Induction of Skin Allograft Chimerism by Pharmacological Mobilization of Endogenous Bone Marrow-Derived Stem Cells.

Skin substitutes including allografts remain a standard therapeutic approach to promote healing of both acute and chronic large wounds. However, none have resulted in the regrowth of lost and damaged tissues and scarless wound healing. Here, we demonstrate skin allograft chimerism and repair through the mobilization of endogenous bone marrow-derived stem and immune cells in rats and swine. We show that pharmacological mobilization of bone marrow stem cells and immune cells into the circulation promotes host repopulation of skin allografts and restoration of the skin's normal architecture without scarring and minimal contracture. When skin allografts from DA rats are transplanted into GFP transgenic Lewis recipients with a combination of AMD3100 and low-dose FK506 (AF) therapy, host-derived GFP-positive cells repopulate and/or regenerate cellular components of skin grafts including epidermis and hair follicles and the grafts become donor-host chimeric skin. Using AF combination therapy, burn wounds with skin allografts were healed by newly regenerated chimeric skin with epidermal appendages and pigmentation and without contracture in swine.

ATP-release pannexin channels are gated by lysophospholipids.

Adenosine triphosphate (ATP) serves as an extracellular messenger that mediates diverse cell-to-cell communication. Compelling evidence supports that ATP is released from cells through pannexins, a family of heptameric large pore-forming channels. However, the activation mechanisms that trigger ATP release by pannexins remain poorly understood. Here, we discover lysophospholipids as endogenous pannexin activators, using activity-guided fractionation of mouse tissue extracts combined with untargeted metabolomics and electrophysiology. We show that lysophospholipids directly and reversibly activate pannexins in the absence of other proteins. Molecular docking, mutagenesis, and single-particle cryo-EM reconstructions suggest that lysophospholipids open pannexin channels by altering the conformation of the N-terminal domain. Our results provide a connection between lipid metabolism and ATP signaling, both of which play major roles in inflammation and neurotransmission. One-Sentence Summary: Untargeted metabolomics discovers a class of messenger lipids as endogenous activators of membrane channels important for inflammation and neurotransmission.

A phase I, first-in-human study to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of MRG-001 in healthy subjects.

Preclinical studies demonstrate that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a fixed-dose drug combination (MRG-001) improves wound healing, promotes tissue regeneration, and prevents allograft rejection. In this phase I, first-in-human study, three cohorts receive subcutaneous MRG-001 or placebo, every other day for 5 days. The primary outcome is safety and tolerability of MRG-001. Fourteen subjects received MRG-001 and seven received a placebo. MRG-001 is safe over the selected dose range. There are no clinically significant laboratory changes. The intermediate dose group demonstrates the most significant white blood cell, stem cell, and immunoregulatory cell mobilization. PBMC RNA sequencing and gene set enrichment analysis reveal 31 down-regulated pathways in the intermediate MRG-001 dose group compared with no changes in the placebo group. MRG-001 is safe across all dose ranges. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration (ClinicalTrials.gov: NCT04646603).

Adaptive radiotherapy for breast cancer.

Research in the field of local and locoregional breast cancer radiotherapy aims to maintain excellent oncological outcomes while reducing treatment-related toxicity. Adaptive radiotherapy (ART) considers variations in target and organs at risk (OARs) anatomy occurring during the treatment course and integrates these in re-optimized treatment plans. Exploiting ART routinely in clinic may result in smaller target volumes and better OAR sparing, which may lead to reduction of acute as well as late toxicities. In this review MR-guided and CT-guided ART for breast cancer patients according to different clinical scenarios (neoadjuvant and adjuvant partial breast irradiation, whole breast, chest wall and regional nodal irradiation) are reviewed and their advantages as well as challenging aspects discussed.

Machine Learning Prediction of Adenovirus D8 Conjunctivitis Complications from Viral Whole-Genome Sequence.

