Refractive outcomes following bilateral implantation of a diffractive toric intraocular lens in a multisurgeon hospital setting.

OBJECTIVE: To assess residual postoperative refractive astigmatism following bilateral implantation of a trifocal toric intraocular lens (IOL) in a real-world multisurgeon setting. DESIGN: Prospective multisurgeon study (6 surgeons at 2 sites). METHODS: Bilateral implantation of a trifocal toric IOL (AcrySof PanOptix IOL; Alcon Vision LLC, Fort Worth, TX, USA) was performed in 140 eyes of 70 patients. Patients were assessed on day 1 and 3 months postoperatively. The primary outcome measure was residual astigmatism. Secondary endpoints included absolute prediction error, IOL rotation, binocular uncorrected and distance-corrected visual acuities at near (40 cm), intermediate (60 cm), and distance (6 m) and spectacle independence evaluated with the validated Intraocular Lens Satisfaction questionnaire. RESULTS: Mean preoperative cylinder was 1.25 ± 0.72 D and was 0.39 ± 0.28 D at 3 months postoperatively. At 3 months postoperatively, mean residual astigmatism was 0.39 ± 0.28 D (range, 0-1.25 D), and 118 eyes (84.3%) had postoperative astigmatism of 0.5 D or less. Mean absolute prediction error was 0.25 ± 0.21 D (range, 0-1.13 D), and 124 eyes (88.6%) had absolute prediction error of 0.5 D or less. At 3 months postoperatively, mean absolute rotation was 2.0 ± 2.7 degrees compared with baseline (range, 0-15 degrees), and 133 IOLs (95.0%) were within 5 degrees of the implanted axis. Additionally, 55 patients (79%) reported never or rarely using spectacles at near, 66 (94%) at intermediate, and 67 (96%) at distance. CONCLUSIONS: The results of this study demonstrate that implantation with the PanOptix toric IOL can provide excellent refractive and visual outcomes with minimal residual astigmatism.

Author Correction: Chimpanzee ethnography reveals unexpected cultural diversity.

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

Nitric oxide dosed in short bursts at high concentrations may protect against Covid 19.

It has long been suggested that NO may inhibit an early stage in viral replication. Furthermore, in vitro tests have shown that NO inhibits the replication cycle of severe acute respiratory syndrome coronavirus. Despite smoking being listed as a risk factor to contract Covid-19, only a low proportion of the smokers suffered from SARS-corona infection in China 2003, and from Covid-19 in China, Europe and the US. We hypothesize, that the intermittent bursts of high NO concentration in cigarette smoke may be a mechanism in protecting against the virus. Mainstream smoke from cigarettes contains NO at peak concentrations of between about 250 ppm and 1350 ppm in each puff as compared to medicinal use of no more than 80 to a maximum of 160 ppm. The diffusion of NO through the cell wall to reach the virus should be significantly more effective at the very high NO concentration in the smoke, according to classic laws of physics. The only oxide of nitrogen in the mainstream smoke is NO, and the NO2 concentration that is inhaled is very low or undetectable, and methemoglobin levels are lower in smokers than non-smokers, reasonably explained by the breaths of air in between the puffs that wash out the NO. Specialized iNO machines can now be developed to provide the drug intermittently in short bursts at high concentration dose, which would then provide both a preventative drug for those at high risk, as well as an effective treatment, without the health hazards associated with smoking.

Chimpanzee ethnography reveals unexpected cultural diversity.

Human ethnographic knowledge covers hundreds of societies, whereas chimpanzee ethnography encompasses at most 15 communities. Using termite fishing as a window into the richness of chimpanzee cultural diversity, we address a potential sampling bias with 39 additional communities across Africa. Previously, termite fishing was known from eight locations with two distinguishable techniques observed in only two communities. Here, we add nine termite-fishing communities not studied before, revealing 38 different technical elements, as well as community-specific combinations of three to seven elements. Thirty of those were not ecologically constrained, permitting the investigation of chimpanzee termite-fishing culture. The number and combination of elements shared among individuals were more similar within communities than between them, thus supporting community-majority conformity via social imitation. The variation in community-specific combinations of elements parallels cultural diversity in human greeting norms or chopstick etiquette. We suggest that termite fishing in wild chimpanzees shows some elements of cumulative cultural diversity.

