LONG-TERM USE OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: Although pivotal trials have demonstrated efficacy of anti-vascular endothelial growth factor therapy in neovascular age-related macular degeneration, there is a paucity of clinical data about the long-term (>5 years) treatment. METHODS: Retrospective analysis of all patients with neovascular age-related macular degeneration who were actively treated, had received >40 anti-vascular endothelial growth factor injections, and were followed for ≥5 years. Snellen-corrected visual acuity, initial drug choice, and times elapsed between treatments were collected. Rates of endophthalmitis and outcomes of submacular hemorrhage were also evaluated. RESULTS: A total of 88 patients (162 eyes) met the inclusion criteria: the average patient age was 86.3 years with an average follow-up period of 7.6 years. The average total number of injections per eye was 69 (18.0 SD); a total of 11,208 injections were given throughout the study period, and 6 cases (0.05%) of endophthalmitis were observed. Overall, there was a clinical and statistical difference in average Snellen-corrected visual acuity at Injections #2,#3, #4, #5, #6, #10, and #20, as compared with baseline ( P = 0.03, P < 0.01, P = 0.02, P < 0.01, P = 0.01, P = 0.01, P < 0.01, respectively). Patients in the Snellen-corrected visual acuity subgroup 20/20 to 20/40 maintained vision until injection #30. Seven eyes experienced a visually significant submacular hemorrhage. CONCLUSION: This neovascular age-related macular degeneration cohort received on average eight anti-vascular endothelial growth factor injections per year for approximately 8 years; eyes with good (≥20/40) initial baseline vision maintained their visual acuity, whereas those with worse Snellen-corrected visual acuity (≤20/50) had a robust initial improvement that diminished with time. Most patients were maintained on the same initial drug of choice and the rate of endophthalmitis was low.

Properties of Cosmic-Ray Sulfur and Determination of the Composition of Primary Cosmic-Ray Carbon, Neon, Magnesium, and Sulfur: Ten-Year Results from the Alpha Magnetic Spectrometer.

We report the properties of primary cosmic-ray sulfur (S) in the rigidity range 2.15 GV to 3.0 TV based on 0.38×10^{6} sulfur nuclei collected by the Alpha Magnetic Spectrometer experiment (AMS). We observed that above 90 GV the rigidity dependence of the S flux is identical to the rigidity dependence of Ne-Mg-Si fluxes, which is different from the rigidity dependence of the He-C-O-Fe fluxes. We found that, similar to N, Na, and Al cosmic rays, over the entire rigidity range, the traditional primary cosmic rays S, Ne, Mg, and C all have sizeable secondary components, and the S, Ne, and Mg fluxes are well described by the weighted sum of the primary silicon flux and the secondary fluorine flux, and the C flux is well described by the weighted sum of the primary oxygen flux and the secondary boron flux. The primary and secondary contributions of the traditional primary cosmic-ray fluxes of C, Ne, Mg, and S (even Z elements) are distinctly different from the primary and secondary contributions of the N, Na, and Al (odd Z elements) fluxes. The abundance ratio at the source for S/Si is 0.167±0.006, for Ne/Si is 0.833±0.025, for Mg/Si is 0.994±0.029, and for C/O is 0.836±0.025. These values are determined independent of cosmic-ray propagation.

Temporal Structures in Positron Spectra and Charge-Sign Effects in Galactic Cosmic Rays.

We present the precision measurements of 11 years of daily cosmic positron fluxes in the rigidity range from 1.00 to 41.9 GV based on 3.4×10^{6} positrons collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The positron fluxes show distinctly different time variations from the electron fluxes at short and long timescales. A hysteresis between the electron fluxes and the positron fluxes is observed with a significance greater than 5σ at rigidities below 8.5 GV. On the contrary, the positron fluxes and the proton fluxes show similar time variation. Remarkably, we found that positron fluxes are modulated more than proton fluxes with a significance greater than 5σ for rigidities below 7 GV. These continuous daily positron fluxes, together with AMS daily electron, proton, and helium fluxes over an 11-year solar cycle, provide unique input to the understanding of both the charge-sign and mass dependencies of cosmic rays in the heliosphere.

Temporal Structures in Electron Spectra and Charge Sign Effects in Galactic Cosmic Rays.