Objective: To obtain complete DNA sequences of adenoviral (AdV) D8 genome from patients with conjunctivitis and determine the relation of sequence variation to clinical outcomes. Design: This study is a post hoc analysis of banked conjunctival swab samples from the BAYnovation Study, a previously conducted, randomized controlled clinical trial for AdV conjunctivitis. Participants: Ninety-six patients with AdV D8-positive conjunctivitis who received placebo treatment in the BAYnovation Study were included in the study. Methods: DNA from conjunctival swabs was purified and subjected to whole-genome viral DNA sequencing. Adenovirus D8 variants were identified and correlated with clinical outcomes, including 2 machine learning methods. Main Outcome Measures: Viral DNA sequence and development of subepithelial infiltrates (SEIs) were the main outcome measures. Results: From initial sequencing of 80 AdV D8-positive samples, full adenoviral genome reconstructions were obtained for 71. A total of 630 single-nucleotide variants were identified, including 156 missense mutations. Sequence clustering revealed 3 previously unappreciated viral clades within the AdV D8 type. The likelihood of SEI development differed significantly between clades, ranging from 83% for Clade 1 to 46% for Clade 3. Genome-wide analysis of viral single-nucleotide polymorphisms failed to identify single-gene determinants of outcome. Two machine learning models were independently trained to predict clinical outcome using polymorphic sequences. Both machine learning models correctly predicted development of SEI outcomes in a newly sequenced validation set of 16 cases (P = 1.5 × 10-5). Prediction was dependent on ensemble groups of polymorphisms across multiple genes. Conclusions: Adenovirus D8 has ≥ 3 prevalent molecular substrains, which differ in propensity to result in SEIs. Development of SEIs can be accurately predicted from knowledge of full viral sequence. These results suggest that development of SEIs in AdV D8 conjunctivitis is largely attributable to pathologic viral sequence variants within the D8 type and establishes machine learning paradigms as a powerful technique for understanding viral pathogenicity.

Systemic prime exacerbates the ocular immune response to heat-killed Mycobacterium tuberculosis.

Post-infectious uveitis describes the condition of chronic immune mediated ocular inflammation associated with pathogens such as Mycobacterium tuberculosis (Mtb). Mtb associated post-infectious uveitis can be modeled in mice by intravitreal injection of heat-killed Mtb (HKMtb). To better understand how prior systemic exposure to the pathogen alters the local immune response to Mtb, we used flow cytometry and multiplex ELISAs to compare ocular responses to intravitreal HKMtb in the presence or absence of a systemic "prime" of HKMtb. Priming resulted in exacerbation of local inflammation with significantly increased clinical and histologic inflammation scores and increased vitreous cytokines concentrations one day after intravitreal injection of HKMtb. Seven days after injection, uveitis in unprimed animals had largely resolved. In contrast in primed animals, clinical signs of chronic inflammation were associated with a significant increase in the number of ocular T cells, NK cells, and Ly6Chi macrophages and increasing vitreous concentrations of IL-17, VEGF, MIG(CXCL9), IP-10(CXCL10), IL-12p40 and MIP-1α(CCL3). In mice lacking mature T and B cells (RAG2 deficient), the impact of priming on the ocular immune response was ameliorated with significantly lower vitreous cytokine concentrations and spontaneous resolution of uveitis. Altogether these results suggest that the ocular response to Mtb is exacerbated by prior systemic Mtb infection and chronic post-infectious uveitis is mediated by local production of cytokines and chemokines that amplify Th17 and Th1 responses. This mouse model of chronic Mtb associated uveitis will help elucidate mechanisms of disease in patients with post-infectious uveitis.

Deep Metagenomic Sequencing for Endophthalmitis Pathogen Detection Using a Nanopore Platform.

