Letter from J[oseph] C. Pickard to John Muir, 1902 Jan 7.

JOSEPH C. PICKARD,MAYWOOD, ILL.January 7th. 1902.My Dear Mr. Muir,I think you will enjoy the enclosed letter. - Mrs. Tydale is now the wife of a Boston lawyer. For some years before marriage she was Professor of English Literature in the University of Iowa of which my brother was President. Wh[illegible] visiting her last summer our talk drifted to yourself. She had not read your Mountains of California - on my return to Boston I sent her a copy, & this letter is her acknowledgement. You need not trouble to return it, as I have made a copy. I trust Christmas and New Year\u27s brought you holiday blessings. The good abide with you.Cordially yoursJ C. Pickard0292

Letter from J[oseph] C. Pickard to John Muir, 1909 Sep 2.

[1]Maywood Ills. 2 Sept. 1909Dr. John MuirMartinez, CaliforniaMy dear Friend.I have read with great pleasure your Stickeen . I find the same pen finds alike in narration & description, and the same genial soul that loveth All things both great and small. I can but recall the day you came to me with wooden clocks & asked a place for them. Wonder-working clocks regulating so much of labor as student & teacher! I trust you have them still in place of honor.A few years ago I was in Edinburg I went into the cemetery at foot of Calton Hill, to see the bronze figure of L[illegible] & the tomb of Hume. I found near those a monument to 3 (or 4) martyrs (banished for love of their fellowman. I copied inscriptions remarks made at their trial. One read as follows: I have devoted myself to the04573 [2]cause of the people. It is a good cause. It shall ultimately prevail. It shall ultimately triumph . Thomas Muir in Court of Judiciary. Aug. 20. 1793. - The cause did ultimately triumph & the people erected the monument. You must know the spot & its memory, as I believe your early life was not far away.- I have thought you must of that noble stock, for in you is somewhat of that heroic grandeurI wish you might meet my brother J. L. who lives in Cupertino (85 years of age) & his grandson in San Francisco, Perhaps you remember Henry Butler & my son Charles as boys about the university. Henry is a lawyer in Superior, & Charles a lawyer in Chicago. Charles spent a week or two this summer with his invalid wife in the Yosemite. I hoped he would find you. Both boys are successful in their profession.Very cordially yoursJ. C. Pickard[3]PS. Ninety years ago my wife\u27s grandfather James St[illegible] & his son published \u27Illustrations of Edinburg with a history of the city. One of the engravings is of the old Tol. booth. I found a copy in a second hand book store, & brought it away with me paying $2.25 for it. A rare work now. MR. St[illegible] was a distinguished delineator & engraver in London.- In the description of Hume\u27s monument is given a suggested epitaph, which you may not have seen. I copy it. Within this circular idea, vulgarly called a tomb- Rest the impressions & ideas That constituted Hume. I quote from memory.JCP0457

Letter from J[oseph] C. Pickard to John Muir, 1901 Dec 1.

[letterhead]December 1st. 1901My Dear Mr. Muir,Returning from a long Sojourn in New England, among native s[cenes?]. With brothers & sisters, I find a copy of the Atlantic Monthly - kindly sent by you. I have read you contribution to that number with the interest which attaches to all others that I see. Thanks for your thoughtful kindness. I wish I could pay in kind , but I have written little that you would care to read. I take pleasure however, in extending knowledge of yourself & of your published book on the Mountains of California among my friends in Maine & Massachusetts from Portland to Cape Cod.With heartiest good will,Your friendJ.C. Pickard0282

Quantum hydrogen-bond symmetrization in the superconducting hydrogen sulfide system.

The quantum nature of the proton can crucially affect the structural and physical properties of hydrogen compounds. For example, in the high-pressure phases of H2O, quantum proton fluctuations lead to symmetrization of the hydrogen bond and reduce the boundary between asymmetric and symmetric structures in the phase diagram by 30 gigapascals (ref. 3). Here we show that an analogous quantum symmetrization occurs in the recently discovered sulfur hydride superconductor with a superconducting transition temperature Tc of 203 kelvin at 155 gigapascals--the highest Tc reported for any superconductor so far. Superconductivity occurs via the formation of a compound with chemical formula H3S (sulfur trihydride) with sulfur atoms arranged on a body-centred cubic lattice. If the hydrogen atoms are treated as classical particles, then for pressures greater than about 175 gigapascals they are predicted to sit exactly halfway between two sulfur atoms in a structure with Im3m symmetry. At lower pressures, the hydrogen atoms move to an off-centre position, forming a short H-S covalent bond and a longer H···S hydrogen bond in a structure with R3m symmetry. X-ray diffraction experiments confirm the H3S stoichiometry and the sulfur lattice sites, but were unable to discriminate between the two phases. Ab initio density-functional-theory calculations show that quantum nuclear motion lowers the symmetrization pressure by 72 gigapascals for H3S and by 60 gigapascals for D3S. Consequently, we predict that the Im3m phase dominates the pressure range within which the high Tc was measured. The observed pressure dependence of Tc is accurately reproduced in our calculations for the phase, but not for the R3m phase. Therefore, the quantum nature of the proton fundamentally changes the superconducting phase diagram of H3S.We acknowledge financial support from the Spanish Ministry of Economy and Competitiveness (FIS2013- 48286-C2-2-P), French Agence Nationale de la Recherche (Grant No. ANR-13-IS10-0003- 392 01), EPSRC (UK) (Grant No. EP/J017639/1), Cambridge Commonwealth Trust, National Natural Science Foundation of China (Grants No. 11204111, 11404148, and 11274136), and 2012 Changjiang Scholars Program of China. Work at Carnegie was supported by EFree, an Energy Frontier Research Center funded by the DOE, Office of Science, Basic Energy Sciences under Award No. DE-SC-0001057. Computer facilities were provided by the PRACE project AESFT and the Donostia International Physics Center (DIPC).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nature1717

