively with fasting.However, he experienced abdominal pain on day 7 with peritoneal stimulation signs, and immediate CT revealed increased fluid in the intra-abdominal cavity. He underwent urgent laparoscopy, which showed intact bowels and perforation of the bladder, which was closed by suturing. From day 8, he started to drink and eat. On day 12, his lower limbs underwent internal fixation. He was then transported to another medical facility for rehabilitation.To our knowledge, this is the first case to show traumatic transient trabecular formation in the bladder. Initially, we thought this was a congenital abnormality or tumor because the trabecular formation did not move, even with the application of pressure during an ultrasound examination ,7. The mThe bladder rupture in the present case was initially missed, though urologists were consulted. The present case did not have pelvic fracture, which is a common cause of blunt traumatic bladder rupture, and the main complaint was foot pain; however, an indwelling bladder catheter revealed gross hematuria, and fluid collection was noted in the rectovesical pouch on initial CT. In addition, our patient showed azotemia and increasing serum creatinine levels. Ascites and increasing serum creatinine levels are often noted in patients with acute kidney injury. However, these findings are also observed in patients with intraperitoneal urinary leakage . Again, This case showed delayed free air, and the free air was initially considered to indicate perforation of a duodenal ulcer. Free air induced by traumatic bladder perforation is an extremely rare finding, and previous reports have also initially treated such cases as bowel perforation ,5. HowevThis was a case of transient trabecular formation in the bladder and delayed free air due to traumatic intraperitoneal bladder rupture. This unique case adds another radiological finding to the list of documented etiologies of traumatic bladder perforation.


This hypothesis may also explain the different clinical pemphigus phenotypes.Pemphigus is a severe autoimmune disease impairing barrier functions of epidermis and mucosa. Autoantibodies primarily target the desmosomal adhesion molecules desmoglein (Dsg) 1 and Dsg 3 and induce loss of desmosomal adhesion. Strikingly, autoantibody profiles in pemphigus correlate with clinical phenotypes. Mucosal-dominant pemphigus vulgaris (PV) is characterised by autoantibodies (PV-IgG) against Dsg3 whereas epidermal blistering in PV and pemphigus foliaceus (PF) is associated with autoantibodies against Dsg1. Therapy in pemphigus is evolving towards specific suppression of autoantibody formation and autoantibody depletion. Nevertheless, during the acute phase and relapses of the disease additional treatment options to stabilise desmosomes and thereby rescue keratinocyte adhesion would be beneficial. Therefore, the mechanisms by which autoantibodies interfere with adhesion of desmosomes need to be characterised in detail. Besides direct inhibition of Dsg adhesion, autoantibodies engage signalling pathways interfering with different steps of desmosome turn-over. With this respect, recent data indicate that autoantibodies induce separate signalling responses in keratinocytes  Pemphigus is a severe autoimmune blistering skin disease disrupting desmosomes and thereby affecting the epidermis of the skin and the mucosa , 2. DesmDSG3 (All pemphigus variants are rather rare and here we focus on the two main variants of the disease pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Incidence and prevalence of PV vary profoundly in different geographical regions as well as ethnicities. In Germany, the prevalence for PV in 2014 was 94.8 per one million population (pmp) . It was DSG3  play a rDSG3 , 39, 40.For PF, the prevalence was 10.01 pmp , with anIn most cases, PV initially shows mucosal erosions sometimes spreading to the oesophagus, the airways, the anogenital mucosa , 55 and For diagnosis of pemphigus, the specific histology with separation at the suprabasal layer for PV and at the granular layer for PF is important , 61 Fig. The secPemphigus is a very severe disease with a mortality of around 71% if untreated. Secondary infections due to the disruption of the skin barrier are the most severe problem , 70. AllNovel therapy options are for example intravenous injection of high doses of IgG of healthy donors , 79, comvia IL-4 on Th2 cells which are involved in pemphigus pathology are a novel target .Finally, it has to be noted that the observation of Dsg3 and Dsg1 to regulate keratinocyte adhesion and function d cornea , 224. Thoperties . Becauseved also –232 .However, it is currently unclear how exactly p38MAPK is activated after antibody binding to Dsg1 and Dsg3. One study reported activation with two peaks in activity at different points in time, which was different esponses . In otheesponses  or experesponses  making iesponses , 5.ex vivo and inactivation of Rho-GTPases induced epidermal splitting similar to autoantibodies .All these effects can be explained by the fact that RhoA  adducin . Adducin adducin . Other a adducin . Thus, iogenesis , 5.via interaction with Dsg1 .As described above, PG is essential for the assembly of desmosomes –257 and ith Dsg1 . It was ith Dsg1 –262 and ith Dsg1 . As descith Dsg1 , 260. Itith Dsg1 , 261. Loith Dsg1 . Howeverith Dsg1 , 256 butith Dsg1  and evenith Dsg1  of kerat in vivo . By its  in vivo . PG incr in vivo , 265. Th in mice , 266. Th in mice , 5.in vitro . Interestingly, the activation of ADAM10 is dependent on the autoantibody profile and restricted to antibodies targeting Dsg1 and Dsg3. In contrast, additional autoantibodies against Dsc2 and 3 triggered a more severe and earlier acantholysis independent of ADAM10 (5).Besides direct activation of EGFR by phosphorylation at Y845, Src is also involved in the release of activating EGFR ligands in response to pemphigus autoantibodies , 228. Inin vitro . Recentlin vitro . ADAM10 f ADAM10  .Dsg1 is a very important antagonist of EGFR signalling. EGFR promotes cell migration and proliferation in the basal layer of the epidermis. In contrast, Dsg1 expression in superficial epidermis shifts the gears more towards keratinocyte differentiation. This antagonistic role is a result of at least one shared pathway. While EGFR is known to activate ERK1/2, Dsg1 is a known suppressor of this signalling pathway –281, 287d ERK1/2 , 279–281d ERK1/2 , 179. Ind PF-IgG , 228. Thd PF-IgG   to the cytoplasm (2+-release-activated-channel). Stim 1 is located at the membrane of the ER , DAG activates novel PKC (nPKC) and translocation activates atypical PKC (aPKC) isoforms, respectively . The resulting Ca2+ flux was reported to lead to mitochondrial swelling and induction of apoptosis-related signals (in vitro (in vivo (Moreover, caspase signalling could also be induced  signals –326. Cas signals , and Rho signals . In linein vitro  and skin(in vivo , 318 werin vitro (in vitro and in vivo before the appearance of lesions but without any other sings of apoptosis (However, the relevance of apoptosis for the pathology of pemphigus is controversly discussed and often attributed to be a secondary effect caused by acantholysis , 154. Itin vitro , 328 as in vitro , 328. Onpoptosis . Taken tpoptosis , 318. Sipoptosis , it can poptosis . The facpoptosis , 5.Most interestingly, autoantibodies in pemphigus not only cause pathogenic effects leading to loss of keratinocyte adhesion but also induce rescue pathways. One compensatory mechanism is up-regulation of Dsg2 expression in PV patients' lesions . It was in vitro and skin blistering in mice in vivo (via PKA-mediated PG phosphorylation (Another protective pathway is dependent on the second messenger cAMP. Increased levels of cAMP were observed after incubation with PV-IgG and a pharmacological increase in cAMP blocked the effects of PV-IgG  in vivo . It was  in vivo . This merylation , 214. Rerylation . Thus, tMost recently it was reported, that mechanical stimulation also plays a very important role for the resistance against pemphigus-IgG-induced effects. Stretching of cells reportedly induced activation of RohA, strengthening the cortical acting network and its crosslinking, leading to increased cell contractility. This was shown to reduce pemphigus IgG induced effects, indicating, that activation of RhoA in pemphigus might represent an insufficient rescue pathway  Figures, 5.2+ appear to be more relevant for skin blistering in pemphigus than others. This is supported by a recent study using an unbiased approach by testing a library of 141 small molecule inhibitors in different experimental models of pemphigus which found that inhibition of ERK and p38MAPK signalling was effective to ameliorate PV-IgG-induced loss of cell adhesion (From this review it can be concluded that some signalling pathways such as p38MAPK, ERK and PLC/Caadhesion .2+ signalling indicating that at least systemic therapy using inhibitors of these pathways are most likely not feasible. Nevertheless, since topical application of Dsg-crosslinking peptides or drugs to increase cAMP were effective in pemphigus mouse models in vivo (On the other hand, inhibition of p38MAPK in clinical studies was not beneficial for pemphigus patients . This ma in vivo , 334 it  in vivo .2+ has been shown to regulate desmosome stability via phosphorylation of DP, the modulation of DP cytoskeletal anchorage may be a promising target for therapy. Similarly, given that p38MAPK induces pathogenic effects via inhibition of RhoA, which via Rho kinase and adducin phosphorylation is important for desmosome assembly (Moreover, identification of signalling mechanisms critical for pemphigus pathology allows to focus on the molecular targets of the associated signalling molecules. Because PKC downstream of PLC/Caassembly , 227, thassembly , new canassembly . TherefoTS: concept, original draft, figure design, and revision. JW: concept and revision. Both 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.