Extended (10-Day) Real-Time Monitoring by Dexamethasone-Enhanced Microdialysis in the Injured Rat Cortex.

Intracerebral microdialysis has proven useful for chemical monitoring in patients following traumatic brain injury. Recent studies in animals, however, have documented that insertion of microdialysis probes into brain tissues initiates a foreign-body response. Within a few days after probe insertion, the foreign body response impedes the use of microdialysis to monitor the K+ and glucose transients associated with spreading depolarization, a potential mechanism for secondary brain injury. Herein, we show that perfusing microdialysis probes with dexamethasone, a potent anti-inflammatory glucocorticoid, suppresses the foreign body response and facilitates the monitoring of spontaneous spreading depolarizations for at least 10 days following controlled cortical injury in the rat. In addition to spreading depolarizations, results of this study suggest that a progressive, apparently permanent, decline in pericontusional interstitial glucose may be an additional sequela of brain injury. This study establishes extended dexamethasone-enhanced microdialysis in the injured rodent cortex as a new paradigm for investigating trauma-induced metabolic crisis.

Pigment Epithelium-Derived Factor (PEDF) as a Regulator of Wound Angiogenesis.

Although the inflammatory and proliferative phases of wound healing have been well described, much less is known about how healing resolves. During the resolution phase, pruning of the capillary bed and maturation of capillaries occurs and influences the final strength and fidelity of the wound. PEDF, an endogenous anti-angiogenic factor, is produced in wounds and may contribute to the removal of capillaries during wound resolution. This study utilized PEDF-/- mice to examine how PEDF influences wound angiogenesis, particularly capillary density and permeability. The absence of PEDF led to transient changes in dermal wound closure and collagen content, but caused substantial changes in wound angiogenesis. Compared to wild type (WT) mice, wounds from PEDF-/- mice exhibited a significant increase in capillaries during the proangiogenic phase of repair, and a delay in capillary pruning. Conversely, the addition of rPEDF caused a reduction in capillary density within skin wounds in WT mice. In vitro studies showed that PEDF inhibited migration and tube formation by dermal microvascular endothelial cells, and caused a decrease in the expression of VEGFR2, VCAM-1, and other surface receptors. The results demonstrate that loss of PEDF causes a distinctive wound healing phenotype that is characterized by increased angiogenesis and delayed resolution. The findings suggest that PEDF most likely acts through multiple mechanisms to regulate proper capillary refinement in wounds.

Missed Opportunities for Chlamydia Screening in Title X Family Planning Clinics.

BACKGROUND: Annual chlamydia (CT) screening is recommended for women younger than 25 years, yet less than half of young women seeking health care are screened annually. We analyzed Title X family planning service data from the Northwest United States to assess factors associated with missed opportunities for CT screening. Our primary hypothesis was screening coverage is higher during annual preventive health visits compared to other visit types. Study objectives were: (1) identify gaps in screening coverage by patient demographics, visit characteristics, and clinic measures; and (2) examine the association between visit type and CT screening by controlling for other covariates and stratifying by state. METHODS: Calendar year 2011 Title X visit records (n = 180,856) were aggregated to the patient level (n = 112,926) to assess CT screening coverage by all characteristics. Screening variation was explored by bivariate and multivariate Poisson regression. Adjusted models for each state estimated association between comprehensive examination and screening controlling for confounders. RESULTS: Clinic and visit characteristics were associated with CT screening. Coverage ranged from 45% in Washington to 80% in Alaska. Only 34% of patients visited for a routine comprehensive examination. Visit type was associated with screening; 75% of patients who had a comprehensive examination were screened versus 34% of those without a comprehensive examination (unadjusted PR, 2.18; 95% confidence interval, 2.16-2.21). The association between comprehensive examination and CT screening varied significantly by state (interaction term, P < 0.001). CONCLUSIONS: Missed screening opportunities are common among women who access brief appointments for specific needs but do not seek routine preventive care, particularly in some states. Structural interventions may help address these systematically missed opportunities.