PURPOSE: To evaluate the utility of nanopore sequencing for identifying potential causative pathogens in endophthalmitis, comparing culture results against full-length 16S rRNA nanopore sequencing (16S Nanopore), whole genome nanopore sequencing (Nanopore WGS), and Illumina (Illumina WGS). DESIGN: Cross-sectional diagnostic comparison. METHODS: Patients with clinically suspected endophthalmitis underwent intraocular vitreous biopsy as per standard care. Clinical samples were cultured by conventional methods, together with full-length 16S rRNA and WGS using nanopore and Illumina sequencing platforms. RESULTS: Of 23 patients (median age 68.5 years [range 47-88]; 14 males [61%]), 18 cases were culture-positive. Nanopore sequencing identified the same cultured organism in all of the culture-positive cases and identified potential pathogens in two culture-negative cases (40%). Nanopore WGS was able to additionally detect the presence of bacteriophages in three samples. The agreements at genus level between culture and 16S Nanopore, Nanopore WGS, and Illumina WGS were 75%, 100%, and 78%, respectively. CONCLUSIONS: Whole genome sequencing has higher sensitivity and provides a viable alternative to culture and 16S sequencing for detecting potential pathogens in endophthalmitis. Moreover, WGS has the ability to detect other potential pathogens in culture-negative cases. Whilst Nanopore and Illumina WGS provide comparable data, nanopore sequencing provides potential for cost-effective point-of-care diagnostics.

Regenerative and restorative medicine for eye disease.

Causes of blindness differ across the globe; in higher-income countries, most blindness results from the degeneration of specific classes of cells in the retina, including retinal pigment epithelium (RPE), photoreceptors, and retinal ganglion cells. Advances over the past decade in retinal regenerative medicine have allowed each of these cell types to be produced ex vivo from progenitor stem cells. Here, we review progress in applying these technologies to cell replacement - with the goal of vision restoration in degenerative disease. We discuss the landscape of human clinical trials for RPE transplantation and advanced preclinical studies for other cell types. We also review progress toward in situ repair of retinal degeneration using endogenous progenitor cells. Finally, we provide a high-level overview of progress toward prosthetic ocular vision restoration, including advanced photovoltaic devices, opsin-based gene therapy, and small-molecule photoswitches. Progress in each of these domains is at or near the human clinical-trial stage, bringing the audacious goal of vision restoration within sight.

Model-Based Selection for Proton Therapy in Breast Cancer: Development of the National Indication Protocol for Proton Therapy and First Clinical Experiences.

AIMS: Proton therapy is a radiation technique that yields less dose in normal tissues than photon therapy. In the Netherlands, proton therapy is reimbursed if the reduced dose to normal tissues is predicted to translate into a prespecified reduction in toxicity, based on nationally approved validated models. The aim of this paper is to present the development of a national indication protocol for proton therapy (NIPP) for model-based selection of breast cancer patients and to report on first clinical experiences. MATERIALS AND METHODS: A national proton therapy working group for breast cancer (PWG-BC) screened the literature for prognostic models able to estimate the individual risk of specific radiation-induced side-effects. After critical appraisal and selection of suitable models, a NIPP for breast cancer was written and subjected to comments by all stakeholders. The approved NIPP was subsequently introduced to select breast cancer patients who would benefit most from proton therapy. RESULTS: The model of Darby et al. (N Engl J Med 2013; 368:987-82) was the only model fulfilling the criteria prespecified by the PWG-BC. The model estimates the relative risk of an acute coronary event (ACE) based on the mean heart dose. The absolute lifetime risk of ACE <80 years was calculated by applying this model to the Dutch absolute incidence of ACE for female and male patients, between 40 and 70 years at breast cancer radiotherapy, with/without cardiovascular risk factors. The NIPP was approved for reimbursement in January 2019. Based on a threshold value of a 2% absolute lower risk on ACE for proton therapy compared with photons, 268 breast cancer patients have been treated in the Netherlands with proton therapy between February 2019 and January 2021. CONCLUSION: The NIPP includes a model that allows the estimation of the absolute risk on ACE <80 years based on mean heart dose. In the first 2 years, 268 breast cancer patients have been treated with proton therapy in The Netherlands.

Molecular and Clinical Characterization of Human Adenovirus E4-Associated Conjunctivitis.

