Investigation of the functional impact of CHED- and FECD4-associated SLC4A11 mutations in human corneal endothelial cells.

Mutations in the solute linked carrier family 4 member 11 (SLC4A11) gene are associated with congenital hereditary endothelial dystrophy (CHED) and Fuchs corneal endothelial dystrophy type 4 (FECD4), both characterized by corneal endothelial cell (CEnC) dysfunction and/or cell loss leading to corneal edema and visual impairment. In this study, we characterize the impact of CHED-/FECD4-associated SLC4A11 mutations on CEnC function and SLC4A11 protein localization by generating and comparing human CEnC (hCEnC) lines expressing wild type SLC4A11 (SLC4A11WT) or mutant SLC4A11 harboring CHED-/FECD4-associated SLC4A11 mutations (SLC4A11MU). SLC4A11WT and SLC4A11MU hCEnC lines were generated to express either SLC4A11 variant 2 (V2WT and V2MU) or variant 3 (V3WT and V3MU), the two major variants expressed in ex vivo hCEnC. Functional assays were performed to assess cell barrier, proliferation, viability, migration, and NH3-induced membrane conductance. We demonstrate SLC4A11-/- and SLC4A11MU hCEnC lines exhibited increased migration rates, altered proliferation and decreased cell viability compared to SLC4A11WT hCEnC. Additionally, SLC4A11-/- hCEnC demonstrated decreased cell-substrate adhesion and membrane capacitances compared to SLC4A11WT hCEnC. Induction with 10mM NH4Cl led SLC4A11WT hCEnC to depolarize; conversely, SLC4A11-/- hCEnC hyperpolarized and the majority of SLC4A11MU hCEnC either hyperpolarized or had minimal membrane potential changes following NH4Cl induction. Immunostaining of primary hCEnC and SLC4A11WT hCEnC lines for SLC4A11 demonstrated predominately plasma membrane staining with poor or partial colocalization with mitochondrial marker COX4 within a subset of punctate subcellular structures. Overall, our findings suggest CHED-associated SLC4A11 mutations likely lead to hCEnC dysfunction, and ultimately CHED, by interfering with cell migration, proliferation, viability, membrane conductance, barrier function, and/or cell surface localization of the SLC4A11 protein in hCEnC. Additionally, based on their similar subcellular localization and exhibiting similar cell functional profiles, protein isoforms encoded by SLC4A11 variant 2 and variant 3 likely have highly overlapping functional roles in hCEnC.

Visual Outcomes Following Surgical Debulking in Exophytic Optic Nerve Sheath Meningiomas.

PURPOSE: To report a case of a globular primary optic nerve sheath meningioma managed surgically with improvement in vision and review the literature for outcomes of purely intraorbital exophytic-globular primary optic nerve sheath meningiomas managed surgically. METHODS: A literature review was conducted using Google Scholar and PubMed with the search terms "primary optic nerve sheath meningioma," "surgery," "exophytic," and "globular." Articles were included if they were available in English. Individual cases from the reviewed articles were included if the tumor was purely intraorbital with a globular or exophytic morphology, was managed with total or subtotal surgical excision, and visual outcomes were reported. Cases were excluded if the tumor extended intracanalicularly or intracranially, tumor morphology was unknown, or surgical management consisted of biopsy, optic nerve sheath decompression, or optic canal decompression rather than tumor debulking. RESULTS: A total of 28 patients with intraorbital globular-exophytic primary optic nerve sheath meningiomas managed surgically have been reported in the literature. Vision improved in 29% (n = 8/28) and remained stable in 43% (n = 12/28) of patients. Furthermore, patients with good (Snellen notation ≥ 0.5) vision (n = 10) typically retained good vision postoperatively and at follow-up, with 1 patient experiencing a decline to poor (Snellen ≤0.1) vision at the last follow-up (92 months postoperatively). Similarly, patients with fair (Snellen notation >0.1 and <0.5) vision (n = 5) often improved to good vision (n = 3) or stayed at fair vision (n = 1), with 1 declining to poor vision at postoperative hospital discharge. CONCLUSIONS: Surgical management of exophytic or globular optic nerve meningiomas does not universally lead to vision loss and may be appropriate in select patients.