Pro-migratory and TGF-ß-activating functions of αvß6 integrin in pancreatic cancer are differentially regulated via an Eps8-dependent GTPase switch.

The integrin αvß6 is up-regulated in numerous carcinomas, where expression commonly correlates with poor prognosis. αvß6 promotes tumour invasion, partly through regulation of proteases and cell migration, and is also the principal mechanism by which epithelial cells activate TGF-ß1; this latter function complicates therapeutic targeting of αvß6, since TGF-ß1 has both tumour-promoting and -suppressive effects. It is unclear how these different αvß6 functions are linked; both require actin cytoskeletal reorganization, and it is suggested that tractive forces generated during cell migration activate TGF-ß1 by exerting mechanical tension on the ECM-bound latent complex. We examined the functional relationship between cell invasion and TGF-ß1 activation in pancreatic ductal adenocarcinoma (PDAC) cells, and confirmed that both processes are αvß6-dependent. Surprisingly, we found that cellular functions could be biased towards either motility or TGF-ß1 activation depending on the presence or absence of epidermal growth factor receptor pathway substrate 8 (Eps8), a regulator of actin remodelling, endocytosis, and GTPase activation. Similar to αvß6, we found that Eps8 was up-regulated in >70% of PDACs. In complex with Abi1/Sos1, Eps8 regulated αvß6-dependent cell migration through activation of Rac1. Down-regulation of Eps8, Sos1 or Rac1 suppressed cell movement, while simultaneously increasing αvß6-dependent TGF-ß1 activation. This latter effect was modulated through increased cell tension, regulated by Rho activation. Thus, the Eps8/Abi1/Sos1 tricomplex acts as a key molecular switch altering the balance between Rac1 and Rho activation; its presence or absence in PDAC cells modulates αvß6-dependent functions, resulting in a pro-migratory (Rac1-dependent) or a pro-TGF-ß1 activation (Rho-dependent) functional phenotype, respectively. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Interventions to Increase Male Attendance and Testing for Sexually Transmitted Infections at Publicly-Funded Family Planning Clinics.

PURPOSE: We assessed the impact of staff, clinic, and community interventions on male and female family planning client visit volume and sexually transmitted infection testing at a multisite community-based health care agency. METHODS: Staff training, clinic environmental changes, in-reach/outreach, and efficiency assessments were implemented in two Family Health Center (San Diego, CA) family planning clinics during 2010-2012; five Family Health Center family planning programs were identified as comparison clinics. Client visit records were compared between preintervention (2007-2009) and postintervention (2010-2012) for both sets of clinics. RESULTS: Of 7,826 male client visits during the time before intervention, most were for clients who were aged <30 years (50%), Hispanic (64%), and uninsured (81%). From preintervention to postintervention, intervention clinics significantly increased the number of male visits (4,004 to 8,385; Δ = +109%); for comparison clinics, male visits increased modestly (3,822 to 4,500; Δ = +18%). The proportion of male clinic visits where chlamydia testing was performed increased in intervention clinics (35% to 42%; p < .001) but decreased in comparison clinics (37% to 33%; p < .001). Subgroup analyses conducted among adolescent and young adult males yielded similar findings for male client volume and chlamydia testing. The number of female visits declined nearly 40% in both comparison (21,800 to 13,202; -39%) and intervention clinics (30,830 to 19,971; -35%) between preintervention and postintervention periods. CONCLUSIONS: Multilevel interventions designed to increase male client volume and sexually transmitted infection testing services in family planning clinics succeeded without affecting female client volume or services.

Ventricular fibrillation cardiac arrest produces a chronic striatal hyperdopaminergic state that is worsened by methylphenidate treatment.