PURPOSE: To determine the characteristics of conjunctivitis associated with human adenovirus E4 (AdV E4). METHODS: Samples and outcomes from 500 patients with conjunctivitis were obtained from the NVC-422 randomized controlled clinical trial comparing auriclosene to placebo. Molecular typing identified 36 cases associated with AdV E4. Signs and symptoms at presentation and at the day 18 endpoint were compared with the larger cohort of 262 subjects with conjunctivitis caused by due to AdV D8. Full viral genomes of 22 AdV E4 isolates were reconstructed. RESULTS: AdV E4 was the most frequently identified adenoviral type in conjunctivitis cases from the United States. Signs and symptoms at presentation were comparable to those associated with AdV D8. Viral load at presentation was comparable between groups but resolution was more rapid in the AdV E4 group. Clinical signs were fully resolved by day 18 in 26 of 36 (72%) patients with AdV E4. Subepithelial infiltrates developed in 12 of 36 (33%) patients with AdV E4 compared with 98 of 215 (45%) patients with AdV D8 (P = .0001). One hundred twenty-four polymorphisms were observed among 22 whole viral genome sequences, which clustered into 3 clades. Patients in each clade developed subepithelial infiltrates. Neither single nucleotide polymorphism analysis nor machine learning approaches identified specific sequence features predictive of presenting signs or outcome. CONCLUSIONS: AdV E4 conjunctivitis may be indistinguishable at presentation from AdV D8-associated disease. Resolution of viral load for AdV E4 appears more rapid than for AdV D8, and the risk for subepithelial infiltrates appears lower. Multiple substrains of AdV E4 are in circulation but all appeared equivalently pathogenic for conjunctivitis. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Endophthalmitis Rate in Immediately Sequential versus Delayed Sequential Bilateral Cataract Surgery within the Intelligent Research in Sight (IRIS®) Registry Data.

PURPOSE: To compare the rate of postoperative endophthalmitis after immediately sequential bilateral cataract surgery (ISBCS) versus delayed sequential bilateral cataract surgery (DSBCS) using the American Academy of Ophthalmology Intelligent Research in Sight (IRIS®) Registry database. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients in the IRIS Registry who underwent cataract surgery from 2013 through 2018. METHODS: Patients who underwent cataract surgery were divided into 2 groups: (1) ISBCS and (2) DSBCS (second-eye surgery ≥1 day after the first-eye surgery) or unilateral surgery. Postoperative endophthalmitis was defined as endophthalmitis occurring within 4 weeks of surgery by International Classification of Diseases (ICD) code and ICD code with additional clinical criteria. MAIN OUTCOME MEASURES: Rate of postoperative endophthalmitis. RESULTS: Of 5 573 639 IRIS Registry patients who underwent cataract extraction, 165 609 underwent ISBCS, and 5 408 030 underwent DSBCS or unilateral surgery (3 695 440 DSBCS, 1 712 590 unilateral surgery only). A total of 3102 participants (0.056%) met study criteria of postoperative endophthalmitis with supporting clinical findings. The rates of endophthalmitis in either surgery eye between the 2 surgery groups were similar (0.059% in the ISBCS group vs. 0.056% in the DSBCS or unilateral group; P = 0.53). Although the incidence of endophthalmitis was slightly higher in the ISBCS group compared with the DSBCS or unilateral group, the odds ratio did not reach statistical significance (1.08; 95% confidence interval, 0.87-1.31; P = 0.47) after adjusting for age, sex, race, insurance status, and comorbid eye disease. Seven cases of bilateral endophthalmitis with supporting clinical data in the DSBCS group and no cases in the ISBCS group were identified. CONCLUSIONS: Risk of postoperative endophthalmitis was not statistically significantly different between patients who underwent ISBCS and DSBCS or unilateral cataract surgery.

Evaluation of owner medication adherence for canine cardiovascular disease in the referral setting.

