Improved Constraints on Primordial Gravitational Waves using Planck, WMAP, and BICEP/Keck Observations through the 2018 Observing Season.

We present results from an analysis of all data taken by the BICEP2, Keck Array, and BICEP3 CMB polarization experiments up to and including the 2018 observing season. We add additional Keck Array observations at 220 GHz and BICEP3 observations at 95 GHz to the previous 95/150/220 GHz dataset. The Q/U maps now reach depths of 2.8, 2.8, and 8.8 µK_{CMB} arcmin at 95, 150, and 220 GHz, respectively, over an effective area of ≈600 square degrees at 95 GHz and ≈400 square degrees at 150 and 220 GHz. The 220 GHz maps now achieve a signal-to-noise ratio on polarized dust emission exceeding that of Planck at 353 GHz. We take auto- and cross-spectra between these maps and publicly available WMAP and Planck maps at frequencies from 23 to 353 GHz and evaluate the joint likelihood of the spectra versus a multicomponent model of lensed ΛCDM+r+dust+synchrotron+noise. The foreground model has seven parameters, and no longer requires a prior on the frequency spectral index of the dust emission taken from measurements on other regions of the sky. This model is an adequate description of the data at the current noise levels. The likelihood analysis yields the constraint r_{0.05}<0.036 at 95% confidence. Running maximum likelihood search on simulations we obtain unbiased results and find that σ(r)=0.009. These are the strongest constraints to date on primordial gravitational waves.

International Initiative for Outcomes (INFO) for vitiligo: workshops with patients with vitiligo on repigmentation.

BACKGROUND: There is no cure or firm clinical recommendations for the treatment of vitiligo. One of the main issues is the heterogeneity of outcome measures used in randomized controlled trials for vitiligo. OBJECTIVES: To define successful repigmentation from the patients' point of view and to propose how and when repigmentation should be evaluated in clinical trials in vitiligo. METHODS: We conducted three workshops with patients with vitiligo and their parents or caregivers. Workshop 1 was held at World Vitiligo Day (Detroit, MI), workshop 2 at the University of Texas Southwestern Medical Center and workshop 3 at the Vitiligo and Pigmentation Institute of Southern California, University of California. RESULTS: Seventy-three participants were recruited. Consensus on the following questions was achieved unanimously: (i) the definition of 'successful repigmentation' was 80-100% of repigmentation of a target lesion and (ii) both an objective and a subjective scale to measure repigmentation should be used. CONCLUSIONS: This was the largest patients' outcomes workshop. We followed the guidance from the CSG-COUSIN and the Vitiligo Global Issues Consensus Group. Our recommendations to use percentage of repigmentation quartiles (0-25%, 26-50%, 51-79%, 80-100%) and the Vitiligo Noticeability Scale are based on the best available current evidence. A limitation of the research is that the workshops were conducted only in the U.S.A., due to pre-existing organisational support and the availability of funding.

A randomized, controlled comparative study of the wrinkle reduction benefits of a cosmetic niacinamide/peptide/retinyl propionate product regimen vs. a prescription 0.02% tretinoin product regimen.

BACKGROUND: Tretinoin is considered the benchmark prescription topical therapy for improving fine facial wrinkles, but skin tolerance issues can affect patient compliance. In contrast, cosmetic antiwrinkle products are well tolerated but are generally presumed to be less efficacious than tretinoin. OBJECTIVES: To compare the efficacy of a cosmetic moisturizer regimen vs. a prescription regimen with 0.02% tretinoin for improving the appearance of facial wrinkles. METHODS: An 8-week, randomized, parallel-group study was conducted in 196 women with moderate to moderately severe periorbital wrinkles. Following 2 weeks washout, subjects on the cosmetic regimen (n = 99) used a sun protection factor (SPF) 30 moisturizing lotion containing 5% niacinamide, peptides and antioxidants, a moisturizing cream containing niacinamide and peptides, and a targeted wrinkle product containing niacinamide, peptides and 0.3% retinyl propionate. Subjects on the prescription regimen (n = 97) used 0.02% tretinoin plus moisturizing SPF 30 sunscreen. Subject cohorts (n = 25) continued treatment for an additional 16 weeks. Changes in facial wrinkling were assessed by both expert grading and image analysis of digital images of subjects' faces and by self-assessment questionnaire. Product tolerance was assessed via clinical erythema and dryness grading, subject self-assessment, and determinations of skin barrier integrity (transepidermal water loss) and stratum corneum protein changes. RESULTS: The cosmetic regimen significantly improved wrinkle appearance after 8 weeks relative to tretinoin, with comparable benefits after 24 weeks. The cosmetic regimen was significantly better tolerated than tretinoin through 8 weeks by all measures. CONCLUSIONS: An appropriately designed cosmetic regimen can improve facial wrinkle appearance comparably with the benchmark prescription treatment, with improved tolerability.