Development and evaluation of checklists to support the recruitment of committed hematopoietic stem cell donors.

BACKGROUND: Checklists are memory recall tools used across healthcare to improve outcomes. Here, we describe the development and evaluation of checklists to support recruitment of committed allogeneic hematopoietic stem cell donors. STUDY DESIGN AND METHODS: Checklists were developed with the following objectives: (1) improve best-practice adherence; (2) reduce errors; and (3) support standardization at stem cell drives. Topics included: recruiting needed donors; securing informed consent; maintaining good-documentation practices; and supervising registration and tissue sample collection. Checklists were iteratively revised with input from stakeholders. We evaluated the checklists by examining recruitment outcomes and errors (i.e., preventing registrants from being listed as donors) pre- (11/2011-8/2016) and post- (9/2016-11/2019) implementation by the Canadian donor recruitment organization Stem Cell Club. Quantitative and qualitative methods were employed to analyze recruiters' perspectives on the checklists. RESULTS: The checklists supported recruitment of donors from needed demographic groups as Stem Cell Club expanded its recruitment effort from 4118 registrants (60% male, 58% non-European) pre-implementation to 10,621 (52% male, 56% non-European) post-implementation. Checklist implementation was associated with a marked reduction in errors (from 13.2% to 1.9%) and a three-fold increase in the match rate of recruited donors (from 0.024% to 0.075%). Qualitative and quantitative analysis of recruiter feedback supported that the checklists' objectives were realized from the recruiter perspective. DISCUSSION: We developed checklists to support donor recruitment and showed that their implementation was valued by recruiters and associated with both reduced errors and improved donor recruitment outcomes. The checklists are relevant to donor recruitment organizations worldwide.

Infectious keratitis in Vietnam: etiology, organisms, and management at Vietnam National Eye Hospital.

AIM: To report the etiologies, risk factors, treatments, and outcomes of infectious keratitis (IK) at a major Vietnamese eye hospital. METHODS: This is a retrospective review of all cases of IK at Vietnam National Eye Hospital (VNEH) in Hanoi, Vietnam. Medical histories, demographics, clinical features, microbiological results, and treatment outcomes were reviewed. RESULTS: IK was diagnosed in 1974 eyes of 1952 patients, with ocular trauma being the greatest risk factor for IK (34.2%), frequently resulting from an agriculture-related injury (53.3%). The mean duration between symptom onset and presentation to VNEH was 19.3±14.4d, and 98.7% of patients had been treated with topical antibiotic and/or antifungal agents prior to evaluation at VNEH. Based on smear results of 1706 samples, the most common organisms identified were bacteria (n=1107, 64.9%) and fungi (n=1092, 64.0%), with identification of both bacteria and fungi in 614 (36.0%) eyes. Fifty-five of 374 bacterial cultures (14.7%) and 426 of 838 fungal cultures (50.8%) were positive, with the most commonly cultured pathogens being Pseudomonas aeruginosa, Streptococcus pneumonia, Fusarium spp., and Aspergillus spp. Corneal perforation and descemetocele developed in 391 (19.8%) and 93 (4.7%) eyes, respectively. Medical treatment was successful in resolving IK in 50.4% eyes, while 337 (17.1%) eyes underwent penetrating or anterior lamellar keratoplasty. Evisceration was performed in 7.1% of eyes, most commonly in the setting of fungal keratitis. CONCLUSION: Ocular trauma is a major risk factor for IK in Vietnam, which is diagnosed in almost 400 patients each year at VNEH. Given this, and as approximately one quarter of the eyes that develop IK require corneal transplantation or evisceration, greater emphasis should be placed on the development of prevention and treatment programs for IK in Vietnam.

Late Onset Interface Calcium Deposition After Laser In Situ Keratomileusis.

