Intraocular Pressure Lowering Associated With Worsening Optic Pit-Like Retinoschisis.

In this article, we present a case of optic pit-like macular retinoschisis in the absence of advanced glaucomatous cupping. Intraocular pressure (IOP)-lowering therapy, which was started due to an early concern for glaucoma, caused a worsening of the retinoschisis, which subsequently resolved on discontinuation of the IOP-lowering therapy. Lower IOP likely triggered intraretinal fluid accumulation by facilitating a translaminar gradient from the subarachnoid to intraretinal space. [Ophthalmic Surg Lasers Imaging Retina 2024;55:100-102.].

Approach to the Ankle in Adult Acquired Flatfoot Deformity.

Adult acquired flatfoot is a progressive deformity of the foot and ankle, which frequently becomes increasingly symptomatic. The posterior tibial tendon is most commonly associated with the deformity. A targeted physical examination with plain film radiographs is the recommended initial assessment, which will further guide a physician toward procuring more advanced imaging or toward surgical intervention. In this chapter the authors review the current literature of their approach to the treatment of the ankle in end stage of adult acquired flatfoot deformity.

Seasonal Variation of Congenital Diaphragmatic Hernia: A Review of the Literature and Database Report from the United States and Canada.

INTRODUCTION: The etiology of congenital diaphragmatic hernia (CDH) remains unknown and only 10 to 30% of patients have a genetic cause. Seasonal variation is known to contribute to the development of some congenital anomalies. Our aim was to investigate whether CDH births have seasonal variation. MATERIALS AND METHODS: A literature review was conducted for CDH and seasonality. Moreover, data from the CDH International Patient Registry Database were collected for infants with due dates between 2008 and 2014. Due dates were used to determine seasonal distribution of births. Birth rates per month in the United States and Canada were extracted from publicly available databases. Data were analyzed using analysis of variance and contingency tables. RESULTS: First, the literature review revealed 11 articles, of which 3 were eligible for inclusion. These studies reported conflicting results on seasonality of CDH. Second, we extracted due dates from the CDH International Patient Registry Database (1,259 patients) and found that there were fewer due dates in winter months (12.1 ± 4 patients/month) than in summer (16.7 ± 6 patients/month; p = 0.011) and fall months (16.3 ± 5 patients/month; p = 0.022). Although this trend was similar to that of all births in the United States and Canada, a lower incidence was observed in winter for CDH infants (20.2%) than for the general population (24.1%, p = 0.0012). CDH survival rate did not vary by season. CONCLUSION: This study provides evidence for a seasonal variation of CDH births. No causative link was established between CDH development and seasonality. Population-based studies with a focus on exposome data are needed to explain seasonal variation in CDH.

Breast Implant Illness and Cutibacterium acnes: A Case Report.

Breast implant illness (BII) is a term to describe a wide range of nonspecific symptoms after breast implant placement. At present, no specific diagnostic criteria for BII exist, and there is limited solid understanding of what causes BII. There is some evidence that biofilm infections such as those caused by Cutibacterium acnes may play a role in the development of BII. We present a case of a 38-year-old White woman who developed BII symptoms (psychological and integumentary). After en bloc explantation, her tissue cultures resulted in C. acnes growth. Plastic surgeons should be aware of this potential complication and discuss it thoroughly with patients before breast implantation. Evidence suggests that biofilm infection with C. acnes may play a role in BII development. En bloc explantation is the typical treatment of choice. Plastic surgeons should be aware of C. acnes as a potential cause of BII and should counsel patients on the potential risks and remedies for BII.

Genetic Analysis of Functional Rare Germline Variants across Nine Cancer Types from an Electronic Health Record Linked Biobank.

