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We employ the best local experts to author our guides, like longtime Paris resident Anna E. Brooke. In this innovative, easy-to-carry, itinerary-based guide she show readers how to see the best of the City of Lights -- in the smartest, most time-efficient way. The book includes chapters on the best of Paris in one, two, or three days, thematic, self-guided tours for every interest, schedule, and taste, and walking tours of the city's best-loved neighborhoods. It features hundreds of evocative photos, bulleted maps that show you how to get from place to place and offers highly opinionated hotel, restaurant, shopping, and nightlife reviews for all budgets along with a tear-resistant foldout map -- enclosed in a handy plastic wallet you can also use for tickets and souvenirs.

Infection with human papillomavirus (HPV) serotypes 16 and 18 in men who have sex with men is a cause of considerable morbidity associated with anal intraepithelial neoplasia. This study shows that the HPV vaccine decreases the risk of HPV-associated anal disease. Anal cancer is biologically similar to cervical cancer, including having a causal relationship with human papillomavirus (HPV) infection. 1 Although HPV type 6 (HPV-6) or HPV type 11 (HPV-11) alone is rarely causal, the proportion of anal cancers associated with infection with HPV type 16 (HPV-16) or HPV type 18 (HPV-18) is as high as or higher than the proportion of cervical cancers. 1 Just as cervical cancer is preceded by high-grade cervical intraepithelial neoplasia (grade ≥2), anal cancer is preceded by high-grade anal intraepithelial neoplasia (grade 2 or 3). 2 – 4 Although not yet formally demonstrated, prevention or treatment of high-grade anal . . .

\"Paris leads the world's other cities in art and cuisine, in architecture and history, in music and sculpture, in philosophy and political ferment, in nearly every other area on interest to the visitor. It has to be seen and experienced, and done so in a thoughtful manner. Understanding the city's story and culture will add immeasurably to a trip to the \"City of Light\". Written by longtime Paris resident Anna E. Brooke, Frommer's EasyGuide to Paris 2020 is a portable tribute to the city and a roadmap to creating a hassle-free trip of a lifetime. From the world-famous panorama of the Champs-Elysâees to the cathedral of Notre-Dame, from how to beat crowds at the Louvre to the ideal way to experience the Eiffel Tower.\"--Publisher's description.

Limited data on the efficacy of the quadrivalent HPV vaccine are available for males. In this trial involving 4065 healthy boys and young men 16 to 26 years of age, the quadrivalent vaccine against HPV reduced the occurrence of external genital lesions by 60%. Human papillomavirus (hpv) infects the squamous epithelium in both sexes, leading to anogenital condylomata acuminata and, in males, to cancers of the penis, anus, and oropharynx. 1 The rate of genital HPV infection among males is similar to that in females. In any 12-month period, the probability that a sexually active male will acquire a new genital HPV infection is 0.29 to 0.39, 2 – 4 which is similar to estimates for females. However, there are differences between the sexes in the immune response to HPV. A larger proportion of females are HPV-seropositive (17.9%, vs. 7.9% of males), and females . . .

Nuclear lamins have been considered an important structural element of the nucleus. The nuclear lamina is thought both to shield DNA from excessive mechanical forces and to transmit mechanical forces onto the DNA. However, to date there is not yet a technical approach to directly measure mechanical forces on nuclear lamins at the protein level. To overcome this limitation, we developed a nanobody-based intermolecular tension FRET biosensor capable of measuring the mechanical strain of lamin filaments. Using this sensor, we were able to show that the nuclear lamina is subjected to significant force. These forces are dependent on nuclear volume, actomyosin contractility, functional LINC complex, chromatin condensation state, cell cycle, and EMT. Interestingly, large forces were also present on nucleoplasmic lamins, indicating that these lamins may also have an important mechanical role in the nucleus. Overall, we demonstrate that the nanobody-based approach allows construction of biosensors for complex protein structures for mechanobiology studies. In this work, a nanobody based intermolecular strain sensor was used to follow the mechanical strain in the nuclear lamina. The results indicate that mechanical state of the nuclear lamina is not only affected by the cell contractility, but also chromatin packing.