Neoplastic transformation in vitro of hamster lens epithelium by simian virus 40.

Hamster lens epithelium infected with simian virus 40 underwent transformation in vitro and produced tumors when injected into homologous hosts. Undisturbed lens epithelium in man and experimental animals has not been observed to undergo neoplastic change. The virus-induced tumors contained undifferentiated cells that were either polygonal or spindle-shaped. Their origin from lens epithelium seems certain since it is possible to isolate this unique structure free of connective tissue and blood vessels.

A global survey of the role of ultraviolet radiation and hormonal influences in the development of melasma.

BACKGROUND: It has been generally believed that the four main causes of melasma are pregnancy, hormonal contraception, family history and sun exposure; however, there are few published comprehensive studies that confirm these assertions. The Pigmentary Disorders Academy - an international group of experts in pigmentary disorders - designed and conducted a global survey of women to investigate the effect of these factors on onset and chronicity of melasma and the course of the disease in order to gain a better understanding of the causative factors associated with this disorder, with a particular focus on hormonal factors and UV exposure in females. METHODS: A 40-item largely self-administered questionnaire was completed by 324 women being treated for melasma in nine clinics worldwide. RESULTS: The mean age at onset of melasma was 34 years, and 48% of subjects questioned had a family history of melasma (97% in a first-degree relative). Subjects with family history of melasma tended to have darker skin (90% types III-VI) compared to those without (77% types III-VI). The most common time of onset was after pregnancy (42%), often years after the last pregnancy, with 29% appearing pre-pregnancy and 26% during pregnancy. Onset was related to darker skin type post-pregnancy (P = 0.002). Risk of onset during pregnancy was associated with having spent more time outdoors (an extra 10 h per week spent working outside increases the odds of onset of melasma during pregnancy by approximately 27%) and an increased maternal age at pregnancy (increased by approximately 8% for each year of age at first pregnancy; P = 0.02). The odds of melasma occurring for the first time during a pregnancy were also increased with multiple pregnancies (twice the odds if 2 vs. 1 pregnancies, three times higher if 3 or more vs. 1 pregnancy). Of the women, 25% who had used hormonal contraception claimed that melasma appeared for the first time after its use, the rate being higher for those without vs. with a family history. CONCLUSIONS: The results suggest that, whilst accepted causes do affect onset of melasma, a combination of these factors often triggers this disorder. These factors may provide further insights into how physicians can manage individual melasma cases, support recommendation of preventative measures and even anticipate treatment results and recurrence.

New oral and topical approaches for the treatment of melasma.

Melasma is a common, therapeutically challenging, and universally relapsing disorder of hyperpigmentation that is most often observed in women and individuals with Fitzpatrick Skin Types III through VI. The pathogenesis of melasma is complex and protean. Contributing factors that are often implicated in the etiopathogenesis of this condition include a genetic predisposition, intense ultraviolet radiation exposure, and hormonal influences. Therapeutic interventions for melasma include a multimodality approach incorporating photoprotection agents, topical and oral skin lighteners, and resurfacing procedures. Given our expanding knowledge of the pathogenesis of melasma, new and effective treatments are expanding our therapeutic armamentarium. This article reviews new and emerging oral and topical treatments for melasma.

A closer look at the role of the dermatologist in championing total women's health through the dermatology gateway.

New data collected by the Women's Dermatologic Society (WDS) through a membership survey conducted in August 2018 reflect the key role of the dermatologist in championing the overall health of the total woman through the dermatology gateway. These meaningful results provide a first-ever metric glimpse into the myriad systemic/internal diseases, disorders, and conditions that WDS dermatologists detect and diagnose in female dermatology patients and the wide scope of our collaborations with other physician specialists to manage complex, underlying medical conditions. Insightful perspectives from medical and health experts outside of dermatology address the importance of teamwork, reaffirm the unique role that dermatologists play on the medical team, and underscore the vital importance of our proclivity toward collaboration, the latter of which is shown to be significant according to the WDS data. Given an apparent general lack of awareness about the role of the dermatologist in the health journey of the total woman, we have an important opportunity to advance this broadened perspective among our colleagues in and outside of dermatology, our patients, the media, and the public at-large. By raising awareness, we can elevate our specialty in the medical profession and in the public eye, increase the likelihood that people will consult a dermatologist (proactively and reactively), inspire mutual referrals and greater cross-specialty teamwork and communications to benefit patients, and positively affect public health.