BACKGROUND: Rare variants play an essential role in the etiology of cancer. In this study, we aim to characterize rare germline variants that impact the risk of cancer. METHODS: We performed a genome-wide rare variant analysis using germline whole exome sequencing (WES) data derived from the Geisinger MyCode initiative to discover cancer predisposition variants. The case-control association analysis was conducted by binning variants in 5,538 patients with cancer and 7,286 matched controls in a discovery set and 1,991 patients with cancer and 2,504 matched controls in a validation set across nine cancer types. Further, The Cancer Genome Atlas (TCGA) germline data were used to replicate the findings. RESULTS: We identified 133 significant pathway-cancer pairs (85 replicated) and 90 significant gene-cancer pairs (12 replicated). In addition, we identified 18 genes and 3 pathways that were associated with survival outcome across cancers (Bonferroni P < 0.05). CONCLUSIONS: In this study, we identified potential predisposition genes and pathways based on rare variants in nine cancers. IMPACT: This work adds to the knowledge base and progress being made in precision medicine.

Concentric Macular Rings Without Ocular Pathology.

Concentric macular rings (CMRs) of Henle's fiber layer (HFL) are an uncommon imaging phenomenon previously associated with foveal hypoplasia and epiretinal membrane. Here, we present a case of a 15-year-old boy with bilateral CMRs, normal visual function, and no ocular pathology. These bilateral findings in the absence of vitreomacular traction, foveal hypoplasia, or any other ocular abnormality suggest that macular rings may occur as a normal but rare variant of HFL architecture. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:353-355.].

Creation and validation of 3D-printed head molds for stereotaxic injections of neonatal mouse brains.

BACKGROUND: An increasing number of rodent model systems use injection of DNA or viral constructs in the neonatal brain. However, approaches for reliable positioning and stereotaxic injection at this developmental stage are limited, typically relying on handheld positioning or molds that must be re-aligned for use in a given laboratory. NEW METHOD: A complete protocol and open-source software pipeline for generating 3D-printed head molds derived from a CT scan of a neonatal mouse head cast, together with a universal adapter that can be placed on a standard stereotaxic stage. RESULTS: A series of test injections with adenovirus encoding red fluorescent protein, or Fluorogold, were conducted using original clay molds and newly generated 3D printed molds. Several metrics were used to compare spread and localization of targeted injections. COMPARISON WITH EXISTING METHODS: The new method of head mold generation gave comparable results to the field standard, but also allowed the rapid generation of additional copies of each head mold with standardized positioning of the head each time. CONCLUSIONS: This 3D printing pipeline can be used to efficiently develop a series of head molds with standardized injection coordinates across multiple laboratories. More broadly, this pipeline can easily be adapted to other perinatal ages or species.

Simultaneous Superiorly Based Pharyngeal Flap and Tonsillectomy: Evaluation of Speech and Pain Outcomes.

ABSTRACT: Controversy remains whether to perform a pharyngeal flap simultaneously with a tonsillectomy in patients with velopharyngeal insufficiency. The aim of this study is to revisit the speech outcomes and complications associated with the combined superiorly based pharyngeal flap and tonsillectomy procedure, while comparing pain outcomes. We hypothesize that the combined procedure will improve speech outcomes with minimal complications, but patients will experience more pain in the combined procedure.A 5-year retrospective review of registry data from Boys Town National Research Hospital was conducted from 2014 to 2019. Data collection included age, surgeries performed, length of stay, pain medication administration occurrences, immediate postoperative complications, postoperative speech outcomes specifically related to articulation (audible nasal airway emissions) and resonance (hypernasality).Eighty-eight patients had a superiorly based pharyngeal flap over this 5-year period. Eighteen patients (20%) had a simultaneous procedure performed. There were no patients who had immediate postoperative complications such as upper airway obstruction or bleeding complications that necessitated a reoperation. One of the patients had a pharyngeal flap dehiscence that required a revision pharyngeal flap in the combined group. Nasal airway emissions and hypernasality were eliminated in 58.3% and 75%of the combined patients, respectively. The total number of narcotic administration occurrences were significantly higher in the combined group than the pharyngeal flap only group (9.0 versus 7.0; P = 0.03).A number of velopharyngeal patients will present with hypertrophied tonsils. We believe that it is safe and beneficial to perform the combined procedure in the same setting.

