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Purpose To identify the incidence of continuation of newly initiated loop diuretics upon intensive care unit (ICU) and hospital discharge and identify factors associated with continuation. Methods This was a single-center retrospective study using electronic health records in the setting of adult ICUs at a quaternary care academic medical center. It involved patients with sepsis admitted to the ICU from January 1, 2014, to June 30, 2019, who received intravenous fluid resuscitation. The endpoints of interest were (1) the incidence of loop diuretic use during an ICU stay following fluid resuscitation, (2) continuation of loop diuretics following transition of care, and (3) potential factors associated with loop diuretic continuation after transition from the ICU. Results Of 3,591 patients who received intravenous fluid resuscitation for sepsis, 39.4% (n = 1,415) were newly started on loop diuretics during their ICU stay. Among patients who transitioned to the hospital ward from the ICU, loop diuretics were continued in 33% (388/1,193) of patients. At hospital discharge, 13.4% (52/388) of these patients were prescribed a loop diuretic to be used in the outpatient setting. History of liver disease, development of acute kidney injury, being on vasopressors while in the ICU, receiving blood products, and receiving greater than 90 mL/kg of bolus fluids were significant potential factors associated with loop diuretic continuation after transition from the ICU. Conclusion New initiation of loop diuretics following intravenous fluid resuscitation in patients with sepsis during an ICU stay is a common occurrence. Studies are needed to assess the effect of this practice on patient outcomes and resource utilization.

Objective This study aims to determine the mechanism of ISLR on the progression of colon cancer. Methods TCGA database was used to analyze ISLR expression in colon cancer tumor tissues. QRT-PCR and western blotting were used to detect ISLR expression in colon cancer cells. CCK-8, colony formation, EDU, wound healing and transwell assays were used to measure cell viability, proliferation, migration and invasion of colon cancer cells, respectively. The signaling pathway enrichment analysis of ISLR was analyzed on the basis of the KEGG database. The protein expression of genes related to signaling pathway was measured by western blotting. Results Results of TCGA analysis, qRT-PC and western blotting showed that ISLR was upregulated in colon cancer tumor tissues and cells. High level of ISLR was related to low overall survival of patients with colon cancer. ISLR silence significantly inhibited cell viability, proliferation, migration and invasion of colon cancer cells. ISLR overexpression markedly enhanced the cell viability, proliferation, migration and invasion of colon cancer cells. KEGG database analyzed showed that ISLR can activate the EMT signaling pathway. Inhibition of the EMT signaling pathway can suppress the growth, migration, and invasion of colon cancer cells and eliminate the promoted effect of ISLR overexpression on colon cancer progression. Conclusion ISLR promotes the progression of colon cancer by activating the EMT signaling pathway.

In our paper, the effects of As4S4 treatments on the growth and migration of gastric cancer (GC) cells were explored, and the potential underlying molecular mechanisms were also identified. Cell viability was evaluated by cell counting kit 8 assay. The expression of Ki-67 was examined using immunofluorescence staining. Cell apoptosis was assessed by flow cytometry. The migratory and invasion abilities of cells were determined using Transwell assay. The mRNA and protein levels of related gene were examined by RT-qPCR and western blotting, respectively. CircRNAs chip was performed to identify the differentiated expression of circRNAs in GC cells following the treatment with As4S4. Our results revealed that the proliferation, migration and invasion of GC cells were remarkably suppressed by the treatment with As4S4, while cell apoptosis was promoted. Furthermore, circRNA_ASAP2 was a novel target of As4S4 in GC, and it is involved in As4S4-modulated biological behavior alterations in GC cells. In addition, the activities of the Wnt/β-catenin signaling in GC cells were affected by the overexpression circRNA_ASAP2 and the treatment with As4S4. Moreover, the behavior changes in GC cells caused by the knockdown of circRNA_ASAP2 were reversed by the treatment with Wnt agonist SKL2001. In summary, As4S4 could function as an antitumor agent in GC through regulating the circRNA_ASAP2/Wnt/β-catenin pathway, which in turn influences the growth and metastasis of GC cells.

Objective The present study is designed to investigate the expressions of microRNA-143-3p (miR-143-3p) and Lysine acetyltransferase 6A (KAT6A) in acute myeloid leukemia (AML) samples and AML cell lines and to explore the possible effects and underlying mechanisms of miR-143-3p on the proliferation of AML cells. Methods The expressions of miR-143-3p and KAT6A in AML samples and cell lines were detected by RT-qPCR assay. CCK-8 and flow cytometry were performed to evaluate the role of KAT6A in viability of AML cells. EdU assay was performed to determine the effects of KAT6A on proliferation of AML cells. Western blot analysis was utilized to assess the impacts of KAT6A on proliferation-related protein expressions of AML cells. ELISA assay was adopted to illustrate the influence of KAT6A on inflammatory responses of AML cells. In addition, the relationship between KAT6A and miR-143-3p was predicted by ENCORI and miRWalk, and confirmed by dual-luciferase reporter assay. Moreover, the effects of KAT6A on the proliferation of AML cells mediated with miR-143-3p were carried out by rescue experiment. Results The expression of KAT6A was significantly upregulated, while miR-134-4p was downregulated both in the AML tissues and in AML cell lines. In addition, the silence of KAT6A significantly inhibited the viability of AML cells. Besides, KAT6A silencing notably suppressed the proliferation of AML cells and reduced the protein expressions of Ki-67 and PCNA. Knockdown of KAT6A notably decreased the expression levels of IL-1β, TNF-α and IL-6, and increased the expression levels of TGF-β and IL-10. Moreover, overexpression of miR-143-3p repressed viability and proliferation of AML cells and overexpression of KAT6A partially reversed the inhibitory effects of miR-143-3p mimic on viability and proliferation of AML cells. Conclusion miR-143-3p/KAT6A played an essential role in the viability and proliferation of AML cells.

OBJECTIVE A retrospective study was conducted to analyze which translational therapy, palliative chemotherapy and surgery is the best treatment for locally advanced and advanced pancreatic cancer, and to screen out the dominant population for the best treatment. PATIENTS AND METHODS A total of 83 patients with pancreatic cancer, including locally advanced and advanced pancreatic cancer, who had lost the opportunity for radical surgery and were admitted to Zhejiang Provincial People's Hospital between January 2015 and July 2021 were collected. A total of 39 patients received palliative chemotherapy, 25 patients received conversion therapy and 19 patients tried surgery at the first visit. We conducted survival follow-up and prognostic evaluation of 83 patients. RESULTS The median overall survival (mOS) and median progression-free survival (mPFS) of 25 pancreatic cancer patients who received conversion therapy were longer than those of pancreatic cancer patients who received palliative chemotherapy (mOS: 16 months vs. 9 months, P = 0.001; mPFS: 11 months vs. 7.5 months, P = 0.038) and surgery (mOS: 16 months vs. 9 months, P = 0.018; mPFS: 11 months vs. 5.5 months, P < 0.001). Multivariate and Kaplan-Meier analysis showed that age, distant metastasis, and the degree of CA199 declined after chemotherapy were independent factors affecting overall survival (OS) of pancreatic cancer patients who received conversion therapy. CONCLUSIONS Conversion therapy can improve OS and progression-free survival in patients with locally advanced or advanced pancreatic cancer to a certain extent. Some patients with advanced pancreatic cancer have surprising results after receiving conversion therapy.