We present the precision measurements of 11 years of daily cosmic electron fluxes in the rigidity interval from 1.00 to 41.9 GV based on 2.0×10^{8} electrons collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The electron fluxes exhibit variations on multiple timescales. Recurrent electron flux variations with periods of 27 days, 13.5 days, and 9 days are observed. We find that the electron fluxes show distinctly different time variations from the proton fluxes. Remarkably, a hysteresis between the electron flux and the proton flux is observed with a significance of greater than 6σ at rigidities below 8.5 GV. Furthermore, significant structures in the electron-proton hysteresis are observed corresponding to sharp structures in both fluxes. This continuous daily electron data provide unique input to the understanding of the charge sign dependence of cosmic rays over an 11-year solar cycle.

Properties of Daily Helium Fluxes.

We present the precision measurement of 2824 daily helium fluxes in cosmic rays from May 20, 2011 to October 29, 2019 in the rigidity interval from 1.71 to 100 GV based on 7.6×10^{8} helium nuclei collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The helium flux and the helium to proton flux ratio exhibit variations on multiple timescales. In nearly all the time intervals from 2014 to 2018, we observed recurrent helium flux variations with a period of 27 days. Shorter periods of 9 days and 13.5 days are observed in 2016. The strength of all three periodicities changes with time and rigidity. In the entire time period, we found that below ∼7 GV the helium flux exhibits larger time variations than the proton flux, and above ∼7 GV the helium to proton flux ratio is time independent. Remarkably, below 2.4 GV a hysteresis between the helium to proton flux ratio and the helium flux was observed at greater than the 7σ level. This shows that at low rigidity the modulation of the helium to proton flux ratio is different before and after the solar maximum in 2014.

Periodicities in the Daily Proton Fluxes from 2011 to 2019 Measured by the Alpha Magnetic Spectrometer on the International Space Station from 1 to 100 GV.

We present the precision measurement of the daily proton fluxes in cosmic rays from May 20, 2011 to October 29, 2019 (a total of 2824 days or 114 Bartels rotations) in the rigidity interval from 1 to 100 GV based on 5.5×10^{9} protons collected with the Alpha Magnetic Spectrometer aboard the International Space Station. The proton fluxes exhibit variations on multiple timescales. From 2014 to 2018, we observed recurrent flux variations with a period of 27 days. Shorter periods of 9 days and 13.5 days are observed in 2016. The strength of all three periodicities changes with time and rigidity. The rigidity dependence of the 27-day periodicity is different from the rigidity dependences of 9-day and 13.5-day periods. Unexpectedly, the strength of 9-day and 13.5-day periodicities increases with increasing rigidities up to ∼10 GV and ∼20 GV, respectively. Then the strength of the periodicities decreases with increasing rigidity up to 100 GV.

CLINICAL OUTCOMES AND TREATMENT COURSE OF EYES WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION FOLLOWING THE DEVELOPMENT OF ENDOPHTHALMITIS.

PURPOSE: To evaluate the clinical course of patients with neovascular age-related macular degeneration (nAMD) after developing endophthalmitis during their treatment with intravitreal injections. METHODS: Multicenter, retrospective series. RESULTS: From April 2013 to October 2018, 196,598 intravitreal anti-vascular endothelial growth factor (VEGF) injections were performed, with 75 cases of endophthalmitis (incidence 0.0381%). There was no association between intravitreal anti-VEGF drug (P = 0.29), anesthetic method (P = 0.26), povidone concentration (P = 0.22), or any intraprocedure variable and endophthalmitis incidence. Seventy-two patients (96%) were treated with intravitreal tap and inject , while 3 underwent immediate pars plana vitrectomy. After endophthalmitis resolution, 17 patients (22.7%) were not re-treated for nAMD (in 10 cases due to inactive disease; follow-up, 115 ± 8.4 weeks). Patients required less frequent anti-VEGF injections after infection (7.4 ± 0.61 weeks vs. 11.5 ± 1.8 weeks; P = 0.004). Preinfection logarithm of the minimum angle of resolution visual acuity was 0.585 ± 0.053 (∼20/77). It worsened with endophthalmitis (1.67 ± 0.08, ∼20/935; P < 0.001) and again on postendophthalmitis treatment day 1 (1.94 ± 0.064; count fingers; P < 0.001), but improved after reinitiating nAMD therapy (1.02 ± 0.11; ∼20/209; P < 0.001). Better visual acuity on postendophthalmitis week 1 (P = 0.002) and reinitiation of nAMD treatment (P = 0.008) were associated with better final visual acuity, and streptococcal culture with worse visual acuity (P = 0.028). The postendophthalmitis treatment interval was associated with the anti-VEGF drug used (aflibercept = ranibizumab > bevacizumab; P < 0.001). CONCLUSION: Patients with nAMD required fewer injections after endophthalmitis, suggesting a biological change in disease activity. Neovascular age-related macular degeneration became quiescent in 13.3% of eyes. Most achieved better outcomes with anti-VEGF reinitiation.