Success and impact metrics in science are based on a system that perpetuates sexist and racist “rewards” by prioritizing citations and impact factors. These metrics are flawed and biased against already marginalized groups and fail to accurately capture the breadth of individuals’ meaningful scientific impacts. We advocate shifting this outdated value system to advance science through principles of justice, equity, diversity, and inclusion. We outline pathways for a paradigm shift in scientific values based on multidimensional mentorship and promoting mentee well-being. These actions will require collective efforts supported by academic leaders and administrators to drive essential systemic change.

Rapid and ongoing change creates novelty in ecosystems everywhere, both when comparing contemporary systems to their historical baselines, and predicted future systems to the present. However, the level of novelty varies greatly among places. Here we propose a formal and quantifiable definition of abiotic and biotic novelty in ecosystems, map abiotic novelty globally, and discuss the implications of novelty for the science of ecology and for biodiversity conservation. We define novelty as the degree of dissimilarity of a system, measured in one or more dimensions relative to a reference baseline, usually defined as either the present or a time window in the past. In this conceptualization, novelty varies in degree, it is multidimensional, can be measured, and requires a temporal and spatial reference. This definition moves beyond prior categorical definitions of novel ecosystems, and does not include human agency, self-perpetuation, or irreversibility as criteria. Our global assessment of novelty was based on abiotic factors (temperature, precipitation, and nitrogen deposition) plus human population, and shows that there are already large areas with high novelty today relative to the early 20th century, and that there will even be more such areas by 2050. Interestingly, the places that are most novel are often not the places where absolute changes are largest; highlighting that novelty is inherently different from change. For the ecological sciences, highly novel ecosystems present new opportunities to test ecological theories, but also challenge the predictive ability of ecological models and their validation. For biodiversity conservation, increasing novelty presents some opportunities, but largely challenges. Conservation action is necessary along the entire continuum of novelty, by redoubling efforts to protect areas where novelty is low, identifying conservation opportunities where novelty is high, developing flexible yet strong regulations and policies, and establishing long-term experiments to test management approaches. Meeting the challenge of novelty will require advances in the science of ecology, and new and creative conservation approaches.

Many sub-Saharan Africa countries are scaling up differentiated service delivery (DSD) models for HIV treatment to increase access and remove barriers to care. We assessed factors associated with attrition after DSD model enrollment in Zambia, focusing on patient-level characteristics. We conducted a retrospective record review using electronic medical records (EMR) of adults (≥15 years) initiated on antiretroviral (ART) between 01 January 2018 and 30 November 2021. Attrition was defined as lost to follow-up (LTFU) or died by November 30, 2021. We categorized DSD models into eight groups: fast-track, adherence groups, community pick-up points, home ART delivery, extended facility hours, facility multi-month dispensing (MMD, 4-6-month ART dispensing), frequent refill care (facility 1-2 month dispensing), and conventional care (facility 3 month dispensing, reference group). We used Fine and Gray competing risk regression to assess patient-level factors associated with attrition, stratified by sex and rural/urban setting. Of 547,281 eligible patients, 68% (n = 372,409) enrolled in DSD models, most commonly facility MMD (n = 306,430, 82%), frequent refill care (n = 47,142, 13%), and fast track (n = 14,433, 4%), with <2% enrolled in the other DSD groups. Retention was higher in nearly all DSD models for all dispensing intervals, compared to the reference group, except fast track for the ≤2 month dispensing group. Retention benefits were greatest for patients in the extended clinic hours group and least for fast track dispensing. Although retention in HIV treatment differed by DSD type, dispensing interval, and patient characteristics, nearly all DSD models out-performed conventional care. Understanding the factors that influence the retention of patients in DSD models could provide an important step towards improving DSD implementation.