To explore the efficacy and safety of palbociclib combined with endocrine therapy (ET) in advanced breast cancer (ABC). We conducted a retrospective study involving patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) ABC who received palbociclib combined with ET in the first- to third-line at three centers in China between January 2018 and October 2020. A total of 151 patients were included in this study. The median age of the patients at palbociclib initiation was 56 years (range 30-86 years) with a median follow-up of 10.9 months (range 2.0-41.2 months). Among these patients, 88 patients received palbociclib combined with ET as first-line therapy, and achieved a median progression-free survival (mPFS) of 19.8 months and an objective response rate (ORR) of 40.9%, meanwhile, in the first-line setting, 62 patients received palbociclib at an initial dose of 125 mg, achieving a mPFS of 20.9 months and an ORR of 46.8%. There were 39 and 24 patients who received palbociclib combined with ET as second- and third-line therapy, the mPFS were 10.0 months and 6.1 months, respectively. The most common and serious adverse events (AEs) were leukopenia and neutropenia. A total of 64 patients (42.4%) underwent palbociclib dose reduction due to AEs. Palbociclib combined with ET is an effective therapeutic regimen for HR+/HER2- ABC, particularly in the first-line setting with palbociclib initial dose of 125 mg, and AEs were manageable.

Pathogenic heterozygous NEXN variants are associated with progressive dilated cardiomyopathy (DCM) usually presenting around 50 years of age. We describe an asymptomatic boy who had transient DCM at 3 months of age, that resolved by 4 months. Presently, at 11 years of age, he has normal cardiac function with signs of mild DCM on cardiac MRI. Genetic diagnostics revealed a paternally derived, heterozygous 1949_1951del class 4 variant in NEXN. His father had mild DCM with mildly reduced systolic function. The second patient presented with fetal hydrops at 33 weeks gestation requiring emergency caesarian delivery. Postnatally she required ventilation and continuous inotropic support for left ventricle systolic dysfunction. She died after 2 weeks when therapy was withdrawn. Homozygous c.1174C > T,p.(R392*) class 4 variants in the NEXN gene were found via WES. Microscopic investigation showed endomyocardial fibroelastosis. Her parents, both heterozygous carriers, had normal cardiac function and the family history was normal. These patients show a new clinical spectrum of pediatric cardiac disease seen in heterozygous and homozygous NEXN variants, ranging from mild, transient DCM to a severe, fatal neonatal DCM. These patients support the inclusion of the NEXN gene in the investigation of pediatric patients with DCM, even in cases with transient DCM.

Activatable cell-penetrating peptide (ACPP) is a tumour-targeting cell-penetrating peptide. Here, we used ACPP to carry anti-p21Ras scFv for Ras-driven cancer therapy. The ACPP-p21Ras scFv fusion protein was prepared by a prokaryotic expression system and Ni-NTA column purification. The human tumour cell lines A549, SW480, U251 and Huh7 and the normal cell line BEAS 2B were used to study the tumor-targeting and membrane-penetrating ability of ACPP-p21Ras scFv. The antitumour activity of ACPP-p21Ras scFv on A549 cells and H1299 cells in vitro was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, scratch wound healing, plate cloning and apoptosis assays. The penetration pathway of ACPP was determined by enhanced green fluorescent protein. The ACPP-p21Ras scFv fusion protein was successfully obtained at a concentration of 1.8 mg/ml. We found that ACPP-p21Ras scFv could penetrate tumour cell membranes with high expression of matrix metalloproteinase-2 (MMP-2), effectively inhibit the migration and proliferation of A549 cells and H1299 cells, and promote the apoptosis of A549 cells and H1299 cells. The membrane penetration experiment demonstrated that ACPP could enter A549 cells by direct penetration. The ability of ACPP to penetrate the membrane was affected by the addition of a membrane affinity inhibitor and a change in the potential difference across the cell membrane but not by the addition of endocytosis inhibitors and a change in temperature. The ACPP-p21Ras scFv fusion protein can penetrate tumour cells with MMP-2 expression and has antitumour activity against A549 cells and H1299 cells in vitro. This molecule is expected to become a potential antitumour drug for Ras gene-driven lung cancer.

Supplemental Digital Content is available in the text., Phosphoglycerate mutase (PGAM) is a critical enzyme in glycolysis. PGAM2 is abundant in several types of tissues and malignant tumours. However, there is limited information regarding their clinicopathological significance in dysplastic nodules and hepatocellular carcinoma (HCC). This study aims to investigate the prognostic value of PGAM2 as a new biomarker for HCC. The PGAM2 expression level was evaluated by immunohistochemistry in liver cirrhosis (n = 10), low-grade dysplastic nodules (n = 15), high-grade dysplastic nodules (n = 15) and HCCs (n = 20) and 178 pairs of HCC and adjacent peritumoral liver tissues. We selected X-tile software for counting cut-point based on the outcomes for prognosis analysis, and used Kaplan–Meier analysis and Cox regression analysis can assess the prognosis of clinicopathologic parameters. Nuclear PGAM2 was significantly overexpressed in peritumoral liver tissues compared with HCC tissues (P = 0.0010). Kaplan–Meier analyses of 178 HCC samples revealed that nuclear PGAM2’s high expression level, but not cytoplasmic PGAM2, was significantly related to good overall survival rate (OS). In addition, univariate and multivariate Cox analyses indicated nuclear PGAM2 expression could be regarded as valuable predictors for OS in HCC. PGAM2 was highly expressed in HCC tissues than liver cirrhosis tissues, and nuclear PGAM2’s high expression might demonstrate HCC patients have poor postoperative results. Thus, nuclear PGAM2 can be regarded as valuable predictors for OS in HCC patients after surgery.