A Painful, Squeaking Pyrolytic Carbon Metacarpophalangeal Joint Replacement.

Metacarpophalangeal (MCP) joint arthroplasty with pyrolytic carbon implants is a common procedure that is performed to alleviate pain from arthritis. The material properties of pyrolytic carbon are discussed with regard to their efficacy in MCP joint arthroplasty. We report a case of a painful, squeaking MCP joint arthroplasty treated with revision arthroplasty. Squeaking is a rare complication of MCP joint arthroplasty and is usually asymptomatic with spontaneous resolution. However, in this case, the squeaking was persistent and likely related to intraoperative findings of implant subsidence, debris, wear, and an incongruent joint. We also see in this case that the revision pyrolytic carbon MCP arthroplasty underwent subsidence within 2 years of revision surgery and ultimately was revised to a silicone MCP arthroplasty.

Comparative study of cholesteatoma in paediatric and adult patients.

BACKGROUND: The aggressiveness of paediatric cholesteatoma has long been a matter of debate. While much of the evidence is substantiated by data from the Western world, it is further limited by the retrospective nature of most studies. Therefore, this paper presents a comparative analysis of various characteristics of cholesteatoma between paediatric and adult populations seen at our centre. METHODS: A total of 50 patients (25 adults and 25 paediatric) with clinical diagnosis of chronic suppurative otitis media with cholesteatoma underwent canal wall down mastoidectomy over a period of two years. The intra-operative findings were noted and patients were followed up for six months. RESULTS: There was more extensive spread and ossicular erosion in paediatric cases. However, complications such as facial canal dehiscence and lateral semicircular canal dehiscence were more common in adults. CONCLUSION: Paediatric cholesteatoma is more aggressive and invasive than adult cholesteatoma, and the clinical behaviour is consistent with findings from other parts of the world.

Evaluation of transdermal steroids for trapeziometacarpal arthritis.

PURPOSE: One conservative treatment for trapeziometacarpal joint arthritis is the delivery of steroids transdermally. In prior transdermal studies on the elbow and foot, there are mixed reports of success. It appears that the benefits of the treatment might be limited to short-term relief (approximately one week). It was hypothesized that transdermal steroid delivery would yield short-term improvements for trapezial-metacarpal joint arthritis, although these improvements would not persist at later follow-up (3 or 6 months). METHODS: Eighty-four consecutive trapeziometacarpal joints in 62 patients presenting to an orthopedic hand surgeon were randomized to receive either steroid delivery by iontophoresis or phonophoresis or placebo delivery via iontophoresis or phonophoresis. The researchers and patients were blinded as to the treatment assignment. Patients were evaluated before treatment and at 3 follow-up appointments. Subjects were assessed via the Michigan Hand Outcomes Questionnaire, Short Form 12, analog pain score, and provocative and strength testing. The subjects' study group, gender, and arthritic grade were statistically analyzed versus patient-reported and physician-assessed data over the different time points. Following subject recruitment, 17 joints discontinued the study due to joint discomfort, electing for other treatments. Approximately half of the 67 subject joints opted for alternative treatment after the first or second follow-up; 34 subject joints completed all follow-up time points. RESULTS: There was no significant predictive relationship between the independent variables and their ability to predict the 9 dependent measures of pain, strength, and well-being. There were trends for the pain to decrease over time, although the trends were not uniform between the different pain metrics and groups. The strength for both iontophoresis groups tended to increase over time, whereas the phonophoresis groups tended to decline. CONCLUSIONS: Although there were some trends in the follow-up data, the overall lack of significant differences in the data suggests that transdermal steroid delivery might not be helpful in providing short- or long-term relief of arthritic symptoms. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

Predictors of Endophthalmitis after Intravitreal Injection: A Multivariable Analysis Based on Injection Protocol and Povidone Iodine Strength.