PURPOSE: The purpose of this study was to report a novel clinical entity characterized by bilateral calcium deposits in the flap interface after uncomplicated laser in situ keratomileusis (LASIK). METHODS: Slit-lamp examination, anterior segment optical coherence tomography imaging, and histopathologic analysis of an interface opacity were performed to characterize and identify the origin of the interface opacities. RESULTS: Two unrelated healthy young men who underwent LASIK in both eyes at 20 (case 1) and 44 (case 2) years of age were diagnosed with bilateral, white anterior stromal opacities 5 years after LASIK surgery. Slit-lamp examination and anterior segment optical coherence tomography imaging demonstrated that the opacities were located at the level of the LASIK interface in both eyes of both cases, with most of the opacities located at the temporal edge of the flap in each eye of case 2. An opacity from case 2 demonstrated birefringence using polarization microscopy and staining with Alizarin red, indicative of calcium deposition. The serum calcium level was borderline elevated in case 1 and within normal limits in case 2. CONCLUSIONS: Intrastromal calcium deposition can occur after LASIK surgery, with the deposits resembling dystrophic deposits located in the LASIK flap interface in individuals with granular corneal dystrophy type 2. Because the etiology and management of calcific and dystrophic interface deposition after LASIK are distinct, it is important for clinicians to differentiate the 2 entities based on the examination, diagnostic imaging, and, if necessary, molecular genetic analysis.

Development and evaluation of a community of practice to improve stem cell donor recruitment in Canada.

Background and Objectives Communities of practice (CoPs) represent effective models to achieve quality outcomes in health care. We report the development and evaluation of a CoP to improve stem cell donor recruitment in Canada. Materials and Methods In September 2017, we invited national stakeholders in stem cell donor recruitment to participate in a Facebook group and regular e-meetings. E-meetings involved speakers and roundtable discussion on topics related to donor recruitment. The Facebook group facilitated sharing of resources. We evaluated stakeholder perspective of the CoP and the impact on recruitment outcomes. Results As of December 2020, the CoP included 382 members who published 243 posts to the Facebook group about patient/donor stories (40%), resources (27%), updates/questions (21%) and recruitment outcomes (12%). In January 2020, we surveyed 44 CoP participants; the majority felt that the Facebook group (86%) and e-meetings (59%) supported the community, and that the CoP fostered collaboration (82%), improved their donor recruitment knowledge (75%) and practice (77%) and improved their ability to recruit needed donors (64%). The launch of the CoP correlated with improved donor recruitment outcomes. In 2016-2017, CoP participants recruited 2918 registrants (46% male; 55.9% non-Caucasian) compared to 4531 registrants in 2018-2019 (52.9% male; 62.7% non-Caucasian). Members of the CoP developed innovative resources to support recruitment efforts and led national campaigns securing coverage in major media outlets. Conclusion We describe the first CoP in stem cell donor recruitment to be formally evaluated. The CoP model may be adopted by donor recruitment organisations, registries and blood banks worldwide to improve recruitment outcomes. HIGHLIGHTS: • A community of practice (CoP) in stem cell donor recruitment was valued by participants and supported efforts to improve recruitment outcomes. • The CoP model may be adopted by donor recruitment organizations, donor registries, and blood banks worldwide to improve recruitment outcomes.

Corneal ectasia associated with posterior lamellar opacification.