Vitiligo: Patient stories, self-esteem, and the psychological burden of disease.

Vitiligo is a relatively common disorder that is characterized by depigmented patches of skin. Multiple studies characterize the overwhelming psychological burden that is experienced by many patients around the globe. This review examines personal patient stories and the impacts of age, culture, sex, race, and ethnicity in relationship to altered self-esteem and quality of life in patients who live with vitiligo.

Determination of trimethylpsoralen in blood, ophthalmic fluids, and skin.

Trimethylpsoralen (TMP) levels in the blood of vitiligo patients were determined through the use of a high-performance liquid chromatographic method. TMP was extracted from blood buffered at pH 9.0 with 95:5 (V/V) hexane-isopropanol mixture; evaporated to dryness, and reconstituted in 50 microliters of ethanol. A 10-microliters aliquot was injected into a Micropack MCH-10 column (Varian HPLC model #5000). The mobile phase consisted of a mixture of water and acetonitrile with a linear gradient. The retention time of TMP was 16.5 min. The calibration curve of the external standards was linear. Overall recovery of the internal stands was 75-92%, with the lower detection limit of TMP at 2 ng/ml. Peak blood levels as low as 140 ng/ml and as high as 800 ng/ml were obtained in vitiligo patients 1-2 hr following the oral administration of 30 mg of trioxsalen tablets (Paul B. Elder Co.). Blood TMP levels peaked consistently at 2 hr when patients were fasted for 8 hr prior to drug ingestion. These results are consistent with the clinical observation that maximum response due to phototherapy is obtained 1-2 hr after oral administration of the drug. Two hours after oral drug administration, TMP levels in the epidermis, dermis, and whole skin of the guinea pig (in ng per g tissue) were: epidermis, 226 +/- 15; dermis, 25 +/- 6; and whole skin 176 +/- 12. Also detected were TMP levels 244 +/- 17 ng/ml in aqueous humor and 63 +/- 6 mg/ml in vitreous humor. These results point to the fact that the eyes of patients must be protected from overexposure to sunlight after psoralen-ultraviolet treatment.

Sex differences in psychiatrists' practice patterns and incomes.

OBJECTIVE AND METHOD: Using data from the APA's 1988-1989 Professional Activities Survey, the authors compared male and female psychiatrists on demographic characteristics, training, practice patterns, and income. RESULTS: In keeping with previous studies' findings, female respondents on the average were younger than male respondents and more likely to have taken a residency or fellowship in child or adolescent psychiatry, worked fewer hours per week, allocated their working hours differently among types of activities, saw fewer patients per week, and worked in somewhat different settings. Multiple regression analysis showed that women had significantly lower mean net annual income than men after the effects of those predictors were statistically controlled. CONCLUSIONS: Differences in age, training, hours worked in specific settings, and numbers of patients do not completely account for the gender gap in psychiatrists' annual incomes.

Galanin immunoreactivity in autonomic innervation of the cat eye.

In an immunohistochemical study, we find that galanin is much more widely distributed in the peripheral innervation of the cat eye than in other animals so far examined. Previous studies of rat and pig eyes have revealed sparse galanin-positive nerves that presumably originate in the trigeminal ganglion. In contrast, the cat has a rich supply of galanin-containing nerve fibers throughout the uvea. Galanin-positive varicose nerves concentrate densely in iris muscles and distribute more sparsely in the ciliary muscle. The ciliary processes have a plexus of galanin-positive nerves underlying the ciliary epithelium at their base and positive nerve fibers coursing within their stroma. The ciliary artery and its branch vessels in the uvea are invested with a dense plexus of galanin-positive nerves. All autonomic ganglia supplying the eye contain cells that express galanin. It is present in 97% of superior cervical ganglion cells, coexisting with both tyrosine hydroxylase and neuropeptide Y; in 80% of pterygopalatine ganglion cells, most of which also contain vasoactive intestinal peptide; and in approximately 25% of ciliary ganglion cells. After unilateral superior cervical ganglionectomy, galanin-positive nerves almost totally disappear from the iris muscles, demonstrating that they are predominantly of sympathetic origin. Galanin-positive nerves investing the ciliary artery and choroidal blood vessels are not detectably reduced by sympathectomy, indicating that perivascular parasympathetic nerves from the pterygopalatine ganglion also express galanin. Other galanin-containing nerves in the eye can originate from the trigeminal and ciliary ganglia. The prominence of galanin in the ocular autonomic innervation of the cat provides an opportunity to explore the physiological effects of this neuropeptide in the eye.