OBJECTIVE: To evaluate owners' medication adherence for management of cardiovascular disease in the small animal specialty setting. ANIMALS, MATERIALS, AND METHODS: A questionnaire-based study of owners at a single, multispecialty, small animal referral center was conducted. Owners completed a written survey evaluating demographics, degree of medication adherence, and difficulties encountered for medication adherence. Owners were free to decline participation in the study. RESULTS: Ninety-six questionnaires were completed during the study period. Fifty-four respondents (56.3%) reported treating their pet for over one year for cardiovascular disease, and myxomatous mitral valve disease was the most common diagnosis (76.0%). Twenty-nine (30.2%) respondents felt they could consistently administer a maximum of three medications daily, and 46 (47.9%) respondents reported twice-daily dosing was the highest frequency of administration that could be consistently achieved. Twenty-two respondents (22.9%) reported that their pet required daily medications for at least one other chronic condition besides cardiac disease. Seventeen respondents (17.7%) reported at least occasionally missing medications, although only one (1.0%) reported it was more than 20% of medications per week. CONCLUSIONS: Medication adherence was high in this study population. Almost one-half of owners surveyed reported being unable to consistently administer more than three medications daily, and approximately one-quarter of patients were treated for at least one additional chronic condition requiring daily medications, in addition to cardiac disease. Clinicians should be aware of these factors when determining optimal treatment protocols for the management of cardiovascular disease in dogs.

A patient decision aid for breast cancer patients deciding on their radiation treatment, no change in decisional conflict but better informed choices.

BACKGROUND AND PURPOSE: In selected breast cancer patients, radiation treatment (RT) lowers the recurrence risk, with minor or no improvement of survival. In these patients, the choice to undergo RT is considered a preference-sensitive decision. To facilitate shared decision-making (SDM) for this choice, a patient decision aid was made. We aimed to evaluate the effect of the PtDA on decisional conflict. MATERIAL AND METHODS: We performed a multi-center pre- and post-intervention study (BRASA-trial). The first 214 patients made a choice without support of the PtDA; the subsequent 189 patients received a link to the PtDA. The primary endpoint was decisional conflict; secondary endpoints were perceived SDM and knowledge on treatment options. Patients filled out questionnaires immediately after, and three months after their decision. Data were analyzed with multi-level regression analysis. RESULTS: After correcting for the difference in age and educational level, the mean (±SD) decisional conflict for the intervention group (27.3 ± 11.4) was similar to the control group (26.8 ± 11.4; difference = 0.86, 95 %CI 1.67,3.36) three months after their decision. This also applied to perceived SDM. Patients exposed to the PtDA pursued additional treatment less often (45% vs 56%, odds ratio 0.59, 95 %CI 0.37,0.95) and scored significantly higher on the knowledge test (7.4 ± 2.5 vs 6.1 ± 2.7, corrected difference = 1.0, 95 %CI 0.50,1.49). There was no significant increase in consultation time. CONCLUSIONS: Handing out the PtDA was not associated with improved scores in decisional conflict or perceived SDM, but it was associated with a choice for less additional treatment and better knowledge about the treatment options.

Two-dimensional supersolidity in a dipolar quantum gas.

Supersolid states simultaneously feature properties typically associated with a solid and with a superfluid. Like a solid, they possess crystalline order, manifesting as a periodic modulation of the particle density; but unlike a typical solid, they also have superfluid properties, resulting from coherent particle delocalization across the system. Such states were initially envisioned in the context of bulk solid helium, as a possible answer to the question of whether a solid could have superfluid properties1-5. Although supersolidity has not been observed in solid helium (despite much effort)6, ultracold atomic gases provide an alternative approach, recently enabling the observation and study of supersolids with dipolar atoms7-16. However, unlike the proposed phenomena in helium, these gaseous systems have so far only shown supersolidity along a single direction. Here we demonstrate the extension of supersolid properties into two dimensions by preparing a supersolid quantum gas of dysprosium atoms on both sides of a structural phase transition similar to those occurring in ionic chains17-20, quantum wires21,22 and theoretically in chains of individual dipolar particles23,24. This opens the possibility of studying rich excitation properties25-28, including vortex formation29-31, and ground-state phases with varied geometrical structure7,32 in a highly flexible and controllable system.