BACKGROUND: Concomitant corneal ectasia and posterior lamellar corneal opacification is rare, and the genetic relationship between these two conditions is unclear. We report the genetic and clinical characterization of this phenotype in three unrelated individuals. MATERIALS AND METHODS: One previously reported affected individual and two unreported, unrelated, affected individuals were recruited for the study. Subjects and unaffected relatives underwent slit lamp examination, refraction, and multi-modal imaging. Saliva samples were obtained from two of the three affected individuals, from which DNA was extracted. Sanger sequencing was performed to identify mutations in genes associated with posterior amorphous corneal dystrophy (PACD), brittle cornea syndrome (BCS), and posterior polymorphous corneal dystrophy (PPCD), while copy number variation (CNV) analysis was used to identify CNV in the PACD locus. RESULTS: Affected individuals demonstrated bilateral corneal steepening, stromal thinning and lamellar posterior corneal opacification. Corneal topography and tomography revealed conical or globular corneal steepening and decreased thickness. Anterior segment optical coherence tomography demonstrated hyperreflectivity of the posterior stroma in each of the affected individuals. Genetic testing did not detect a heterozygous deletion involving the PACD locus on chromosome 12 or a pathogenic mutation in the genes associated with BCS or PPCD. CONCLUSIONS: Corneal ectasia may be associated with posterior lamellar stromal opacification that appears consistent with PACD. However, genetic testing for PACD as well as BCS and PPCD in affected individuals fails to reveal pathogenic deletions or mutations, indicating that other genetic factors are involved.

Single horizontal rectus muscle vertical augmented transposition with posterior fixation suture in management of monocular elevation deficiency.

We describe successful management of three cases of acquired monocular elevation deficiency (MED) with superior transposition of the lateral rectus augmented with a posterior fixation suture with or without simultaneous inferior rectus muscle weakening. In each case, the lateral rectus muscle was transposed superiorly to the superior rectus muscle along the spiral of Tillaux, with maintained distance between the original lateral rectus muscle poles and the limbus. Augmentation was achieved with a posterior fixation suture 8 mm posterior to the muscles' insertion. At the time of lateral rectus transposition, simultaneous inferior rectus recession by 5.5 mm was performed in case 1 whereas simultaneous botulinum toxin injection was performed in case 3. With regards to all three cases, the mean age was 32 years [10-46 years] and the mean follow-up period was 10 months. The mean hypotropia was reduced from 35 prism diopters (PD) (range: 20 to 60 PD) to 4.67 PD (range: 0 to 14 PD) with a mean correction of 32.57 ± 9.34 PD after 9 months. In our experience, full-tendon-width transposition of the lateral rectus to the superior rectus with posterior fixation suture corrects primary position hypotropia in MED and does not always require simultaneous inferior rectus recession. When transposing the lateral rectus muscle along the spiral of Tillaux, the measured distance of the original muscle insertion point to the limbus must be maintained in order to prevent recession of the muscle.

Comparison of early visual outcomes after low-energy SMILE, high-energy SMILE, and LASIK for myopia and myopic astigmatism in the United States.

PURPOSE: To compare uncorrected distance visual acuities (UDVAs) and induced higher-order aberrations (HOAs) in the early postoperative period between low-energy (LE) small-incision lenticule extraction (SMILE), high-energy (HE) SMILE, and femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) procedures. SETTING: University based refractive surgery center. STUDY DESIGN: Retrospective cohort study. METHODS: Records of patients who underwent SMILE or FS-LASIK were retrospectively reviewed. SMILE patients were separated into 2 groups: HE settings (125 nJ, 3.0 µm spot spacing) and LE settings (125-130 nJ, 4.5 µm spot spacing). UDVA was measured at postoperative day (POD) 1. Corneal HOAs and UDVA were measured at postoperative month (POM) 1. Induced spherical aberration, vertical coma, horizontal coma, total coma, and total HOAs were calculated. RESULTS: The study included 147 eyes of 106 patients, 49 in each group. For SMILE patients, the difference in mean UDVA at POD1 was highly statistically significant in favor of the LE group (-0.003 vs 0.141, P < .0001). No significant difference in mean UDVA at POD1 was noted between the LE group and FS-LASIK group (-0.003 vs -0.011, P = .498). Induced change in spherical aberration was less in LE SMILE than that in FS-LASIK (0.136 vs 0.186 µm, P = .02) at POM1. No significant differences in POM1 mean UDVA (-0.033 vs -0.036) or induced change in all other HOAs were noted between LE SMILE and FS-LASIK. CONCLUSIONS: LE settings were associated with significantly improved POD1 UDVA. POD1 and POM1 UDVA were comparable with those of FS-LASIK. Spherical aberration induction was less with LE SMILE than that with FS-LASIK, whereas all other induced HOAs were comparable with FS-LASIK.