Cardiac arrest survival rates have improved with modern resuscitation techniques, but many survivors experience impairments associated with hypoxic-ischemic brain injury (HIBI). Currently, little is understood about chronic changes in striatal dopamine (DA) systems after HIBI. Given the common empiric clinical use of DA enhancing agents in neurorehabilitation, investigation evaluating dopaminergic alterations after cardiac arrest (CA) is necessary to optimize rehabilitation approaches. We hypothesized that striatal DA neurotransmission would be altered chronically after ventricular fibrillation cardiac arrest (VF-CA). Fast-scan cyclic voltammetry was used with median forebrain bundle (MFB) maximal electrical stimulations (60Hz, 10s) in rats to characterize presynaptic components of DA neurotransmission in the dorsal striatum (D-Str) and nucleus accumbens 14 days after a 5-min VF-CA when compared to Sham or Naïve. VF-CA increased D-Str-evoked overflow [DA], total [DA] released, and initial DA release rate versus controls, despite also increasing maximal velocity of DA reuptake (Vmax ). Methylphenidate (10 mg/kg), a DA transporter inhibitor, was administered to VF-CA and Shams after establishing a baseline, pre-drug 60 Hz, 5 s stimulation response. Methylphenidate increased initial evoked overflow [DA] more-so in VF-CA versus Sham and reduced D-Str Vmax in VF-CA but not Shams; these findings are consistent with upregulated striatal DA transporter in VF-CA versus Sham. Our work demonstrates that 5-min VF-CA increases electrically stimulated DA release with concomitant upregulation of DA reuptake 2 weeks after brief VF-CA insult. Future work should elucidate how CA insult duration, time after insult, and insult type influence striatal DA neurotransmission and related cognitive and motor functions.

Wound healing in Mac-1 deficient mice.

Mac-1 (CD11b/CD18) is a macrophage receptor that plays several critical roles in macrophage recruitment and activation. Because macrophages are essential for proper wound healing, the impact of Mac-1 deficiency on wound healing is of significant interest. Prior studies have shown that Mac-1-/- mice exhibit deficits in healing, including delayed wound closure in scalp and ear wounds. This study examined whether Mac-1 deficiency influences wound healing in small excisional and incisional skin wounds. Three millimeter diameter full thickness excisional wounds and incisional wounds were prepared on the dorsal skin of Mac-1 deficient (Mac-1-/- ) and wild type (WT) mice, and wound healing outcomes were examined. Mac-1 deficient mice exhibited a normal rate of wound closure, generally normal levels of total collagen, and nearly normal synthesis and distribution of collagens I and III. In incisional wounds, wound breaking strength was similar for Mac-1-/- and WT mice. Wounds of Mac-1 deficient mice displayed normal total macrophage content, although macrophage phenotype markers were skewed as compared to WT. Interestingly, amounts of TGF-ß1 and its downstream signaling molecules, SMAD2 and SMAD3, were significantly decreased in the wounds of Mac-1 deficient mice compared to WT. The results suggest that Mac-1 deficiency has little impact on the healing of small excisional and incisional wounds. Moreover, the findings demonstrate that the effect of single genetic deficiencies on wound healing may markedly differ among wound models. These conclusions have implications for the interpretation of the many prior studies that utilize a single model system to examine wound healing outcomes in genetically deficient mice.

Predictive Analysis of Mechanistic Triggers and Mitigation Strategies for Pathological Scarring in Skin Wounds.

Wound fibrosis (i.e., excessive scar formation) is a medical problem of increasing prevalence, with poorly understood mechanistic triggers and limited therapeutic options. In this study, we employed an integrated approach that combines computational predictions with new experimental studies in mice to identify plausible mechanistic triggers of pathological scarring in skin wounds. We developed a computational model that predicts the time courses for six essential cell types, 18 essential molecular mediators, and collagen, which are involved in inflammation and proliferation during wound healing. By performing global sensitivity analyses using thousands of model-simulated wound-healing scenarios, we identified five key processes (among the 90 modeled processes) whose dysregulation may lead to pathological scarring in wounds. By modulating a subset of these key processes, we simulated fibrosis in wounds. Moreover, among the 18 modeled molecular mediators, we identified TGF-ß and the matrix metalloproteinases as therapeutic targets whose modulation may reduce fibrosis. The model predicted that simultaneous modulation of TGF-ß and matrix metalloproteinases would be more effective in treating excessive scarring than modulation of either therapeutic target alone. Our model was validated with previously published and newly generated experimental data, and suggested new in vivo experiments.

The Pathophysiology of Nitrogen Dioxide During Inhaled Nitric Oxide Therapy.