A novel OCT signature in leukemic papillopathy masquerading as autoimmune or infectious uveitis.

PURPOSE: With therapeutic advances, central nervous system (CNS) involvement in leukemia has become more common. Leukemic optic disc infiltration, often a clinical diagnosis, can present as an isolated finding in primary or relapsed CNS disease and therefore requires early recognition. Not previously well appreciated, we report here signs of intraocular inflammation accompanying leukemic optic disc infiltration, suggesting infectious or non-infectious uveitis as an alternative diagnosis. We describe a novel optical coherence tomography (OCT) sign favoring leukemic infiltration. METHODS: Retrospective consecutive case series of all leukemic patients with disc edema (5 patients, 6 eyes) presenting to the University of Michigan's Ocular Oncology Clinic between October 2019 and March 2020. RESULTS: We report five leukemic patients (6 eyes) who were evaluated for disc edema and vitritis and eventually diagnosed with leukemic papillopathy. All five patients initially had a bland lumbar puncture (LP), and all four patients who underwent magnetic resonance imaging (MRI) had no retrobulbar nerve involvement. Clinical findings included preserved visual acuity (n = 5 eyes, 83%), anterior chamber (AC) cell (n = 3 eyes, 50%), vitreous cell (n = 6 eyes, 100%), and retinal whitening (n = 4 eyes, 66%). In five eyes (83%), a diagnosis of infectious or non-infectious uveitis was initially considered. The OCT finding of inner retinal thickening and loss of inner retinal lamination with largely preserved outer retinal architecture helped point towards a leukemic infiltrative process emanating from the disc and spreading retrograde through the nerve fiber layer. CONCLUSIONS: These cases highlight the difficulty of distinguishing intraocular inflammation associated with leukemic papillopathy from infectious or non-infectious uveitis, especially considering bland LP and negative retrobulbar MRI signal in all our patients. We propose juxtapapillary inner retinal infiltration with the loss of inner retinal lamination and relative preservation of outer retinal architecture on OCT imaging as a finding that supports the diagnosis of leukemic papillopathy.

On-Call Examinations for Acute Onset of Flashes, Floaters, or Curtain by Junior Ophthalmology Residents: Outcomes, Safety, and Resource Use.

PURPOSE: To determine whether an on-call system serviced by junior residents can safely triage patients with symptoms concerning for posterior vitreous detachment, retinal tear, and retinal detachment. DESIGN: Quality improvement study structured as a prospective cohort study. PARTICIPANTS: All symptomatic patients seen in 2017 by an on-call junior resident were followed up (257 patients). Those with follow-up within 6 months of initial presentation (228 patients, 246 unique encounters) were included. METHODS: We prospectively tracked all symptomatic patients seen on-call by a junior resident in 2017 at a major academic medical center. MAIN OUTCOME MEASURES: Incidence and predictors of true retinal tears or detachments, false-positive tears or detachments, false-negative tears or detachments, and resource use. RESULTS: Of 246 symptomatic encounters, 83 (33.7%) had a perceived retinal tear or detachment. Residents used B-scan ultrasonography in a high number of encounters (41.0%). Ten (4.1%) false-positive tears or detachments were identified, with the presence of intraretinal hemmorhage predicting a false-positive examination (adjusted odds ratio, 3.86; 95% confidence interval, 1.1-13.5). Thirteen (5.3%) false-negative tears and no false-negative detachments were identified. Eleven (84.6%) false-negative tears underwent follow-up within days based on high-risk characteristics, and no false-negative tears progressed to detachment at follow-up. Measures of resource use included an in-person confirmation of examination findings by the senior resident or fellow in 59 encounters (24.0%) and shorter follow-up times to a retina rather than a nonretina clinic for 52 of 151 patients who showed no pathologic features on initial examination. CONCLUSIONS: Junior residents can safely provide on-call triage of patients with symptoms concerning for a posterior vitreous detachment, retinal tear, or retinal detachment. The system requires moderate resource use, including occasional confirmatory examinations by a second physician and shorter follow-up times to retina clinic for high-risk patients.