Identification of A Novel TGFBI Gene Mutation (p.Serine524Cystine) Associated with Late Onset Recurrent Epithelial Erosions and Bowman Layer Opacities.

BACKGROUND: Most transforming growth factor beta-induced (TGFBI) corneal dystrophies are associated with a characteristic phenotype, clinical course, and a conserved mutation in the TGFBI gene. However, we report a novel TGFBI missense mutation associated with a late-onset, variant Bowman layer dystrophy. METHODS: Participants underwent slit-lamp examination and multimodal imaging. Polymerase chain reaction amplification and Sanger sequencing were performed on saliva-derived genomic DNA to screen TGFBI exons 4 and 12 as well as COL17A1 exon 46. PolyPhen-2 and SIFT were used to predict the functional impact of any identified variants. RESULTS: A 56-year-old Thai woman reported a four-year history of decreased vision and intermittent eye irritation, suggestive of recurrent epithelial erosions, in both eyes. Slit-lamp exam revealed bilateral, irregular, limbal-sparing Bowman layer opacities, which were also noted on anterior segment optical coherence tomography. Phototherapeutic keratectomy was performed in the right eye, improving the best-corrected visual acuity from 20/50 to 20/30. Sequencing of the TGFBI gene revealed a novel heterozygous, missense mutation in exon 12 (c.1571 C > G; p.Ser524Cys), which was present in an affected son and absent in an unaffected son, and was predicted to be damaging by PolyPhen-2 and SIFT. The patient was diagnosed with a variant Bowman layer dystrophy given the late onset of an atypical phenotype and the identification of a novel TGFBI mutation. CONCLUSIONS: A novel TGFBI missense mutation is associated with a late-onset Bowman layer dystrophy. Given the atypical clinical appearance and course, molecular genetic analysis was utilized to establish a definitive diagnosis.

Telehealth in Pediatric Heart Transplant Patients: Exercise, Nutrition, and Parental Imaging.

Telehealth is a promising new tool in medicine that has changed the landscape of medical care. The benefits of telehealth technology are immense, including improved access to care and potential savings in monetary and opportunity costs. Current challenges of incorporating telehealth services into regular clinical care include licensure and regulatory barriers, difficulty obtaining insurance reimbursements, and high costs of setting up successful telehealth infrastructures. These challenges threaten telehealth's future scalability and expansion to reach all patients in need.

Current Status of Ophthalmology Residency Training in China: The Experience From Well-Structured Centers Around the Country.

Chinese ophthalmology residency training is continuously evolving with an emphasis on standardization. In this article, we assess the current status of ophthalmology residency training in China compared with that in the United States through analysis of literature review and onsite data collection. We comprehensively review various aspects of the residency training structure in China, including accreditation, resident selection, clinical and surgical curricula, research requirements, and evaluation. Our report demonstrates significant regional differences among training programs due to the lack of a national standard, resulting in varying competencies of graduating Chinese ophthalmology residents. The Chinese ophthalmology community is determined to improve the standardization process and quality of training for their ophthalmologists, an important goal that will facilitate international fellowship studies, exchange scholars, and research collaboration.

Healthy Hearts via Live Videoconferencing: An Exercise and Diet Intervention in Pediatric Heart Transplant Recipients.