Neuropeptide Y-like immunoreactivity localizes to preganglionic axon terminals in the rhesus monkey ciliary ganglion.

PURPOSE: To characterize neuropeptide distribution in the ciliary ganglion of rhesus monkeys (Macaca mulatta). METHODS: Cryostat tissue sections of fixed rhesus monkey ciliary, pterygopalatine, superior cervical, and trigeminal ganglia were incubated with antisera to neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), tyrosine hydroxylase (TH), and dopamine-beta-hydroxylase (DBH). Antibody binding was visualized by indirect immunofluorescence. RESULTS: NPY-like immunoreactive (LI) nerve terminals surrounded 80% of ciliary ganglion cells, but ciliary ganglion cell somata were unstained. NPY-LI cells were present in the superior cervical ganglion, in which almost all cells were TH- and DBH-LI, and in the pterygopalatine ganglion, in which almost all cells were VIP-LI. Because neither TH, DBH, nor VIP immunoreactivity was detected in nerves contacting ciliary ganglion cells, the NPY-LI input to ciliary neurons does not likely derive from the autonomic ganglia. The trigeminal ganglion, another potential source, had no NPY-LI neurons. CGRP- and SP-LI axons from the nasociliary nerve traversed the ciliary ganglion; a small number of varicose axons were distributed among ganglion cells and rarely surrounded cell somata. Most ciliary ganglion cells were TH-LI, but only a few were DBH-LI. CONCLUSIONS: Based on these patterns of peptide immunoreactivities, the NPY-LI nerve fibers investing ciliary ganglion cells in the rhesus monkey are most likely preganglionic axon terminals of mesencephalic parasympathetic neurons. Although the origin and function of these NPY-LI nerves remains to be established, the present finding adds to the remarkable diversity of neuropeptide immunoreactivity so far identified in preganglionic and postganglionic cells of the ciliary ganglion in different species of birds and mammals, including primates.

Abnormal eye development associated with Cat4a, a dominant mouse cataract mutation on chromosome 8.

PURPOSE: Cat4a, one of four mutant alleles at the mouse Cat4 locus, causes central corneal opacity and anterior polar cataract in heterozygotes and microphthalmia in homozygotes. The Cat4 locus has been mapped to chromosome 8, 31 cM from the centromere. In this study ocular development of Cat4a mutant mice was investigated to characterize the defects in eye morphogenesis. METHODS: Serial sections from eyes of wild-type, heterozygous, and homozygous littermates were examined by means of light microscopy at selected intervals from embryonic day 11 to postnatal day 1. Eyes of adult heterozygous and homozygous mice also were evaluated histologically. RESULTS: Failure of separation of the lens vesicle from the surface ectoderm was the earliest structural defect observed. In heterozygous embryos, the abnormality was limited to persistent connection of the anterior pole of the lens to the cornea. Adult heterozygotes had defects in the central corneal stroma and endothelium and anterior polar cataracts with or without keratolenticular adhesion. In homozygous embryos, the persistent connection of lens to surface ectoderm was associated with aborted lens development, failure of closure of the optic fissure, and impairment of growth of the eyecup. Microphthalmic eyes of adult homozygous mice had a poorly developed cornea, and the anterior chamber and vitreous compartment were absent. An extensively folded retina and remnants of a degenerated lens filled the interior of the globe. CONCLUSIONS: A developmental defect inhibits separation of the lens vesicle from surface ectoderm in mice heterozygous or homozygous for the Cat4a mutation. In homozygotes subsequent lens and eye morphogenesis are also severely affected. Cat4a shows phenotypical similarity to several other independent mouse mutations including Small eye, a mutation of the Pax6 gene. Cat4 may be one of several genes involved in a common developmental path and may be part of the Pax6-regulated gene cascade governing eye morphogenesis.

Mapping of the autosomal dominant cataract mutation (Coc) on mouse chromosome 16.

PURPOSE: To characterize the mouse cataract mutation Coc. METHODS: Coc is an X-radiation-induced autosomal dominant cataract mutation maintained on a murine C3H inbred strain. The affected heterozygotes were outcrossed to C57BL/6, and (C3H Coc/+ x C57BL/6) mice that were Coc/+ were then backcrossed to C57BL/6 to generate a panel of 103 progeny for mapping. For linkage analysis, microsatellites from each autosome were selected. The maximum distance between markers was 30 centimorgans (cM). RESULTS: The initial genome-wide screen of 14 backcrossed progeny indicated that the Coc locus resides on chromosome 16. Further mapping with additional markers from chromosome 16 for all 103 backcrossed progeny positioned Coc between markers D16Mit134 and D16Mit63. This region is syntenic to human chromosome 3. CONCLUSIONS: Mapping of the Coc locus to mouse chromosome 16 provides the positional information necessary to identify the candidate gene responsible for the Coc phenotype. The molecular characterization of the gene disrupted in the Coc mutation will provide insight into the mechanisms involved in cataract formation.