Synthesis of high-molar-activity [18F]6-fluoro-L-DOPA suitable for human use via Cu-mediated fluorination of a BPin precursor.

[18F]6-fluoro-L-DOPA ([18F]FDOPA) is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that is used to image Parkinson's disease, brain tumors, and focal hyperinsulinism of infancy. Despite these important applications, [18F]FDOPA PET remains underutilized because of synthetic challenges associated with accessing the radiotracer for clinical use; these stem from the need to radiofluorinate a highly electron-rich catechol ring in the presence of an amino acid. To address this longstanding challenge in the PET radiochemistry community, we have developed a one-pot, two-step synthesis of high-molar-activity [18F]FDOPA by Cu-mediated fluorination of a pinacol boronate (BPin) precursor. The method is fully automated, has been validated to work well at two separate sites (an academic facility with a cyclotron on site and an industry lab purchasing [18F]fluoride from an outside vendor), and provides [18F]FDOPA in reasonable radiochemical yield (2.44 ± 0.70 GBq, 66 ± 19 mCi, 5 ± 1%), excellent radiochemical purity (>98%) and high molar activity (76 ± 30 TBq/mmol, 2,050 ± 804 Ci/mmol), n = 26. Herein we report a detailed protocol for the synthesis of [18F]FDOPA that has been successfully implemented at two sites and validated for production of the radiotracer for human use.

Author Correction: An exome-wide rare variant analysis of Korean men identifies three novel genes predisposing to prostate cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An exome-wide rare variant analysis of Korean men identifies three novel genes predisposing to prostate cancer.

Since prostate cancer is highly heritable, common variants associated with prostate cancer have been studied in various populations, including those in Korea. However, rare and low-frequency variants have a significant influence on the heritability of the disease. The contributions of rare variants to prostate cancer susceptibility have not yet been systematically evaluated in a Korean population. In this work, we present a large-scale exome-wide rare variant analysis of 7,258 individuals (985 cases with prostate cancer and 6,273 controls). In total, 19 rare variant loci spanning 7 genes contributed to an association with prostate cancer susceptibility. In addition to replicating previously known susceptibility genes (e.g., CDYL2, MST1R, GPER1, and PARD3B), 3 novel genes were identified (FDR q < 0.05), including the non-coding RNAs ENTPD3-AS1, LOC102724438, and protein-coding gene SPATA3. Additionally, 6 pathways were identified based on identified variants and genes, including estrogen signaling pathway, signaling by MST1, IL-15 production, MSP-RON signaling pathway, and IL-12 signaling and production in macrophages, which are known to be associated with prostate cancer. In summary, we report novel genes and rare variants that potentially play a role in prostate cancer susceptibility in the Korean population. These observations demonstrated a path towards one of the fundamental goals of precision medicine, which is to identify biomarkers for a subset of the population with a greater risk of disease than others.

Perioperative Management and Factors Associated With Transfusion in Cranial Vault Reconstruction.