Change in the nutritional quality of phytoplankton is a key mechanism through which ocean acidification can affect the function of marine ecosystems. Copepods play an important role transferring energy from phytoplankton to higher trophic levels, including fatty acids (FA)-essential macronutrients synthesized by primary producers that can limit zooplankton and fisheries production. We investigated the direct effects of pCO2 on phytoplankton and copepods in the laboratory, as well as the trophic transfer of effects of pCO2 on food quality. The marine cryptophyte Rhodomonas salina was cultured at 400, 800, and 1200 μatm pCO2 and fed to adult Acartia hudsonica acclimated to the same pCO2 levels. We examined changes in phytoplankton growth rate, cell size, carbon content, and FA content, and copepod FA content, grazing, respiration, egg production, hatching, and naupliar development. This single-factor experiment was repeated at 12°C and at 17°C. At 17°C, the FA content of R. salina responded non-linearly to elevated pCO2 with the greatest FA content at intermediate levels, which was mirrored in A. hudsonica; however, differences in ingestion rate indicate that copepods accumulated FA less efficiently at elevated pCO2. A. hudsonica nauplii developed faster at elevated pCO2 at 12°C in the absence of strong food quality effects, but not at 17°C when food quality varied among treatments. Our results demonstrate that changes to the nutritional quality of phytoplankton are not directly translated to their grazers, and that studies that include trophic links are key to unraveling how ocean acidification will drive changes in marine food webs.

AbstractObjectiveTo examine the association between antihypertensive treatment and specific adverse events.DesignSystematic review and meta-analysis.Eligibility criteriaRandomised controlled trials of adults receiving antihypertensives compared with placebo or no treatment, more antihypertensive drugs compared with fewer antihypertensive drugs, or higher blood pressure targets compared with lower targets. To avoid small early phase trials, studies were required to have at least 650 patient years of follow-up.Information sourcesSearches were conducted in Embase, Medline, CENTRAL, and the Science Citation Index databases from inception until 14 April 2020.Main outcome measuresThe primary outcome was falls during trial follow-up. Secondary outcomes were acute kidney injury, fractures, gout, hyperkalaemia, hypokalaemia, hypotension, and syncope. Additional outcomes related to death and major cardiovascular events were extracted. Risk of bias was assessed using the Cochrane risk of bias tool, and random effects meta-analysis was used to pool rate ratios, odds ratios, and hazard ratios across studies, allowing for between study heterogeneity (τ2).ResultsOf 15 023 articles screened for inclusion, 58 randomised controlled trials were identified, including 280 638 participants followed up for a median of 3 (interquartile range 2-4) years. Most of the trials (n=40, 69%) had a low risk of bias. Among seven trials reporting data for falls, no evidence was found of an association with antihypertensive treatment (summary risk ratio 1.05, 95% confidence interval 0.89 to 1.24, τ2=0.009). Antihypertensives were associated with an increased risk of acute kidney injury (1.18, 95% confidence interval 1.01 to 1.39, τ2=0.037, n=15), hyperkalaemia (1.89, 1.56 to 2.30, τ2=0.122, n=26), hypotension (1.97, 1.67 to 2.32, τ2=0.132, n=35), and syncope (1.28, 1.03 to 1.59, τ2=0.050, n=16). The heterogeneity between studies assessing acute kidney injury and hyperkalaemia events was reduced when focusing on drugs that affect the renin angiotensin-aldosterone system. Results were robust to sensitivity analyses focusing on adverse events leading to withdrawal from each trial. Antihypertensive treatment was associated with a reduced risk of all cause mortality, cardiovascular death, and stroke, but not of myocardial infarction.ConclusionsThis meta-analysis found no evidence to suggest that antihypertensive treatment is associated with falls but found evidence of an association with mild (hyperkalaemia, hypotension) and severe adverse events (acute kidney injury, syncope). These data could be used to inform shared decision making between doctors and patients about initiation and continuation of antihypertensive treatment, especially in patients at high risk of harm because of previous adverse events or poor renal function.RegistrationPROSPERO CRD42018116860.