The present study investigated the impact of major comorbidities, including hypertension, type 2 diabetes mellitus (T2DM), and chronic hepatitis B virus (HBV) infection, on the progression-free survival (PFS) and overall survival (OS) of extensive-stage small-cell lung cancer (ES-SCLC) patients in China. Patients having a pathologic diagnosis of ES-SCLC between 2009 and 2017 were enrolled and grouped according to their specific comorbidities. The PFS and OS for each group were evaluated using the Kaplan–Meier method and Cox proportional hazard models. In total, 632 patients were analyzed. The median PFS (mPFS) of these patients was 9 months [95% confidence interval (CI), 6–12 months]. The mPFS of patients without hypertension or T2DM was 9 months; conversely, it was significantly reduced for patients with hypertension [7 months (P < 0.0001)] or T2DM [5 months (P < 0.0001)]. However, mPFS was not significantly different between patients with and without HBV infection (P = 0.2936). A similar trend was observed for OS as well. Further multivariate analyses showed that the OS of patients with hypertension [hazard ratio (HR), 1.344; 95% CI, 1.073–1.683; P = 0.010] or T2DM (HR, 1.455; 95% CI, 1.134–1.868; P = 0.003) was significantly shorter than that of patients without these comorbidities. Accordingly, mortality risk was the highest in patients with concurrent hypertension and T2DM (HR, 1.665; 95% CI, 1.037–2.672; P = 0.00058). Our study found that hypertension and T2DM may be associated with a worse prognosis in ES-SCLC patients. Considerable attention should be paid to the accompanying anti-comorbidity therapies available for patients with ES-SCLC.

Purpose Pharmacists are well positioned to provide transitions of care (TOC) services to patients with heart failure (HF); however, hospitalizations for patients with HF likely exceed the capacity of a TOC pharmacist. We developed and validated a tool to help pharmacists efficiently identify high-risk patients with HF and maximize their potential impact by intervening on patients at the highest risk for 30-day all-cause readmission. Methods We conducted a retrospective cohort study including adults with HF admitted to a health system between October 1, 2016, and October 31, 2019. We randomly divided the cohort into development (n = 2,114) and validation (n = 1,089) subcohorts. Nine models were applied to select the most important predictors of 30-day readmission. The final tool, called the Tool for Pharmacists to Predict 30-day hospital readmission in patients with Heart Failure (ToPP-HF) relied upon multivariable logistic regression. We assessed discriminative ability using the C statistic and calibration using the Hosmer-Lemeshow goodness-of-fit test. Results The risk of 30-day all-cause readmission was 15.7% (n = 331) and 18.8% (n = 205) in the development and validation subcohorts, respectively. The ToPP-HF tool included 13 variables: number of hospital admissions in previous 6 months; admission diagnosis of HF; number of scheduled medications; chronic obstructive pulmonary disease diagnosis; number of comorbidities; estimated glomerular filtration rate; hospital length of stay; left ventricular ejection fraction; critical care requirement; renin-angiotensin-aldosterone system inhibitor use; antiarrhythmic use; hypokalemia; and serum sodium. Discriminatory performance (C statistic of 0.69; 95% confidence interval [CI], 0.65-0.73) and calibration (Hosmer-Lemeshow P = 0.28) were good. Conclusions The ToPP-HF performs well and can help pharmacists identify high-risk patients with HF most likely to benefit from TOC services.

Ring‐finger protein 213 (RNF213) encodes a protein of unknown function believed to play a role in cellular metabolism and angiogenesis. Gene variants are associated with susceptibility to moyamoya disease. Here, we describe two children with moyamoya disease who also demonstrated kidney disease, elevated aminotransferases, and recurrent skin lesions found by exome sequencing to have de novo missense variants in RNF213. These cases highlight the ability of RNF213 to cause Mendelian moyamoya disease in addition to acting as a genetic susceptibility locus. The cases also suggest a new, multi‐organ RNF213‐spectrum disease characterized by liver, skin, and kidney pathology in addition to severe moyamoya disease caused by heterozygous, de novo C‐terminal RNF213 missense variants.

Contains fulltext : 237970.pdf (Publisher’s version ) (Open Access) The CEP83 protein is an essential part in the first steps of ciliogenesis, causing a ciliopathy if deficient. As a core component of the distal appendages of the centriole, CEP83 is located in almost all cell types and is involved in the primary cilium assembly. Previously reported CEP83 deficient patients all presented with nephronophthisis and kidney dysfunction. Despite retinal degeneration being a common feature in ciliopathies, only one patient also had retinitis. Here, we present two unrelated patients, who both presented with retinitis pigmentosa, without nephronophthisis or any form of kidney dysfunction. Both patients harbor bi-allelic variants in CEP83. This report expands the current clinical spectrum of CEP83 deficiency. For timely diagnosis of CEP83 deficiency, we advocate that CEP83 should be included in gene panels for inherited retinal diseases.

Background and objectives Treatment modalities have been developed to address patient concerns with skin laxity and focal adipose excess. A previously published multicenter clinical trial reported improvement in cellulite severity after a single dermal and subcutaneous treatment on the upper thigh with a microneedle radiofrequency device. In the current study, this device was used to improve the esthetic appearance of body skin laxity and localized fat deposits above the knee, upper arms, and upper-mid back/axillary region ("bra-line"). Study design/materials and methods Subjects with cellulite, skin laxity, and/or subcutaneous adipose excess in the suprapatellar region of the anterior thigh, upper arms, and bra-line underwent a single dermal and/or subcutaneous treatment. Investigators and subjects assessed outcome at 1-, 3-, and 6-month follow-up, using 5-point Likert scales for global esthetic improvement, skin laxity improvement, and satisfaction. Results In total, 31 females (mean age 51 ± 9 years) with Fitzpatrick skin types I-IV received a single treatment on 62 treatment areas: 22 upper arms, 34 suprapatellar, and 6 bra-lines. Investigator assessments at 1, 3, and 6 months for global esthetic improvement and skin laxity for the upper arms and bra-line demonstrated improvements in 100% of subjects at all timepoints; for the suprapatellar region, these values were 69%, 92%, 65%, and 85%, 92%, 65%, respectively. Investigator satisfaction at each timepoint was satisfied or very satisfied in 80%, 100%, 90% for upper arms; 80%, 80%, 80% for bra-line; and 50%, 81%, 65% for suprapatellar region. Subject self-assessments at 1, 3, and 6 months for global esthetic improvement and skin laxity for the upper arms demonstrated improvements in 100% of subjects at all timepoints; for the bra-line, these values were 40%, 60%, 80%, and 60%, 60%, 80%, respectively; for the suprapatellar region, these values were 81%, 92%, 88%, and 69%, 85%, 88%, respectively. Subject satisfaction at each timepoint was satisfied or very satisfied in 80%, 100%, 100% for upper arms; 40%, 40%, 80% for bra-line; and 50%, 77%, 65% for suprapatellar. Treatments were well tolerated with subjects reporting transient erythema and edema associated with 69% and 46% of treatments, respectively. Mild bruising, resolving within 5 days, was reported after 32% of the treatments. Conclusion Microneedle fractional radiofrequency provides a single treatment protocol to improve the esthetic appearance of body skin laxity and localized adipose excess to the upper arms, bra-line, and suprapatellar regions. Further study is warranted to evaluate the degree of improvement and long-term effect beyond 6 months post-treatment. Lasers Surg. Med. © 2021 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.