Evaluation of Early vs Standard Liver Transplant for Alcohol-Associated Liver Disease.

Importance: Traditionally, liver transplant (LT) for alcohol-associated liver disease (ALD) requires 6 months of abstinence. Although early LT before 6 months of abstinence has been associated with decreased mortality for decompensated ALD, this practice remains controversial and concentrated at a few centers. Objective: To define patient, allograft, and relapse-free survival in early LT for ALD, and to investigate the association between these survival outcomes and early vs standard LT. Design, Setting, and Participants: This cohort study analyzed all patients with ALD who underwent their first LT at a single academic referral center between October 1, 2012, and November 13, 2020. Patients with known pretransplant hepatocellular carcinoma, hepatitis B or C, or an alternative cause of liver failure were excluded. Follow-up period was defined as the time from LT to the most recent encounter with a transplant center or death. Exposures: The exposure of interest was early LT, which was defined as less than 180 days of pre-LT abstinence. Standard LT was defined as 180 days or more of pre-LT abstinence. Patients were separated into early LT and standard LT by time from abstinence to LT. Main Outcomes and Measures: The outcomes were patient, allograft, relapse-free, and hazardous relapse-free survival for patients who underwent early LT or standard LT. These groups were compared by log-rank testing of Kaplan-Meier estimates. Hazardous relapse was defined as binge, at-risk, or frequent drinking. Abstinence was reassessed at the most recent follow-up visit for all patients. Results: Of the 163 patients with ALD included in this study, 88 (54%) underwent early LT and 75 (46%) underwent standard LT. This cohort had a mean (SD) age at transplant of 52 (10) years and was predominantly composed of 108 male patients (66%). Recipients of early LT vs standard LT were younger (median [interquartile range (IQR)] age, 49.7 [39.0-54.2] years vs 54.6 [48.7-60.0] years; P < .001) and had a higher median (IQR) Model for End-stage Liver Disease score at listing (35.0 [29.0-39.0] vs 20.0 [13.0-26.0]; P < .001). Both recipients of early LT and standard LT had similar 1-year patient survival (94.1% [95% CI, 86.3%-97.5%] vs 95.9% [95% CI, 87.8%-98.7%]; P = .60), allograft survival (92.7% [95% CI, 84.4%-96.7%] vs 90.5% [95% CI, 81.0%-95.3%]; P = .42), relapse-free survival (80.4% [95% CI, 69.1%-88.0%] vs 83.5% [95% CI, 72.2%-90.6%]; P = .41), and hazardous relapse-free survival (85.8% [95% CI, 75.1%-92.2%] vs 89.6% [95% CI, 79.5%-94.9%]; P = .41). Conclusions and Relevance: Adherence to the 6-month rule was not associated with superior patient survival, allograft survival, or relapse-free survival among selected patients. This finding suggests that patients with ALD should not be categorically excluded from LT solely on the basis of 6 months of abstinence, but rather alternative selection criteria should be identified that are based on need and posttransplant outcomes.

Refractive Outcomes After Immediate Sequential vs Delayed Sequential Bilateral Cataract Surgery.