BACKGROUND: Bleeding is the most common adverse event in patients undergoing cranial vault reconstruction. The authors compare the transfusion rates against a national sample to determine whether the patients experience lower transfusion rates. METHODS: The authors queried the Pediatric National Surgical Quality Improvement Program (Peds-NSQIP) for patients who underwent cranial vault reconstruction (CPT 61559) and compared them to patients who underwent cranial vault reconstruction for sagittal craniosynostosis at Children's Hospital and Medical Center (CHMC) in Omaha, Nebraska. Patients over the age of 24 months were excluded. Binary logistic regression analysis was performed using IBM-SPSS v24.0 to determine factors associated with transfusion at CHMC. RESULTS: Patient demographics, preoperative hematocrit and platelet counts, readmission rates, and reoperation rates did not differ between CHMC (N = 54) and Peds-NSQIP (N = 1320) cohorts. Patients in the CHMC cohort had shorter preincision anesthesia times (47 versus 80 minutes, P < 0.001), shorter operative times (108 versus 175 minutes, P < 0.001), lower transfusion rates (50% versus 73%, P < 0.001), and smaller mean transfusion volumes (16 versus 33 mL/kg, P < 0.001); however mean length of stay was longer (4.1 versus 3.6 days, P < 0.001). Factors independently associated with transfusion at CHMC included preoperative hematocrit (odds ratio [OR] 0.423, P = 0.002), administration of an antifibrinolytic agent (OR 0.004, P = 0.001) and temperature at the time of incision (OR 0.020, P = 0.043). CONCLUSION: Patients at CHMC require less transfused blood and experience low transfusion rates. Preoperative hematocrit, administration of antifibrinolytic agents, and temperature at the time of incision are all modifiable factors associated with perioperative transfusion.

Exome-Wide Rare Variant Analysis From the DiscovEHR Study Identifies Novel Candidate Predisposition Genes for Endometrial Cancer.

Endometrial cancer is the fourth most commonly diagnosed cancer in women. Family history is a known risk factor for endometrial cancer. The incidence of endometrial cancer in a first-degree relative elevates the relative risk to range between 1.3 and 2.8. It is unclear to what extent or what other novel germline variants are at play in endometrial cancer. We aim to address this question by utilizing whole exome sequencing as a means to identify novel, rare variant associations between exonic regions and endometrial cancer. The MyCode community health initiative is an excellent resource for this study with germline whole exome data for 60,000 patients available in the first phase, and further 30,000 patients independently sequenced in the second phase as part of DiscovEHR study. We conducted exome-wide rare variant association using 472 cases and 4,110 controls in 60,000 patients (discovery cohort); and 261 cases and 1,531 controls from 30,000 patients (replication cohort). After binning rare germline variants into genes, case-control association tests performed using Optimal Unified Approach for Rare-Variant Association, SKAT-O. Seven genes, including RBM12, NDUFB6, ATP6V1A, RECK, SLC35E1, RFX3 (Bonferroni-corrected P < 0.05) and ATP8A1 (suggestive P < 10-5), and one long non-coding RNA, DLGAP4-AS1 (Bonferroni-corrected P < 0.05), were associated with endometrial cancer. Notably, RECK, and ATP8A1 were replicated from the replication cohort (suggestive threshold P < 0.05). Additionally, a pathway-based rare variant analysis, using pathogenic and likely pathogenic variants, identified two significant pathways, pyrimidine metabolism and protein processing in the endoplasmic reticulum (Bonferroni-corrected P < 0.05). In conclusion, our results using the single-source electronic health records (EHR) linked to genomic data highlights candidate genes and pathways associated with endometrial cancer and indicates rare variants involvement in endometrial cancer predisposition, which could help in personalized prognosis and also further our understanding of its genetic etiology.

Considerations for Thyroidectomy as Treatment for Graves Disease.

