In principle, evolutionary outcomes could be largely predicted if all of the relevant physicochemical variants of a particular protein function under selection were known and integrated into an appropriate physiological model. We have tested this principle by generating a family of variants of the tetracycline resistance protein TetX2 and identified the physicochemical properties most correlated with organismal fitness. Surprisingly, small changes in the K m(MCN) , less than twofold, were sufficient to produce highly successful adaptive mutants over clinically relevant drug concentrations. We then built a quantitative model directly relating the in vitro physicochemical properties of the mutant enzymes to the growth rates of bacteria carrying a single chromosomal copy of the tet(X2) variants over a wide range of minocycline (MCN) concentrations. Importantly, this model allows the prediction of enzymatic properties directly from cellular growth rates as well as the physicochemical-fitness landscape of TetX2. Using experimental evolution and deep sequencing to monitor the allelic frequencies of the seven most biochemically efficient TetX2 mutants in 10 independently evolving populations, we showed that the model correctly predicted the success of the two most beneficial variants tet(X2) T280A and tet(X2) N371I . The structure of the most efficient variant, TetX2 T280A , in complex with MCN at 2.7 Å resolution suggests an indirect effect on enzyme kinetics. Taken together, these findings support an important role for readily accessible small steps in protein evolution that can, in turn, greatly increase the fitness of an organism during natural selection. experimental evolution | genome to phenome | oxidoreductase W hat determines success or failure of variants within a population undergoing selection? To answer this challenging question, experimental evolution, genomics, and biochemistry have proved to be powerful approaches to the formulation of specific and testable hypotheses that can be validated in a quantitative manner. Most recently, experimental evolution has provided a wealth of insights into epistasis (1-3), adaptive convergence among populations (4, 5), and the role of mutation supply (6, 7) in asexual populations (8). Dean and Thornton coined the term "functional synthesis" to encompass the increasingly relevant role for molecular biology, biochemistry, and biophysics in elucidating a strong quantitative link between changes in genomes (genotype) to their resultant changes in molecular properties (phenotype) and fitness, the property that selection acts upon (9). Dykhuizen and coworkers were among the first to recognize the importance of the functional synthesis when they successfully modeled the adaptive landscape of the lactose operon to quantitatively predict growth rates (10). Whereas the qualitative link between an enzyme function under selection and fitness is typically straightforward, it has proved very challenging to predict how specific adaptive changes in readily measurable in vitro biophysi...

Although Bell's palsy is a common etiology for isolated facial paralysis, it is important clinicians perform a complete neurologic examination to avoid misdiagnosis. Multiple cranial neuropathy is often caused by tumor or infection.

Aims. This chart review of a quaternary academic medical center electronic medical record (EMR) aimed to identify patients at risk of development of maculopathy with exposure to pentosan polysulfate sodium (PPS). Methods. A review of electronic medical records of a quaternary medical center of patients with either documented exposure to PPS or diagnosis of interstitial cystitis (IC) from 2007 to 2019 was performed for retinal imaging and visual acuity; the study was conducted in August of 2019. Results. 216 charts were included for analysis, of which 96 had documented eye exams and 24 had retinal imaging done. We identified three patients with maculopathy in the context of long-term exposure to PPS via chart review, and one additional patient was identified by referral. The median PPS exposure duration was 11 years (range 7 to 19 years). Median logMAR BCVA OD 0.6 range was 0.0–1.9 (approximate Snellen equivalent 20/80 range (20/20–20/1600)) and OS 0.7 range was 0.1–1.9 (approximate Snellen equivalent 20/100 range (20/25–20/1600)). Ultrawidefield color fundus imaging and fundus autofluorescence revealed findings of pigmentary changes and patchy macular atrophy. Optical coherence tomography (OCT) demonstrated outer retinal thinning and increased choroidal transmission coincident with areas of atrophy seen on fundus imaging. Conclusions. Less than half of patients at risk for development of maculopathy due to exposure to PPS had received eye examinations, suggesting that those at risk are not receiving adequate screening. We found two patients with PPS maculopathy who had relatively preserved central vision, one patient with bitemporal vision loss, and one patient who developed vision loss in both eyes.

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Metastatic neuroendocrine neoplasms to the breast are rare and histopathologic overlap with mammary carcinomas has led to misdiagnosis. We present a case of a middle-aged woman with diplopia and a right medial rectus mass. Metastatic breast cancer was initially suspected based on a history of invasive ductal carcinoma. Detailed immunohistochemistry of the orbital biopsy, gallium-68 dotatate positron emission tomography–CT, and reevaluation of her prior breast specimen, demonstrated that her initial breast carcinoma diagnosis was in error and she was ultimately diagnosed with a previously unknown gastrointestinal neuroendocrine tumour metastatic to both the orbit and breast. This case highlights the challenges of differentiating between metastatic neuroendocrine tumours and invasive mammary carcinomas with neuroendocrine differentiation both in the breast and in the orbit. It is important to recognise the overlap so that a primary neuroendocrine neoplasm is not missed, or treatment significantly delayed.

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BACKGROUND AND OBJECTIVE: To evaluate the financial sustainability of teleophthalmology screening for diabetic retinopathy (DR) using telehealth billing codes. PATIENTS AND METHODS: The authors performed an Institutional Review Board-approved retrospective review of medical records, billing data, and quality metrics at the University of California Davis Health System from patients screened for DR through an internal medicine-based telemedicine program using CPT codes 92227 or 92228. RESULTS: A total of 290 patients received teleophthalmology screening over a 12-month period, resulting in an increase in the DR screening rate from 49% to 63% ( P < .0001). The average payment per patient was $19.86, with an estimated cost of $41.02 per patient. The projected per-patient incentive bonus was $43.06 with a downstream referral revenue of $39.38 per patient. One hundred seventy-eight clinic visits were eliminated, providing an estimated cost savings of $42.53 per patient. CONCLUSION: Sustainable teleophthalmology screening may be achieved by billing telehealth codes but only with health care incentive bonuses, patient referrals, and by accounting for the projected cost-savings of eliminating office visits. [ Ophthalmic Surg Lasers Imaging Retina. 2020;51:S26–S34.]

Metastases arising from primary tumors of the gastrointestinal tract are not commonly encountered in the orbit. Colorectal carcinomas are subcategorized based on morphological and genetic characteristics with these distinctions bearing therapeutic and prognostic significance. The behavior of these subcategories, including their propensity for orbital metastasis, differs, and clinicians treating these tumors must be aware of their metastatic profiles. This report describes a 51-year-old female with right upper lid swelling and ptosis ultimately found, what we believe to be, the first reported case of signet ring cell colon carcinoma metastasizing to the levator muscle and superior orbit. This case serves as a reminder to all clinicians to consider orbital metastasis even in malignancies not typically found in this location.