Importance: Approximately 2 million cataract operations are performed annually in the US, and patterns of cataract surgery delivery are changing to meet the increasing demand. Therefore, a comparative analysis of visual acuity outcomes after immediate sequential bilateral cataract surgery (ISBCS) vs delayed sequential bilateral cataract surgery (DSBCS) is important for informing future best practices. Objective: To compare refractive outcomes of patients who underwent ISBCS, short-interval (1-14 days between operations) DSBCS (DSBCS-14), and long-interval (15-90 days) DSBCS (DSBCS-90) procedures. Design, Setting, and Participants: This retrospective cohort study used population-based data from the American Academy of Ophthalmology Intelligent Research in Sight (IRIS) Registry. A total of 1 824 196 IRIS Registry participants with bilateral visual acuity measurements who underwent bilateral cataract surgery were assessed. Exposures: Participants were divided into 3 groups (DSBCS-90, DSBCS-14, and ISBCS groups) based on the timing of the second eye surgery. Univariable and multivariable linear regression models were used to analyze the refractive outcomes of the first and second surgery eye. Main Outcomes and Measures: Mean postoperative uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA) after cataract surgery. Results: This study analyzed data from 1 824 196 patients undergoing bilateral cataract surgery (mean [SD] age for those <87 years, 70.03 [7.77]; 684 916 [37.5%] male). Compared with the DSBCS-90 group, after age, self-reported race, insurance status, history of age-related macular degeneration, diabetic retinopathy, and glaucoma were controlled for, the UCVA of the first surgical eye was higher by 0.41 (95% CI, 0.36-0.45; P < .001) letters, and the BCVA was higher by 0.89 (95% CI, 0.86-0.92; P < .001) letters in the DSBCS-14 group, whereas in the ISBCS group, the UCVA was lower by 2.79 (95% CI, -2.95 to -2.63; P < .001) letters and the BCVA by 1.64 (95% CI, -1.74 to -1.53; P < .001) letters. Similarly, compared with the DSBCS-90 group for the second eye, in the DSBCS-14 group, the UCVA was higher by 0.79 (95% CI, 0.74-0.83; P < .001) letters and the BCVA by 0.48 (95% CI, 0.45-0.51; P < .001) letters, whereas in the ISBCS group, the UCVA was lower by -1.67 (95% CI, -1.83 to -1.51; P < .001) letters and the BCVA by -1.88 (95% CI, -1.98 to -1.78; P < .001) letters. Conclusions and Relevance: The results of this cohort study of patients in the IRIS Registry suggest that compared with DSBCS-14 or DSBCS-90, ISBCS is associated with worse visual outcomes, which may or may not be clinically relevant, depending on patients' additional risk factors. Nonrandom surgery group assignment, confounding factors, and large sample size could account for the small but statistically significant differences noted. Further studies are warranted to determine whether these factors should be considered clinically relevant when counseling patients before cataract surgery.

Postmastectomy radiotherapy for all node positive patients: The case against.

Postmastectomy radiotherapy (PMRT) is accepted as the standard of care for women with early breast cancer with 4 or more involved axillary nodes. However the role of PMRT in women with 1-3 involved nodes remains controversial and guidelines vary. We present the arguments against advocating postmastectomy radiotherapy for all women with node positive breast cancer.

Elevated levels of Merkel cell polyoma virus in the anophthalmic conjunctiva.

The human ocular surface hosts a paucibacterial resident microbiome and virome. The factors contributing to homeostasis of this mucosal community are presently unknown. To determine the impact of ocular enucleation and prosthesis placement on the ocular surface microbiome, we sampled conjunctival swabs from 20 anophthalmic and 20 fellow-eye intact conjunctiva. DNA was extracted and subjected to quantitative 16S rDNA PCR, biome representational karyotyping (BRiSK), and quantitative PCR (qPCR) confirmation of specific organisms. 16S ribosomal qPCR revealed equivalent bacterial loads between conditions. Biome representational in silico karyotyping (BRiSK) demonstrated comparable bacterial fauna between anophthalmic and intact conjunctiva. Both torque teno virus and Merkel cell polyoma virus (MCPyV) were detected frequently in healthy and anophthalmic conjunctiva. By qPCR, MCPyV was detected in 19/20 anophthalmic samples compared with 5/20 fellow eyes. MCPyV copy number averaged 891 copies/ng in anophthalmic conjunctiva compared with 193 copies/ng in fellow eyes (p < 0.001). These results suggest that enucleation and prosthesis placement affect the ocular surface flora, particularly for the resident virome. As MCPyV has been shown to be the etiologic cause of Merkel cell carcinoma, understanding the mechanisms by which the ocular surface regulates this virus may have clinical importance.