Administration of inhaled nitric oxide (NO) with the existing compressed gas delivery systems is associated with unavoidable codelivery of nitrogen dioxide (NO2), an unwanted toxic contaminant that forms when mixed with oxygen. The NO2 is generated when NO is diluted with O2-enriched air before delivery to the patient. When NO2 is inhaled by the patient, it oxidizes protective antioxidants within the epithelial lining fluid (ELF) and triggers extracellular damage in the airways. The reaction of NO2 within the ELF triggers oxidative stress (OS), possibly leading to edema, bronchoconstriction, and a reduced forced expiratory volume in 1 second. Nitrogen dioxide has been shown to have deleterious effects on the airways of high-risk patients including neonates, patients with respiratory and heart failure, and the elderly. Minimizing co-delivery of NO2 for the next generation delivery systems will be a necessity to fully optimize the pulmonary perfusion of NO because of vasodilation, whereas minimizing the negative ventilatory and histopathological effects of NO2 exposure during inhaled NO therapy.

How do changes in the population tested for chlamydia over time affect observed trends in chlamydia positivity? Analysis of routinely collected data from young women tested for chlamydia in family planning clinics in the Pacific Northwest (USA), between 2003 and 2010.

UNLABELLED: Background The proportion of chlamydia tests that are positive (positivity) is dependent on the population tested and the test technology used. The way in which changes in these variables might affect trends in positivity over time is investigated. METHODS: Data from 15- to 24-year-old women tested for chlamydia in family planning clinics participating in the Infertility Prevention Project in the Pacific Northwest, United States (USA Public Health Service Region X) during 2003-2010 (n=590557) were analysed. Trends in positivity and in test, demographic and sexual behaviour variables were identified. Unadjusted and adjusted trends in chlamydia positivity were calculated using logistic regression. RESULTS: The proportion of tests carried out using nucleic acid amplification tests (NAATs) increased dramatically during the analysis period in two states. Smaller changes in demographic and behavioural characteristics were seen. Controlling for test technology used had the largest effect on the trend in testing positive per year, leading to a fall in the calculated odds ratio of testing positive from 1.06 to 1.02 in Oregon, and from 1.07 to 1.02 in Idaho. Controlling for other variables had minimal effect on chlamydia positivity trends. CONCLUSIONS: Changes in NAAT use had a large effect on observed trends in chlamydia positivity over time in the two states where NAATs were introduced during the analysis period. While trends in chlamydia positivity may be a useful metric for monitoring chlamydia burden, it is important to consider changes in test type when interpreting these data.

Age of Childhood Onset in Type 1 Diabetes and Functional Brain Connectivity in Midlife.

OBJECTIVES: The development of Type 1 diabetes mellitus (T1DM) within the first 7 years of life has been linked to poorer cognitive performance. Adults with T1DM have altered functional brain connectivity, but no studies have examined whether earlier age of T1DM onset is associated with functional connectivity later in life. Accordingly, we tested the relationship between age of onset and resting state functional connectivity in a cohort of middle-aged adults with childhood-onset T1DM. METHODS: Participants were from a subsample of the Pittsburgh Epidemiology of Diabetes Complications cohort and included 66 adults (mean age = 47.54 years, 32 men). Resting state blood oxygen level-dependent activity was used to calculate mean connectivity for eight functional brain networks. A multivariate analysis of variance examined associations between age of onset and network connectivity. Diffusion tensor and fluid-attenuated inversion recovery images were analyzed to identify microstructural alterations and white-matter hyperintensity volumes. RESULTS: Later childhood onset of T1DM was associated with lower connectivity (F(8,57) = 2.40, p = .026). A significant interaction was present for current age such that an inverse association with age of onset for functional connectivity was present in older individuals (F(8,55) = 2.88, p = .035). Lower connectivity was associated with older age, increased white-matter hyperintensity volume, and lower microstructural integrity. CONCLUSIONS: Diagnosis of T1DM later in childhood may be associated with lower brain functional connectivity, particularly in those surviving into older ages. These alterations may be an early marker for subsequent cognitive decrements. Future studies are warranted to understand the pathways underlying these associations.