Background Pediatric heart transplant recipients have high-risk cardiovascular profiles that can affect their long-term outcomes; however, promoting exercise and healthy diet has not been a major focus in the field. The objective of this study was to test the feasibility and impact of a supervised exercise and diet intervention delivered via live videoconferencing in this population. Methods and Results Patients 8 to 19 years of age at least 1 year post heart transplantation were enrolled. The 12- to 16-week intervention phase included live video-supervised exercise (×3/week) and nutrition (×1/week) sessions. The 12- to 16-week maintenance phase included ×1/week live video-supervised exercise and nutrition sessions and ×2/week self-directed exercise sessions. Cardiac, vascular, nutritional, and functional health indices were obtained at baseline, after intervention, and after maintenance. Fourteen patients (median age, 15.2; interquartile range, 14.3-16.7 years) at a median of 3.3 (interquartile range, 1.5-9.7) years after heart transplant completed the intervention. Patients attended 89.6±11% of exercise and 88.4±10% of nutrition sessions during the intervention and 93.4±11% of exercise and 92.3±11% of nutrition sessions during maintenance. After intervention, body mass index percentile (median, -27%; P=0.02), endothelial function (median, +0.29; P=0.04), maximum oxygen consumption (median, +2 mL/kg per minute; P=0.002). Functional Movement Screening total score (median, +2.5; P=0.002) and daily consumption of saturated fat (median, -6 g; P=0.02) improved significantly. After maintenance, improvements in maximum oxygen consumption (median, +3.2 mL/kg per minute; P=0.02) and Functional Movement Screening total score (median, +5; P=0.002) were sustained. Conclusions In pediatric heart transplant recipients, a live video-supervised exercise and diet intervention is feasible. Our results demonstrate excellent adherence with significant improvements in cardiovascular and functional health. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02519946.

Severe Acquired Restrictive Strabismus Fixus in Patients with Trisomy 21.

Acquired strabismus fixus is a rare form of severe esotropia described most frequently in patients with high axial myopia and infrequently associated with other conditions. Refractive errors, cataracts, and ocular motility disorders are common in patients with trisomy 21. We report two unusual cases of patients with trisomy 21 who developed severe acquired restrictive strabismus fixus. Both patients were successfully treated with medial rectus recession followed by lateral rectus and superior rectus myopexy combined with additional medial rectus weakening, including free tenotomy in one case.

Vascular Health of Children Conceived via In Vitro Fertilization.

OBJECTIVE: To evaluate whether in vitro fertilization (IVF) has an effect on the cardiovascular health of offspring. STUDY DESIGN: This was a cross-sectional pilot study. We performed vascular health assessment for 17 children aged 10-14 years who were conceived via IVF with autologous oocytes at Stanford University. Carotid artery ultrasound evaluated intima-media thickness and stiffness, carotid-femoral pulse wave velocity determined segmental arterial stiffness, and endothelial pulse amplitude testing assessed endothelial function. We compared IVF offspring with control adolescents assessed in the same laboratory, with all comparisons adjusted for age, sex, and race/ethnicity. RESULTS: All participants had normal body mass index and blood pressure. Compared with controls, IVF children had thicker common carotid artery intima-media thickness (0.44 ± 0.03 mm vs 0.38 ± 0.03 mm; P < .01), higher elastic modulus (395.29 ± 185.33 mm Hg vs 242.79 ± 37.69 mm Hg; P = .01), higher ßstiffness (2.65 ± 0.38 vs 2.28 ± 0.23; P < .01), and higher peak velocity (142.29 ± 31.62 cm/s vs 117.71 ± 32.69 cm/s; P = .04). The mean endothelial pulse amplitude testing reactive hyperemia index was not significantly different between IVF and controls. The mean pulse wave velocity was 4.69 ± 0.51 m/s compared with the controls 4.60 ± 0.57 m/s (P = .11), with 8 (47%) having abnormal values. CONCLUSION: In an assessment of endothelial function and arterial properties of children conceived via IVF, we found that children conceived via IVF seem to have evidence of abnormal vascular health. Further studies with larger sample size and long-term follow-up are warranted.

Healthy hearts in pediatric heart transplant patients with an exercise and diet intervention via live video conferencing-Design and rationale.