PURPOSE: To determine the incidence of endophthalmitis after anti-vascular endothelial growth factor (VEGF) therapy at our institution and to identify potential risk factors for endophthalmitis occurring after injection. DESIGN: Retrospective, single-center cohort study. PARTICIPANTS: All patients who received an intravitreal injection of an anti-VEGF medication between January 1, 2014, and March 31, 2017. METHODS: Current Procedural Terminology and International Classification of Diseases billing codes were used to identify instances of anti-VEGF administration and cases of endophthalmitis. Medical records and injection technique were reviewed carefully in each case. Multivariable logistic regression analysis was performed in a stepwise fashion to determine independent predictors of endophthalmitis based on injection protocol. MAIN OUTCOME MEASURES: Incidence of endophthalmitis after injection and odds of endophthalmitis by injection technique with 95% confidence intervals (CIs). RESULTS: A total of 154 198 anti-VEGF injections were performed during the period of interest, resulting in 58 cases of endophthalmitis (0.038% [1:2659]). After adjustment for confounders, both 2% lidocaine jelly (odds ratio [OR], 11.28; 95% CI, 3.39-37.46; P < 0.001) and 0.5% Tetravisc (Ocusoft, Richmond, TX; OR, 3.95; 95% CI, 1.15-13.50; P = 0.03) use were independent risk factors for endophthalmitis after injection. Lid speculum use, povidone iodine strength (5% vs. 10%), injection location (superior or inferior), conjunctival displacement, use of provider gloves, use of a strict no-talking policy, use of subconjunctival lidocaine, and topical antibiotic use were not statistically significant predictors of endophthalmitis after injection. There was no difference in endophthalmitis rate among the anti-VEGF agents (bevacizumab, ranibizumab 0.3 mg, ranibizumab 0.5 mg, and aflibercept). CONCLUSIONS: The incidence of endophthalmitis after anti-VEGF injections is low. Use of lidocaine jelly or Tetravisc may increase the risk of endophthalmitis after injection.

Prevalence of extended spectrum beta-lactamases producing clinical isolates from patients of urinary tract infection in a tertiary care hospital in Delhi.

A total of 250 urinary isolates (188 Escherichia coli and 62 Klebsiella pneumoniae) were studied for ESBL production by double disc approximation test and disc diffusion confirmatory test (NCCLS). ESBL production was found to be 56% in E. coli and 52% in K. pneumoniae. The double disc approximation test showed false ESBL production in five (2.6%) isolates of E. coli and one (1.6%) K. pneumoniae. The susceptibility of ESBL producers to imipenem, amikacin, nitrofurantion was found to be 100%, 86% and 84% respectively. A high degree of co-resistance to co- trimaxazole and norfloxacin was found in strains of ESBL producers. Seventy five per cent of ESBL producers detected were from hospitalized patients admitted in ICU or undergoing surgery.

A Hydrothermal-Sedimentary Context for the Origin of Life.

Critical to the origin of life are the ingredients of life, of course, but also the physical and chemical conditions in which prebiotic chemical reactions can take place. These factors place constraints on the types of Hadean environment in which life could have emerged. Many locations, ranging from hydrothermal vents and pumice rafts, through volcanic-hosted splash pools to continental springs and rivers, have been proposed for the emergence of life on Earth, each with respective advantages and certain disadvantages. However, there is another, hitherto unrecognized environment that, on the Hadean Earth (4.5-4.0 Ga), would have been more important than any other in terms of spatial and temporal scale: the sedimentary layer between oceanic crust and seawater. Using as an example sediments from the 3.5-3.33 Ga Barberton Greenstone Belt, South Africa, analogous at least on a local scale to those of the Hadean eon, we document constant permeation of the porous, carbonaceous, and reactive sedimentary layer by hydrothermal fluids emanating from the crust. This partially UV-protected, subaqueous sedimentary environment, characterized by physical and chemical gradients, represented a widespread system of miniature chemical reactors in which the production and complexification of prebiotic molecules could have led to the origin of life. Key Words: Origin of life-Hadean environment-Mineral surface reactions-Hydrothermal fluids-Archean volcanic sediments. Astrobiology 18, 259-293.

Designing ligand-enhanced optical absorption of thiolated gold nanoclusters.

The optical spectra of thiolated Au25(SR)18/Au23(SR)16 clusters with different R residues are investigated via TDDFT simulations. Significant enhancements in the optical region and effective electron delocalization are simultaneously achieved by tuning the ligands' steric hindrance and electronic conjugating features, producing a resonance phenomenon between the Au-S core motif and the ligand fragments.

Fully compact higher-order computation of steady-state natural convection in a square cavity.