The presence of multiple large (>1 Mb) copy number variants (CNVs) in non‐malignant tissue is rare in human genetics. We present a liveborn male with a birth weight below the first percentile associated with placental mosaicism involving eight 2.4–3.9 Mb de novo duplications. We found that the duplications likely co‐localized to the same cells, were mosaic in the placenta, and impacted maternal and paternal chromosomes. In addition, 27.4 Mb and 240 genes were duplicated in affected cells, including candidate placental genes KISS1 and REN. We ruled out involvement of homologous recombination‐based mechanisms or an altered epigenome in generating the CNVs. This case highlights the diversity of genetic abnormalities in the human placenta and the gaps in our knowledge of how such errors arise.

The COVID‐19 pandemic has affected the health and healthcare of individuals of all ages worldwide. There have been multiple reports and reviews documenting a milder effect and decreased morbidity and mortality in the pediatric population, but there have only been a small number of reports discussing the SARS‐CoV‐2 infection in the setting of an inborn error of metabolism (IEM). Here, we report two patients with underlying metabolic disorders, propionic acidemia and glutaric aciduria type 1, and discuss their clinical presentation, as well as their infectious and metabolic management. Our report demonstrates that individuals with an underlying IEM are at risk of metabolic decompensation in the setting of a COVID‐19 infection. The SARS‐CoV‐2 virus does not appear to cause a more severe metabolic deterioration than is typical.

Pudendal neuralgia (PN) is an impairing neuropathic disorder, affecting both men and women, involving a severe burning and sharp pain along the course of the pudendal nerve. Treatment is often insufficient, and options are limited. Pulsed radiofrequency (PRF) is a technique which might be useful in therapy. This case series aims to determine the effectiveness of PRF in patients with PN in the context of evaluation of care. Between 2010 and 2016, all female patients of University Medical Center Utrecht diagnosed with PN who experience insufficient pain relief after common treatment were offered PRF. Patient Global Impression of Improvement (PGI‐I) scores were assessed at 3‐month follow‐up and at long‐term follow‐up (median 4 years). PGI‐I scores were recorded to evaluate our quality of care. Twenty patients with PN consented to undergo PRF. We lost one patient in follow‐up. Seventy‐nine percent of the patients described their condition as “(very) much better” at 3‐month follow‐up. At long‐term follow‐up, 89% of the patients described their condition as “(very) much better.” No serious side effects were observed. In conclusion, PRF is a successful treatment option in patients not responding to standard treatment options, including pudendal nerve blocks. PRF of the pudendal nerve can be used for PN to provide relief in patients’ chronic pelvic pain.

Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that originates in the outer layer of the adrenal gland. Most ACCs are sporadic, but a small percentage of cases are due to hereditary cancer syndromes such as Li‐Fraumeni syndrome (LFS), Lynch syndrome (LS), and familial adenomatous polyposis (FAP). Multiple endocrine neoplasia type 2A (MEN2A) is an inherited disorder that predisposes to medullary thyroid cancer, pheochromocytoma, and parathyroid hyperplasia. We present here a case of ACC with both LS and MEN2A; the family and medical history were consistent with Lynch. This is, to our knowledge, the first report of a patient with ACC associated with germline mutations in RET and MSH2, and no phenotypical characteristics of MEN2A.

Intracerebral hemorrhage is rare in term born neonates. Besides several non-genetic risk factors, pathogenic variants in COL4A1 and COL4A2 have been described to play a role in the pathophysiology of neonatal intracerebral hemorrhage. To the best of our knowledge, no intragenic COL4A2 duplications have been reported in humans to date. We report a neonate with intracerebral hemorrhage and a de novo intragenic COL4A2 duplication. Although it is not clear yet whether this genetic factor fully explains the clinical phenotype, it may have contributed at least as a risk factor for cerebral hemorrhage. Screening for intragenic COL4A1 and COL4A2 duplications as part of collagen IV diagnostics should be considered as part of the fetal and neonatal work-up for unexplained cerebral hemorrhages and to collect more evidence of the pathogenicity of this genetic mechanism.

Background and Objectives Genitourinary syndrome of menopause (GSM) is a common condition affecting of most postmenopausal women, which greatly impacks the quality of life,and need to treat. This prospective multicenter cohort study aimed to compare the efficacy and safety of the fractional carbon dioxide (CO2) laser with that of topical estrogen for vaginal treatment and relieving symptoms of genitourinary syndrome of menopause (GSM). Study Design/Materials and Methods This study included 162 postmenopausal patients who received vaginal laser or topical Estriol cream therapy between January 2017 and May 2019 at eight study centers in China. The degree of GSM‐related symptoms (vaginal burning, dryness, and dyspareunia) was evaluated using the Vaginal Health Index score (VHIS) and Visual Analog Scale (VAS) at baseline, 1, 3, 6, and 12 months posttreatment. The primary endpoint was the improvement in vaginal burning, dryness, and dyspareunia at 6 months after treatment. Multivariate logistic regression was used to compare the rate of improvement in the two groups. Results At baseline, the laser and control groups showed no significant difference in the mean age, time after menopause, and the VHIS (all P > 0.05). In the laser group, compared with baseline, significant differences were seen in the VHIS after the first or second treatment session and at 1, 3, 6, and 12 months posttreatment (P 0.05). The VHIS scores were significantly higher after 1 month (16.63 ± 2.79 vs. 15.57 ± 2.43) and 12 months (15.72 ± 2.59 vs. 12.12 ± 4.08) of treatment in both the groups (P 0.05). The VAS findings at 6 months posttreatment were significantly different when compared with the pretreatment findings (P

This study was performed to investigate pneumothorax characteristics and association with clinical outcomes in patients with osteosarcoma treated with apatinib. We retrospectively reviewed the medical records of osteosarcoma patients treated with apatinib between January 2016 and April 2020 at three institutions. We evaluated the prevalence, healing time, recurrence, severity, clinical management, and prognosis of pneumothorax in these patients. A total of 54 osteosarcoma patients who received apatinib treatment were enrolled in this study. Among them, 14 patients had pneumothorax. There were significant differences between the patients with and without pneumothorax with regard to the cavitating rate of lung metastases (92.86 vs. 32.50%, respectively, P

Background and Objective Magnetic muscle stimulation (MMS) is a relatively new energy‐based technology that provides a non‐invasive option for body contouring through stimulation and toning of underlying skeletal muscles. This study was conducted to examine the safety, efficacy, and body satisfaction scores of MMS using a CoolToneTM prototype for the aesthetic improvement of abdominal and buttock contour. Study Design/Materials and Methods This was a prospective, non‐comparative, non‐randomized, 12‐week, multicenter study. Male and female participants aged 22‐65 years received 4 MMS treatment sessions to the abdomen and/or buttocks. Body Satisfaction Questionnaire (BSQ) scores for abdomen and/or buttocks were assessed at baseline, immediately post final treatment, at 4 weeks (primary endpoint), and 12 weeks post final treatment. Subject‐rated Global Aesthetic Improvement Scale (SGAIS) was assessed at 4 weeks post final treatment (secondary endpoint), and 12 weeks post final treatment. Additional efficacy assessment included abdominal circumference obtained by 3D imaging at baseline, immediately post final treatment, and at 4 and 12 weeks post final treatment. A Subject Experience Questionnaire (SEQ) was used to assess treatment satisfaction and perspectives at 4 weeks and 12 weeks post final treatment. Adverse events (AEs) were monitored throughout the study. Results A total of 110 participants were recruited, who were 75% female, 80% Caucasian (mostly non‐Hispanic), average age of 39.5 years (range 22–59) with an average body mass index (BMI) of 23.3 kg/m2 (range 18–29.9). At the 4‐week post final treatment visit, the average BSQ score for participants receiving abdominal treatment (n = 93) was significantly improved with a 5.1 average increase in total score from baseline (possible score range 10–50) and by a 5.5 average increase from baseline for participants receiving buttocks treatment (n = 32) (p “Improved” was 68.1% for participants receiving treatment of the abdomen (n = 94), and 81.8% for those receiving buttocks treatment (n = 33). The mean total decrease from baseline in waist circumference was significant at all time points. At the 12‐week post final treatment visit, SEQ data revealed that a majority of participants were “Satisfied” or “Very Satisfied” with overall treatment results and “Agreed” or “Strongly Agreed” that they were motivated to maintain results either by working out or by additional treatment. A total of 6 AEs related to the device and/or treatment were reported, which resolved spontaneously during the study. Conclusion Treatment of the abdomen and/or buttocks with MMS was well‐tolerated and demonstrated significant improvement in aesthetic appearance through the 12‐week post final treatment study duration. As a stand‐alone treatment, MMS expands the range of options for individualized treatment planning for patients seeking abdominal and/or gluteal muscle toning. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals, Inc.

Background and objectives Acoustic wave therapy is a novel facial tightening technique that involves nonthermal penetration of the skin and subcutaneous tissue, affecting cells and their metabolism, and resulting in an increased release of unwanted fat and activation of blood and lymphatic flow in tissues. The objective of this study was to investigate the effectiveness of acoustic wave therapy. Study design/materials and methods A total of 333 patients underwent multiple facial tightening treatment sessions using focused and radial acoustic waves. Each patient received 2,000-3,000 pulses of focused acoustic waves at a power of 0.45-0.88 mJ/mm2 with a pulse frequency of 3-5 Hz and 4,000 pulses of radial acoustic waves at 4-bar power at a frequency of 21 Hz. These sessions were performed more than three times, and treatments were repeated at 1-month intervals. Digital photographs superimposed three-dimensional volumetric assessments, and three-dimensional skin surface displacement calculations using vectors were used to evaluate the results 12 months after the last treatment. Patients also evaluated the results using a 5-point Likert scale. Results Improvements in skin texture, clarity, and laxity were observed in digital photographs. Superimposed three-dimensional color images showed marked volumetric reduction and/or formative modification for even contour toward the lower mid-face. Most vectors showed three-dimensional skin surface displacement at the lateral sides of the temples, cheeks, and chin, in an upward direction. These results were obtained and sustained for up to 12 months without edematous reactions. Almost all patients reported improvement, with 79% reporting "good" or "excellent" improvement. Complications were minor and transitory. Persistent side effects were not observed. Conclusion Acoustic wave therapy could be used as a standard facial tightening treatment, with skin rejuvenation effects shown on digital photographs and three-dimensional quantification assessments. This noninvasive acoustic wave approach was found to be a safe, long-lasting, and effective method for facial tightening. Lasers Surg. Med. 00:00-00, 2020. © 2020 Wiley Periodicals LLC.

Immunotherapy has been shown to prolong survival in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in front-line use; however, subsequent systemic therapy has not been optimized. This study aimed to evaluate the safety and efficacy of cetuximab-containing chemotherapy after immunotherapy. We retrospectively analyzed patients with recurrent or metastatic SCCHN who underwent cetuximab-containing regimens after progression on immunotherapy. Of the 22 patients who met the inclusion criteria, 21 received paclitaxel and cetuximab, and 1 carboplatin and fluorouracil and cetuximab after immunotherapy. Nine patients achieved a partial response, 10 patients had stable disease as their best response on cetuximab-containing chemotherapy, yielding an overall response rate and disease control rate of 40.9 and 86.4%, respectively. The median progression-free survival was 5.2 months, and the median overall survival was 14.5 months. Ten patients developed grade 3-4 adverse events, including neutropenia (31.8%), acneiform rash (9.1%), anemia (4.5%), hypertransaminasemia (4.5%) and stomatitis (4.5%). The most frequent cetuximab-related toxicities across all grades were skin reactions (77.3%), hypomagnesemia (40.9%), stomatitis (27.3%), paronychia (13.6%) and keratitis (4.5%). There was no treatment-related death. Taken together, cetuximab-containing chemotherapy was effective and feasible even after immunotherapy.

Contains fulltext : 221392.pdf (Publisher’s version ) (Open Access) Witteveen-Kolk syndrome (WITKOS) is a rare neurodevelopmental disorder characterized by developmental delay/intellectual disability, facial dysmorphisms, and short stature. The syndrome is caused by loss of function of switch-insensitive 3 transcription regulator family member A (SIN3A). Regarding behavioral functioning, Autism Spectrum Disorders (ASD), obsessive-compulsive behaviors, as well as Attention-Deficit/Hyperactivity Disorder symptoms (ADHD) have been suggested. The present study explores various aspects of neurocognitive functioning in five individuals (age range 10-23) with WITKOS. Medical records and results of extensive neuropsychological assessment are used to describe developmental trajectories and neurocognitive profiles. Systematic analysis of medical records displays developmental difficulties described as ASD or ADHD in childhood, sleep problems and internalizing problems during adolescence. Results of cognitive assessments indicate profoundly disabled (n = 1), mildly disabled (n = 2), borderline (n = 1), and average (n = 1) levels of intelligence. Furthermore, results indicate weaknesses in speed of information processing/sustained attention in all participants, and difficulties in planning and maintaining overview in three participants. Furthermore, parent reports of behavioral functioning primarily suggest problems in social functioning. Implications of both cognitive problems and social-emotional vulnerabilities for counseling are discussed and supplemented with suggestions for interventions. 7 p.

Background and objectives More studies are needed to assess the long-term safety profile and clinical outcomes of lasers and energy-based devices to treat the symptoms associated with vulvovaginal atrophy. This study evaluated a series of three fractional CO2 laser treatments to the vulva and vagina with a 1-year follow-up in a postmenopausal population. Study design/materials and methods In this prospective, self-controlled, open-label clinical study, 18 postmenopausal females with atrophic vaginitis received 3 monthly treatments to the vulva and vagina with a fractional CO2 laser system and 1-, 3-, 6-, and 12-month follow-up. Investigators used the Vaginal Health Index (VHI) to assess changes in vaginal elasticity, fluid volume, vaginal pH, epithelial integrity, and moisture. Sexual function at each timepoint was subject-reported, using the validated Female Sexual Function Index (FSFI). Results Treatment of the vulva and vagina in postmenopausal women with fractional CO2 laser resurfacing resulted in statistically significant improvements as compared with baseline at all post-treatment and follow-up intervals to 12 months in VHI and FSFI (P ≤ 0.003 and P ≤ 0.03, respectively). Mean total VHI score increased from a baseline of 11.8-22.8 (93.2% improved) at 6-month follow-up (P = 0.0002) slightly decreasing to 21.4 (81.4% improved) at 12-month follow-up post-treatment (P = 0.0003). Mean FSFI Scores increased from a baseline of 17.9-26.3 (46.9% improvement) at 12-month follow-up post-treatment (P ≤ 0.0048). Cohort analysis revealed restoration of normal or near-normal (23-25) VHI following laser treatment in the recently menopausal (1-3 years) greatly exceeded that of the >3 years postmenopausal population and the difference was statistically significant (P ≤ 0.05). Normal/near-normal VHI at 3-, 6-, and 12-month post-treatment was 88%, 88%, and 63% in the recently postmenopausal cohort, as compared with 30%, 40%, and 10% of the >3 years postmenopausal group (P ≤ 0.05). Patient satisfaction following treatment was rated as high at 94% at 12-month follow-up. Safety findings demonstrated no-to-slight discomfort in the majority of subjects and transient erythema and edema, with no adverse events associated with treatment. Conclusion Fractional CO2 laser treatment of the vulva and vagina resulted in statistically significant improvements in VHI and FSFI compared with baseline in postmenopausal population that were sustained to 12-month follow-up. Restoration of normal VHI was observed in a statistically significant greater percentage in the recently postmenopausal cohort (1-3 years) as compared with postmenopausal cohort of >3 years, suggesting that early intervention is correlated with improved outcomes. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.

Background and objectives This study describes the effects of nanosecond pulsed electric fields (nsPEF) on the epidermis and dermis of normal skin scheduled for excision in a subsequent abdominoplasty. NsPEF therapy applies nanosecond pulses of electrical energy to induce regulated cell death (RCD) in cellular structures, with negligible thermal effects. Prior pre-clinical studies using nsPEF technology have demonstrated the ability to stimulate a lasting immune response in animal tumor models, including melanoma. This first-in-human-use of nsPEF treatment in a controlled study to evaluate the dose-response effects on normal skin and subcutaneous structures is intended to establish a safe dose range of energies prior to use in clinical applications using nsPEF for non-thermal tissue modification. Study design/materials and methods Seven subjects with healthy tissue planned for abdominoplasty excision were enrolled. Five subjects were evaluated in a longitudinal, 60-day study of effects with doses of six nsPEF energy levels. A total of 30 squares of spot sizes 25mm2 or less within the planned excision area were treated and then evaluated at 1 day, 5 days, 15 days, 30 days, and 60 days prior to surgery. Photographs were taken over time of each treated area and assessed by three independent and blinded dermatologists for erythema, flaking and crusting using a 5-point scale (0 = low, 4 = high). Punch biopsies of surgically removed tissue were processed and evaluated for tissue changes using hematoxylin and eosin, trichome, caspase-3, microphthalmia transcription factor, and elastin stains and evaluated by a dermatopathologist. The skin of two subjects received additional treatments at 2 and 4 hours post-nsPEF and was evaluated in a similar manner. Results Most energy settings exhibited delayed epidermal loss followed by re-epithelization by day 15 and a normal course of healing. Histologic analysis identified the appearance of activated caspase-3 at two and four hours after nsPEF treatment, but not at later time points. At the 1-day time point, a nucleolysis effect was observed in epidermal cells, as evidenced by the lack of nuclear staining while the epidermal plasma membranes were still intact. Cellular structures within the treatment zone such as melanocytes, sebaceous glands, and hair follicles were damaged while acellular structures such as elastic fibers and collagen were largely unaffected except for TL6 which showed signs of dermal damage. Melanocytes reappeared at levels comparable with untreated controls within 1 month of nsPEF treatment. Conclusions The selective effect of nsPEF treatment on cellular structures in the epidermal and dermal layers suggests that this non-thermal mechanism for targeting cellular structures does not affect the integrity of dermal tissue within a range of energy levels. The specificity of effects and a favorable healing response makes nsPEF ideal for treating cellular targets in the epidermal or dermal layers of the skin, including treatment of benign and malignant lesions. NsPEF skin treatments provide a promising, non-thermal method for treating skin conditions and removing epidermal lesions. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

Background and objectives A novel helium plasma device was evaluated for efficacy and safety for dermal resurfacing (ClinicalTrials.gov Identifier: NCT03286283). The helium plasma device delivers energy in a controlled, bimodal fashion that when compared with the nitrogen plasma predicate device in a porcine animal model demonstrated a more limited depth of thermal effect but a greater skin tissue contraction. Study design/materials and methods Fifty-five eligible subjects seeking improvement in facial rhytids were enrolled for study at one of three investigational sites. Most subjects underwent full-face treatment. Power levels were limited to 20% at peri-oral and peri-orbital areas-a level that correlates to an energy density 40% lower than the highest setting on the predicate device. Three-month post-treatment Fitzpatrick Wrinkle and Elastosis Scale (FWS) scores were compared with baseline scores as determined by blinded independent photographic reviewers (IPRs) and study investigators. Results Blinded IPRs observed a ≥1-point FWS improvement in 63.64% of subjects whereas study investigators noted a ≥1-point FWS improvement in 54 of 55 subjects (98.18%) of subjects. 90.9% of subjects indicated "improvement" in appearance utilizing the modified Global Aesthetic Improvement Scale. Subgroup analysis showed 1-point (±0.05) FWS improvement by IPRs and study investigators for Fitzpatrick Skin Types II and III, age≥62, two of three study sites, and post-treatment oral steroid use. Eighty Non-Serious Adverse Events in 39 subjects were reported, most of which resolved within 14 days or less. There were no Serious Adverse Events or Unanticipated Device Effects reported. Conclusion At the modest power level studied, a significant improvement from a single pass helium plasma dermal resurfacing treatment was observable in most subjects by IPRs and investigators, and no serious adverse events were reported. The discrepancy between IPR and study investigator FWS improvement may be explained in part by the limitations of assessing two-dimensional photographs versus live in-person evaluation of subjects. Studies evaluating higher energy levels and/or multiple treatment passes are ongoing. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals, Inc.

Background and objectives In our previous proof-of-principle study, transcranial photobiomodulation (tPBM) with 1,064-nm laser was reported to significantly increase concentration changes of oxygenated hemoglobin (∆[HbO]) and oxidized-state cytochrome c oxidase (∆[oxi-CCO]) in the human brain. This paper further investigated (i) its validity in two different subsets of young human subjects at two study sites over a period of 3 years and (ii) age-related effects of tPBM by comparing sham-controlled increases of ∆[HbO] and ∆[oxi-CCO] between young and older adults. Study design/materials and methods We measured sham-controlled ∆[HbO] and ∆[oxi-CCO] using broadband near-infrared spectroscopy (bb-NIRS) in 15 young (26.7 ± 2.7 years of age) and 5 older (68.2 ± 4.8 years of age) healthy normal subjects before, during, and after right-forehead tPBM/sham stimulation with 1,064-nm laser. Student t tests were used to test statistical differences in tPBM-induced ∆[HbO] and ∆[oxi-CCO] (i) between the 15 young subjects and those of 11 reported previously and (ii) between the two age groups measured in this study. Results Statistical analysis showed that no significant difference existed in ∆[HbO] and ∆[oxi-CCO] during and post tPBM between the two subsets of young subjects at two study sites over a period of 3 years. Furthermore, the two age groups showed statistically identical net increases in sham-controlled ∆[HbO] and ∆[oxi-CCO]. Conclusions This study provided strong evidence to validate/confirm our previous findings that tPBM with 1,064-nm laser enables to increase cerebral ∆[HbO] and ∆[oxi-CCO] in the human brain, as measured by bb-NIRS. Overall, it demonstrated the robust reproducibility of tPBM being able to improve cerebral hemodynamics and metabolism of the human brain in vivo in both young and older adults. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals, Inc.

Lateral meningocele syndrome (LMS) is due to specific pathogenic variants in the last exon of NOTCH3 gene. Besides the lateral meningoceles, this condition presents with dysmorphic features, short stature, congenital heart defects, and feeding difficulties. Here, we report a girl with neurosensorial hearing loss, severe gastroesophageal reflux disease, congenital heart defects, multiple renal cysts, kyphosis and left‐convex scoliosis, dysmorphic features, and mild developmental delay. Exome sequencing detected the previously unreported de novo loss‐of‐function variant in exon 33 of NOTCH3 p.(Lys2137fs). Following the identification of the gene defect, MRI of the brain and spine revealed temporal encephaloceles, inner ears anomalies, multiple spinal lateral meningoceles, and intra‐ and extra‐dural arachnoid spinal cysts. This case illustrates the power of reverse phenotyping to establish clinical diagnosis and expands the spectrum of clinical manifestations related to LMS to include inner ear abnormalities and multi‐cystic kidney disease.

BACKGROUND AND OBJECTIVES Fluorescence-guided resection of glioblastomas (GBM) using 5-aminolevulinic acid (5-ALA) improves intraoperative tumor visualization and is thus widely used nowadays. During resection, different fluorescence levels can usually be distinguished within the same tumor. Recently, we demonstrated that strong, vague, and no fluorescence correspond to distinct histopathological characteristics in newly diagnosed GBM. However, the qualitative fluorescence classification by the neurosurgeon is subjective and currently no comprehensive data on interobserver variability is available. The aim of this study was thus to investigate the interobserver variability in the classification of 5-ALA fluorescence levels in newly diagnosed GBM. STUDY DESIGN/MATERIALS AND METHODS A questionnaire investigating the interobserver variability in 5-ALA fluorescence quantification was performed at a nation-wide neurosurgical oncology meeting. The participants involved in the neurosurgical/neurooncological field were asked to categorize 30 cases of 5-ALA fluorescence images derived from GBM resection on a lecture hall screen according to the widely used three-tier fluorescence classification scheme (negative, vague, or strong fluorescence). Additionally, participants were asked for information on their medical background such as specialty, level of training, and experience with 5-ALA fluorescence-guided procedures. Interobserver agreement was defined as the calculated mean κ values for each observer. RESULTS A total of 36 questionnaires were included in the final analysis. The mean average κ value in fluorescence classification within the entire cohort was 0.71 ± 0.12 and 29 (81%) participants had a substantial or almost perfect interobserver agreement (κ values 0.6-1.0). Interobserver agreement was significantly higher in neurosurgeons (mean κ: 0.83) as compared with non-neurosurgeons involved in the neurooncological field (mean κ: 0.52; P

Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra‐renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one‐day‐old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post‐zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow‐up studies for presumed de novo and low‐level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.

The relatively low toxicity profile of nab-paclitaxel plus carboplatin and its feasibility as an adjuvant administration was reported previously. This study aimed to evaluate the survival efficacy for completely resected patients with stage IB, II, and IIIA nonsmall cell lung cancer (NSCLC). Twenty-nine eligible patients with NSCLC who received surgical resection for pathological stage IB, II, or IIIA, followed by postoperative adjuvant chemotherapy with modified 3-week cycles of either nab-paclitaxel (nab-P) (100 mg/m2) on days 1 and 8 followed by carboplatin area (area under the curve = 6) on day 1 were prospectively enrolled and assessed for survival outcomes against patients with the same stages who received other postoperative adjuvant chemotherapy regimens during the same period. There were no significant differences in clinicopathological features, including age, gender, smoking status, performance status, surgical procedures, tumor histology, and pathological stage between the two groups. The cumulative overall survival (OS) rates at 5 years of the experimental and control groups in pathological stage IB–IIIA were 85.4% and 63.9%, respectively (P = 0.598), while recurrence-free survival (RFS) rates in these groups at 5 years were 65.2% and 34.8%, respectively (P = 0.344). Moreover, the cumulative OS rates of the experimental and control groups in pathological stage II–IIIA were 83.6% and 63.6%, respectively (P = 0.970), while RFS rates in these groups at 5 years were 61.1% and 37.3%, respectively (P = 0.460). This new regimen was considered an attractive alternative postoperative adjuvant chemotherapy option with relatively low toxicity and moderate survival outcomes for completely resected NSCLC.