BACKGROUND: Pediatric heart transplant (PedHtx) patients have increased cardiovascular risk profiles that affect their long-term outcomes and quality of life. We designed a 12- to 16-week diet and exercise intervention delivered via live video conferencing to improve cardiovascular health. Our methodology and baseline assessment of the first 13 enrolled patients are reported. METHODS: Inclusion criteria are as follows: (a) 8-19 years old; (b) heart transplant >12 months; (c) ability to fast overnight; (d) cardiac clearance by cardiologist; and (e) presence of an adult at home during exercise sessions for patients <14 years old. Exclusion criteria are as follows: (a) acute illness; (b) latex allergy; (c) transplant rejection <3 months ago; and (d) multi-organ transplantation. The intervention consists of one diet and three exercise sessions weekly via live video conferencing. Study visits are conducted at baseline, intervention completion, and end of maintenance period. RESULTS: A total of 13 participants (15.2 [2.3] years) have been enrolled. Median percent-predicted VO2 max was 56.8 [20.7]% (10 patients <70%). Ten patients had abnormal endothelial function (reactive hyperemia index <1.9; 1.4 [0.325]) and 11 patients had stiff arteries (pulse wave velocity ≧5.5 m/s for 15-19 years, ≧4.5 m/s for 8-14 years; 5.6 [0.7] m/s). Patients had suboptimal diets (saturated fat: 22.7 [23.8] g/d, sodium: 2771 [1557] mg/d) and were sedentary at a median of 67.5 [13.8]% of their time. CONCLUSIONS: Baseline assessment confirms that PedHtx patients have abnormal cardiac, vascular, and functional health indices, poor dietary habits, and are sedentary. These results support the rationale to test the feasibility and impact of a non-pharmacologic lifestyle intervention in this patient population.

Biochemical and Skeletal Outcomes of Parathyroidectomy for Normocalcemic (Incipient) Primary Hyperparathyroidism.

BACKGROUND: Normocalcemic (incipient) primary hyperparathyroidism (PHPT) is characterized by inappropriately elevated parathyroid hormone (PTH) levels in the setting of normal serum calcium. The biochemical and skeletal outcomes after parathyroidectomy for normocalcemic PHPT are not well-described. METHODS: All patients who underwent parathyroidectomy for normocalcemic PHPT at a single institution were retrospectively reviewed (2006-2016). Pre- and postoperative calcium, PTH, and bone mineral density (BMD) were compared between patients with normalized versus persistently elevated PTH levels > 6 months after parathyroidectomy. Multivariable Cox regression was used to identify risk factors associated with persistently elevated PTH levels after parathyroidectomy. RESULT: Parathyroidectomy was performed in 71 patients with normocalcemic PHPT, of whom 38 (53.5%) had multi-gland disease. No patients became hypercalcemic, with a median follow-up of 23.1 months. Persistently elevated PTH levels were noted in 33 (46.5%) patients. In multivariable analysis, preoperative PTH > 100 pg/mL was associated with persistently elevated PTH levels after parathyroidectomy. In 38 patients with available pre- and postoperative BMD measurements, the mean preoperative BMD improved + 5.6% (p < 0.01) in patients with normalized PTH, while no significant change was observed in patients with persistently elevated PTH levels (- 2.2%, p = 0.47). CONCLUSIONS: Elevated PTH levels are common after parathyroidectomy for normocalcemic PHPT. Improvements in BMD may be predicated on long-term normalized PTH levels following surgery.

Rev7 and 53BP1/Crb2 prevent RecQ helicase-dependent hyper-resection of DNA double-strand breaks.

Poly(ADP ribose) polymerase inhibitors (PARPi) target cancer cells deficient in homology-directed repair of DNA double-strand breaks (DSBs). In preclinical models, PARPi resistance is tied to altered nucleolytic processing (resection) at the 5' ends of a DSB. For example, loss of either 53BP1 or Rev7/MAD2L2/FANCV derepresses resection to drive PARPi resistance, although the mechanisms are poorly understood. Long-range resection can be catalyzed by two machineries: the exonuclease Exo1, or the combination of a RecQ helicase and Dna2. Here, we develop a single-cell microscopy assay that allows the distinct phases and machineries of resection to be interrogated simultaneously in living S. pombe cells. Using this assay, we find that the 53BP1 orthologue and Rev7 specifically repress long-range resection through the RecQ helicase-dependent pathway, thereby preventing hyper-resection. These results suggest that 'rewiring' of BRCA1-deficient cells to employ an Exo1-independent hyper-resection pathway is a driver of PARPi resistance.