Hyperthyroidism is a clinical state that results from abnormally elevated thyroid hormones. Thyroid gland affects many organ systems; therefore, patients usually present with multiple clinical manifestations that involve many organ systems such as the nervous, cardiovascular, muscular, and endocrine system as well as skin manifestations. Hyperthyroidism is most commonly caused by Graves disease, which is caused by autoantibodies to the thyrotropin receptor (TRAb). Other causes of hyperthyroidism include toxic multinodular goiter, toxic single adenoma, and thyroiditis. Diagnosis of hyperthyroidism can be established by measurement of thyroid-stimulating hormone (TSH), which will be suppressed with either elevated free T4 and/or T3 (overt hyperthyroidism) or normal free T3 and T4 (subclinical hyperthyroidism). Hyperthyroidism can be treated with antithyroid drugs (ATDs), radioactive iodine (RAI), or thyroidectomy. ATDs have a higher replacement rate when compared with RAI or thyroidectomy. Recent evidence has shown that thyroidectomy is a very effective, safe treatment modality for hyperthyroidism and can be performed as an outpatient procedure. This review article provides some of the most recent evidence on diagnosing and treating patients with hyperthyroidism.

Correction to: Systematic characterization of germline variants from the DiscovEHR study endometrial carcinoma population.

Following publication of the original article [1], the authors reported that Fig. 1 was not correctly processed during the production process. The correct Fig. 1 is given below.

Systematic characterization of germline variants from the DiscovEHR study endometrial carcinoma population.

BACKGROUND: Endometrial cancer (EMCA) is the fifth most common cancer among women in the world. Identification of potentially pathogenic germline variants from individuals with EMCA will help characterize genetic features that underlie the disease and potentially predispose individuals to its pathogenesis. METHODS: The Geisinger Health System's (GHS) DiscovEHR cohort includes exome sequencing on over 50,000 consenting patients, 297 of whom have evidence of an EMCA diagnosis in their electronic health record. Here, rare variants were annotated as potentially pathogenic. RESULTS: Eight genes were identified as having increased burden in the EMCA cohort relative to the non-cancer control cohort. None of the eight genes had an increased burden in the other hormone related cancer cohort from GHS, suggesting they can help characterize the underlying genetic variation that gives rise to EMCA. Comparing GHS to the cancer genome atlas (TCGA) EMCA germline data illustrated 34 genes with potentially pathogenic variation and eight unique potentially pathogenic variants that were present in both studies. Thus, similar germline variation among genes can be observed in unique EMCA cohorts and could help prioritize genes to investigate for future work. CONCLUSION: In summary, this systematic characterization of potentially pathogenic germline variants describes the genetic underpinnings of EMCA through the use of data from a single hospital system.

Anterior Cranial Vault Reconstruction With Distraction for Primary and Secondary Craniosynostosis Repair.

Traditional fronto-orbital advancement continues to be a useful operation for correction of craniosynostosis involving the coronal or metopic sutures. Recently, distraction osteogenesis has been used to correct a variety of cranial deformities. Studies have mostly focused on posterior vault distraction due to its simplicity and greater volume gain when compared with anterior vault distraction. However, certain patients are not candidates for posterior distraction due to anterior deformity and need for expansion of the frontal skull. The authors have developed a technique that allows for both reshaping as well as distraction of the anterior cranial vault.This was a retrospective chart review performed between March 2012 and October 2016 at a single institution by a single plastic surgeon. Thirty-nine (39) patients were included in this study. The indications for surgical intervention were signs of increased intracranial pressure or severe anterior skull deformity in the setting of craniosynostosis. The authors reviewed patient characteristics, length of follow-up, number of previous and subsequent surgeries, complications, and rate of relapse.The average age of patients undergoing the procedure was 5.2 years (range 6 months-15 years). Twenty-four (24) patients had 1 previous surgery, 3 had 2 previous surgeries, 1 had 3 previous surgeries, and 11 had no previous surgeries. The average follow-up was 2.5 years (range 6 months-4 years). One patient had a broken activation wire requiring return to the operating room. Three (3) patients (2 Apert and 1 Crouzon) underwent subsequent posterior vault distraction surgery. All patients demonstrated significant improvement in forehead cosmesis.Anterior cranial vault reconstruction with distraction is a safe alternative to traditional cranial vault reconstruction. It can improve forehead shape and position in older children who have had previous surgery as well as patients with severe anterior skull deformity associated with craniosynostosis.