The joint occurrence of short stature, congenital dislocation of the hip, carpal coalition, dislocation of the radial head, cavus deformity, scoliosis, and vertebral anomalies was first described in 1993 by Steel et al. (OMIM #615155) in 23 children from Puerto Rico. The condition is caused by a deficient matrix protein, collagen type XXVII alpha 1 chain, due to bi‐allelic loss of function mutations in the gene COL27A1. Outside of Puerto Rico, only four families have been described, in three of which the patients also had hearing loss. However, structural eye defects have not yet been reported in conjunction with this rare autosomal recessive syndrome. Here, we describe a 9‐year‐old girl born to nonconsanguineous Syrian parents with the characteristic features of Steel syndrome, including short stature, massive malalignment of large joints, kyphoscoliosis, hearing loss, and typical facial dysmorphism. However, she was also born with bilateral colobomata of the irides and choroido‐retinae with unilateral affection of the macula. Whole exome sequencing identified two pathogenic compound heterozygous variants in COL27A1: c.93del, p.(Phe32Leufs*71) and c.3075del, p.(Lys1026Argfs*33). There was no discernible alternative cause for the colobomata. Our findings might indicate an association of this exceptionally rare disorder caused by COL27A1 mutations with developmental defects of the eye from the anophthalmia/microphthalmia/coloboma spectrum.

Background Congenital microtia is a common craniofacial malformation resulting from both environmental and genetic factors. Recurrent chromosomal imbalances were observed in patients with microtia. The 22q11.2 deletion is one of the most common microdeletions in human beings. The cell division cycle 45 gene (CDC45) embedded in the proximal 22q11.2 deleted region is involved in craniofacial development. However, only a few studies have focused on the 22q11.2 deletion as genetic etiology in microtia patients and studied its associated external ear deformity characteristics in detail. Methods In this research, a total of 65 patients from north China with sporadic microtia were studied. Copy number variations of CDC45 were screened using AccuCopy assay. The 22q11.2 deletion harboring CDC45 was identified by whole‐genome sequencing and targeted next‐generation sequencing. A parental test was carried out to determine the origin of the deletion. Results CDC45 copy number loss was identified in two patients with microtia. A set of qPCR assays demonstrated two patients carried a typical proximal 22q11.2 deletion between the low‐copy repeats on chromosome 22q11.2 (LCR22A and LCR22D), encompassing CDC45. The 22q11.2 deletions were de novo in each patient. In‐depth auricular phenotype assessment showed these two patients have a distinct concha‐type ear malformation while other microtia patients have lobule‐type microtia among the 65 microtia patient cohort in this study. Conclusion Here we present two additional Chinese microtia patients with de novo 22q11.2 proximal deletion harboring CDC45 and further report these patients’ distinct ear malformation., Here, we report two additional Chinese microtia patients with 22q11.2 deletion. Concha‐type microtia was observed in these two patients, distinguished from other lobule‐type microtia patients. We suggest 22q11.2 deletion should be considered in the patient with microtia who presents the described ear malformation.

One of the challenges of genetic testing in patients with hemophilia A is the interpretation of sequence variants. Here we report a silent variant found in exon 2 in the F8 gene in a 47‐year‐old patient with a previous von Willebrand disease (VWD) type 1 diagnosis. Clinically he had mild bleeding symptoms restricted to prolonged bleeding from minor wounds. Sanger sequencing of F8 gene using genomic DNA showed a hemizygous silent variant in exon 2: c.222G>T, p.Thr74Thr. When applying ACMG criteria, the variant was predicted to be “likely benign” in the analyzing software or VUS after curating. Sanger sequencing of the patient's cDNA after nested polymerase chain reaction showed that the patient had both a normal transcript containing exons 1–4 and a defect transcript lacking exon 2. These findings explain the patient's low FVIII:C level and led to the diagnosis of mild hemophilia A instead of VWD type 1. This case illustrates that mRNA work‐up may be needed to clarify a patient's phenotype–genotype., A patient with low FVIII levels was first misdiagnosed as von Willebrand disease. Genetic analysis revealed a silent variant in F8:c.222G>T.Sanger sequencing of the patient's cDNA after nested polymerase chain reaction showed that the patient had both a normal transcript containing exons 1–4 and a defect transcript lacking exon 2. The patient could be diagnosed with mild hemophilia A due to partial exon skipping.

Background The NADH:ubiquinone oxidoreductase complex assembly factor gene (NDUFAF5) has been linked to the occurrence of Leigh syndrome, but few causative mutations have been identified. Here we report a rare case of Leigh syndrome in an infant who died in the early postnatal period. Methods We performed whole‐exome sequencing (WES) and mutation analysis of NDUFAF5 to obtain genetic data on the patient and describe the clinical and genetic characteristics. Results The proband was a 2‐month‐old male infant who suffered from recurrent vomiting and persistent seizure and died at 2 months of age after early medical support and treatment. His parents reported the unexplained death of the infant's older brother at 1 year of age. WES of the patient's DNA revealed c.357C>G and c.611C>T compound heterozygous mutations in NDUFAF5; analysis with the MutationTaster application indicated that both were pathogenic (p = 0.99). Significant structural changes in the transport domain of the protein were predicted using SWISS‐MODEL. We estimated the stability of the mutant protein using a mutation cutoff scanning matrix and found reductions in Gibbs free energy (−0.623 kcal/mol for p.D119E and −0.813 kcal/mol for p.A204V), indicating that the mutations led to an unstable protein structure. We speculated that the patient died as a result of impaired mitochondrial function caused by the NDUFAF5 mutations, and made a diagnosis of Leigh syndrome. Conclusion Our results demonstrate that molecular genetic screening is useful for the diagnosis of mitochondrial diseases, especially in children with a positive family history. Leigh syndrome should be considered in the diagnosis of patients presenting with severe recurrent vomiting and feeding difficulties with persistent seizure. Our findings expand the mutation spectrum of the NDUFAF5 gene and contribute to the genotype–phenotype map of mitochondrial respiratory chain complex I deficiency., Our results demonstrate that molecular genetic screening is useful for the diagnosis of mitochondrial diseases, especially in children with a positive family history. Leigh syndrome should be considered in the diagnosis of patients presenting with severe recurrent vomiting and feeding difficulties with persistent seizure. Our findings expand the mutation spectrum of the NDUFAF5 gene and contribute to the genotype‐phenotype map of mitochondrial respiratory chain complex I deficiency.