Recent Pregnancy Is Not Associated with High-Risk Pathological Features of Well-Differentiated Thyroid Cancer.

BACKGROUND: Thyroid cancer is commonly diagnosed in the first postpartum year, supporting the theory that high levels of estrogen may stimulate progression of hormone-mediated thyroid cancer. The aim of this study was to assess the effect of recent pregnancy on histopathologic disease characteristics of well-differentiated thyroid cancer (WDTC). METHODS: Cases of WDTC (1999-2012) were identified from the California Cancer Registry and linked to data from the Office of Statewide Health Planning and Development. Using a matched control design, recently pregnant women (pregnancy up to five years before and nine months after a thyroid cancer diagnosis) were compared with non-pregnant controls matched by age and race/ethnicity. The main outcome measures were histopathologic tumor characteristics (tumor size, extrathyroidal extension, and nodal metastases), disease status at last follow-up, and five-year disease-specific survival. RESULTS: The study sample of 1204 women (Mage ± standard deviation = 30.9 ± 5.5 years; 46.5% Caucasian and 40.0% Hispanic) included 301 recently pregnant women matched against 903 non-pregnant controls. Comparing recently pregnant versus non-pregnant women, no significant differences were observed with respect to tumor size (M = 2.2 ± 1.6 vs. 2.3 ± 3.9 cm; p = 0.39), extrathyroidal extension (12.0% vs. 14.1%; p = 0.46), stage at diagnosis (localized disease: 67.4% vs. 62.8%; regional metastases: 30.6% vs. 33.4%; distant metastases: 2.0% vs. 3.8%; p = 0.17), disease status at last follow-up (free of tumor vs. not free of tumor; p = 0.48), and five-year disease-specific survival (99.5% vs. 99.5%). In multivariate analyses, after controlling for patient age and ethnicity, recent pregnancy was not a significant predictor of tumor size, extrathyroidal extension, nodal metastases, or distant metastases. CONCLUSIONS: In this cohort, recent pregnancy was not associated with high-risk pathological features of differentiated thyroid cancer. These findings provide reassurance with regards to the concern that pregnancy may act as a potential stimulus for thyroid cancer growth.

Development and Validation of a Racial Discrimination Measure for Cambodian American Adolescents.

To date, the majority of studies examining experiences of racial discrimination among youth use measures initially developed for African American and Latino adults or college students. Few studies have attended to the ways in which discrimination experiences may be unique for Asian American youth, particularly subgroups such as Southeast Asians. The purpose of this study was twofold: (a) to describe the development of a racial discrimination measure using community-based participatory research with Cambodian American adolescents and (b) to psychometrically test the measure with respect to validity and reliability. This research used mixed-methods and comprised 3 phases. Phase 1 consisted of qualitative focus group research to assess community-identified needs. Phase 2 included quantitative survey development with community members and resulted in an 18-item measure assessing the frequency of ethnicity-based discrimination. Phase 3 involved psychometric testing of the measure's validity and reliability (n = 423). Exploratory factor analysis procedures yielded a 3-factor structure describing peer, school, and police discrimination from all items, capturing 96% of the combined variance. Using confirmatory factor analysis, the data demonstrated good fit with the 3-factor structure (CFI = .98; RMSEA = .054), with factor loadings ranging from .59 to .96 and all estimates statistically significant at the p < .05 level. Correlational analyses of racial discrimination subfactors and depression supported concurrent validity. In sum, this measure can be used to examine the degree and sources of racial discrimination reported by Cambodian American adolescents and potentially other adolescents of Southeast Asian descent living in diverse urban communities.