Carboxyfluorescein. A probe of the blood-ocular barriers with lower membrane permeability than fluorescein.

We have examined the permeability of the blood-ocular barriers to carboxyfluorescein, a dye similar in spectral properties but more polar than fluorescein. Octanol-buffer partition ratios of carboxyfluorescein, measured as an indication of lipid solubility, were approximately 1,000 times lower than those of fluorescein at pH values between 6.40 and 8.03. The partition ratios of both dyes show pronounced pH dependence. We also evaluated intraocular dye distribution by fluorescence microscopy after intravenous (IV) injection in rats. Carboxyfluorescein does not penetrate ciliary or iris epithelial cells, whereas fluorescein prominently stains these cells. Quantitative measurement of fluorescence intensity demonstrates that carboxyfluorescein does not enter the retina even when high doses are administered. Fluorescein, in contrast, can be detected throughout the retina with fluorescence intensity levels proportional to the IV dose administered. The relative inability of carboxyfluorescein to penetrate the blood-ocular barriers is not caused by greater binding to plasma proteins, since the plasma concentration of free carboxyfluorescein is greater than that of fluorescein. We conclude that carboxyfluorescein has potential experimental and clinical use as a probe of the blood-ocular barriers. Because of its low membrane permeability, it may yield a better definition of the nature of barrier abnormalities than is now possible with fluorescein.

A permeability defect of the retinal pigment epithelium. Occurrence in early streptozocin diabetes.

The permeability of the blood-retina barrier was tested in rats with early streptozocin-induced diabetes. Two different tracer substances were used: fluorescein sodium and horseradish peroxidase (HRP). After intravenous administration, the ocular distribution of fluorescein was studied by fluorescence microscopy of freeze-dried tissue. A permeability defect of the pigment epithelium to fluorescein was present in one half of the rats four weeks after induction of diabetes. The dye entered the pigment epithelial cells but could not be detected among the photoreceptors. The only dyd visible in neural retina was within the retinal blood vessels. For HRP, no fault whatsoever in the blood retina barrier was found: there was no increase of vesicular uptake by the pigment epithelial cells; the tight junctions between pigment epithelial cells were intact as were those between the endothelial cells of retinal blood vessels.

Acidosis alters fluorescein permeability. Differential tracer penetration through pigment epithelium.

The permeability of the blood-retinal barrier to infusion of fluorescent tracers was examined in tissue sections of frozen eyes from conscious rats that had breathed either air (control) or 25% carbon dioxide in air for one hour. For all animals the blood-retinal barrier remained impermeable to either carboxyfluorescein or Evans blue, indicating a functionally intact tight junctional barrier during hypercapnia. However, in hypercapnic animals, fluorescein penetrated into the neural retina, mainly via the pigment epithelium. Fluorescein also passed through the pigment epithelium in rats with metabolic acidosis induced by intravenous infusion of ammonium chloride, which lowered arterial blood pH without raising the Paco2 or BP. The results indicate an increased permeability of fluorescein through the cell membranes of the pigment epithelium during respiratory and metabolic acidosis. The effect on fluorescein may be due to a pH-dependent increase in the plasma concentration of the associated, more lipid-soluble form of this weak acid.

Azelaic acid 20% cream in the treatment of facial hyperpigmentation in darker-skinned patients.

This multicenter, randomized, double-masked, parallel-group study assessed the efficacy, safety, and tolerability of azelaic acid 20% cream compared with those of its vehicle for the treatment of facial hyperpigmentation in darker-skinned patients (phototypes IV to VI). Following a 24-week treatment period, azelaic acid produced significantly greater decreases in pigmentary intensity than did vehicle as measured by both an investigator's subjective scale (P = 0.021) and a chromometer analysis (P = 0.039). There was a significantly greater global improvement with azelaic acid than with vehicle at week 24 (P = 0.008). Azelaic acid produced a slightly but significantly greater amount of burning (weeks 4 and 12, P < or = 0.046) and stinging (week 4, P = 0.002) than did vehicle. At the end of the study, more patients treated with azelaic acid than with vehicle reported having much smoother skin and being very satisfied or satisfied with their treatment. Also, more patients treated with azelaic acid than with vehicle rated their medication as being more effective or the same as past treatments. Thus azelaic acid is an effective and well-tolerated treatment for hyperpigmentation in darker-skinned patients.