The flow in a thermally driven square cavity with adiabatic top and bottom walls and differentially heated vertical walls for a wide range of Rayleigh numbers (10(3)< or =Ra< or =10(7)) has been computed with a fourth-order accurate higher-order compact scheme, which was used earlier only for the stream-function vorticity (psi-omega) form of the two-dimensional steady-state Navier-Stokes equations. The boundary conditions used are also compact and of identical accuracy. In particular, a compact fourth-order accurate Neumann boundary condition has been developed for temperature at the adiabatic walls. The treatment of the derivative source term is also compact and has been done in such a way as to give fourth-order accuracy and easy assimilation with the solution procedure. As the discretization for the psi-omega formulation, boundary conditions, and source term treatment are all fourth-order accurate, highly accurate solutions are obtained on relatively coarser grids. Unlike other compact solution procedure in literature for this physical configuration, the present method is fully compact and fully higher-order accurate. Also, use of conjugate gradient and hybrid biconjugate gradient stabilized algorithms to solve the symmetric and nonsymmetric algebraic systems at every outer iteration, ensures good convergence behavior of the method even at higher Rayleigh numbers.

Fatal non-bacterial thrombotic endocarditis following viperine bite.

Non-bacterial thrombotic endocarditis (NBTE) commonly occurs in patients with wasting disease (e.g. malignancy) or with valves damaged following trauma due to intra-cardiac foreign body, scarring or marked turbulence. Although disseminated intravascular coagulation (DIC) is well documented following viperine bite and the underlying mechanism of NBTE is thought to be DIC, there is no report of NBTE in humans following snake bite. We report a young male who following viperine bite developed local swelling, superficial gangrene of tissues at the site of bite, and oliguria and died following multiple cerebral infarcts and acute renal failure. The post-mortem examination showed NBTE of the aortic valve, multiple embolic infarcts of brain, spleen and kidneys, acute tubular necrosis and features of DIC in the brain in the form of fibrin thrombi in the capillaries, perivascular hemorrhages and necrosis.

Anhidrotic ectodermal dysplasia presenting as atrophic rhinitis.

Atrophic rhinitis is a chronic inflammatory disease of the nose. The aetiology of primary atrophic rhinitis is not yet known, although secondary atrophic rhinitis is known to be associated with chronic granulomatous diseases such as tuberculosis and leprosy. The authors report a case of atrophic rhinitis, which was a presenting feature of a rare genetic disorder known as Christ-Siemens-Touraine syndrome, also known as anhidrotic ectodermal dysplasia.

Tuberculosis of the pyriform fossa--a rare entity.

Tuberculosis of the pharynx is less common than tuberculosis of the larynx. We present a rare case of tuberculosis of the pyriform fossa which clinically masqueraded as a malignancy. Our patient showed a prompt improvement in symptoms after commencing antitubercular treatment.

Parathyroid cyst: a rare cause of an anterior neck mass.

Parathyroid cysts are rare. Most of them present in the anterior neck as cystic neck swellings. A case of cervical parathyroid cyst is presented, along with a brief review of the literature regarding the aetiology, clinical features, diagnosis and management of this condition.

Biomechanical performance of variable and fixed angle locked volar plates for the dorsally comminuted distal radius.

BACKGROUND: The ideal treatment strategy for the dorsally comminuted distal radius fracture continues to evolve. Newer plate designs allow for variable axis screw placement while maintaining the advantages of locked technology. The purpose of this study is to compare the biomechanical properties of one variable axis plate with two traditional locked constructs. METHODS: Simulated fractures were created via a distal 1 cm dorsal wedge osteotomy in radius bone analogs. The analogs were of low stiffness and rigidity to create a worst-case strength condition for the subject radius plates. This fracture-gap model was fixated using one of three different locked volar distal radius plates: a variable axis plate (Stryker VariAx) or fixed axis (DePuy DVR, Smith & Nephew Peri-Loc) designs. The constructs were then tested at physiologic loading levels in axial compression and bending (dorsal and volar) modes. Construct stiffness was assessed by fracture gap motion during the different loading conditions. As a within-study control, intact bone analogs were similarly tested. RESULTS: All plated constructs were significantly less stiff than the intact control bone models in all loading modes (p<0.040). Amongst the plated constructs, the VariAx was stiffest axially (p=0.032) and the Peri-Loc was stiffest in bending (p<0.024). CONCLUSION: In this analog bone fracture gap model, the variable axis locking technology was stiffer in axial compression than other plates, though less stiff in bending.