High-Resolution Genotyping of the Endemic Salmonella Typhi Population during a Vi (Typhoid) Vaccination Trial in Kolkata

Typhoid fever is caused by the bacterium Salmonella enterica serovar Typhi (S. Typhi) and is a major health problem especially in developing countries. Vaccines against typhoid are commonly used by travelers but less so by residents of endemic areas. We used single nucleotide polymorphism (SNP) typing to investigate the population structure of 372 S. Typhi bacteria isolated from typhoid patients during a typhoid disease burden study and Vi anti-typhoid vaccine trial in Kolkata, India. Approximately sixty thousand people were enrolled for fever surveillance for 19 months prior to, and 24 months following, vaccination of one third of the study population against typhoid (May 2003–December 2006, vaccinations given December 2004). We detected a diverse population of S. Typhi, including 21 different genetic forms (haplotypes) of the bacteria. The most common (69%) were of a haplogroup known as H58, which included all multidrug resistant isolates (bacteria resistant to the antibiotics chloramphenicol, ampicillin and co-trimoxazole). Resistance to quinolones, a class of antibiotics commonly used to treat typhoid fever, was particularly high among a subgroup of H58 (H58-G). Vi vaccination did not obviously impact on the haplotype distribution of the S. Typhi circulating during the study period

The First Post-Kepler Brightness Dips of KIC 8462852

We present a photometric detection of the first brightness dips of the unique variable star KIC 8462852 since the end of the Kepler space mission in 2013 May. Our regular photometric surveillance started in October 2015, and a sequence of dipping began in 2017 May continuing on through the end of 2017, when the star was no longer visible from Earth. We distinguish four main 1-2.5% dips, named "Elsie," "Celeste," "Skara Brae," and "Angkor", which persist on timescales from several days to weeks. Our main results so far are: (i) there are no apparent changes of the stellar spectrum or polarization during the dips; (ii) the multiband photometry of the dips shows differential reddening favoring non-grey extinction. Therefore, our data are inconsistent with dip models that invoke optically thick material, but rather they are in-line with predictions for an occulter consisting primarily of ordinary dust, where much of the material must be optically thin with a size scale <<1um, and may also be consistent with models invoking variations intrinsic to the stellar photosphere. Notably, our data do not place constraints on the color of the longer-term "secular" dimming, which may be caused by independent processes, or probe different regimes of a single process

Cognitive Motor Dissociation in Disorders of Consciousness.

Patients with brain injury who are unresponsive to commands may perform cognitive tasks that are detected on functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). This phenomenon, known as cognitive motor dissociation, has not been systematically studied in a large cohort of persons with disorders of consciousness. In this prospective cohort study conducted at six international centers, we collected clinical, behavioral, and task-based fMRI and EEG data from a convenience sample of 353 adults with disorders of consciousness. We assessed the response to commands on task-based fMRI or EEG in participants without an observable response to verbal commands (i.e., those with a behavioral diagnosis of coma, vegetative state, or minimally conscious state-minus) and in participants with an observable response to verbal commands. The presence or absence of an observable response to commands was assessed with the use of the Coma Recovery Scale-Revised (CRS-R). Data from fMRI only or EEG only were available for 65% of the participants, and data from both fMRI and EEG were available for 35%. The median age of the participants was 37.9 years, the median time between brain injury and assessment with the CRS-R was 7.9 months (25% of the participants were assessed with the CRS-R within 28 days after injury), and brain trauma was an etiologic factor in 50%. We detected cognitive motor dissociation in 60 of the 241 participants (25%) without an observable response to commands, of whom 11 had been assessed with the use of fMRI only, 13 with the use of EEG only, and 36 with the use of both techniques. Cognitive motor dissociation was associated with younger age, longer time since injury, and brain trauma as an etiologic factor. In contrast, responses on task-based fMRI or EEG occurred in 43 of 112 participants (38%) with an observable response to verbal commands. Approximately one in four participants without an observable response to commands performed a cognitive task on fMRI or EEG as compared with one in three participants with an observable response to commands

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice