6 research outputs found
The paradigms of management sciences
No full textW artykule scharakteryzowano różne typologie paradygmatów organizacji. Przedstawione zostały m.in.: paradygmaty nauk społecznych, paradygmaty nauk o zarządzaniu, perspektywy poznawcze w teorii organizacji według M.J. Hatch oraz paradygmaty poznawcze zarządzania według P. Johnsona i J. Duberly. Następnie przeprowadzono analizę możliwości zastosowania paradygmatów G. Burrella i G. Morgana w teorii i metodologii nauk o zarządzaniu.This paper presents an analysis of paradigms of management sciences. First of all the author presents the various possible typologies of organization and management paradigms and chooses the most adequate, in terms of the purposes of the article, approaches of G. Burrell and G. Morgan. Then each of the paradigms are characterized by describing its methodological development. Then on the canvas the concept of the paradigms of G. Burrell and G. Morgan, an analysis of their applicability into the theory and methodology of management science. The author presents four paradigms: the Interpretive-Symbolic paradigm which combines subjectivism with regulation, the Neo-positivist-Functionalist-Systems paradigm which combines objectivism with regulation, radical humanism (postmodernism) - a paradigm combining subjectivism with radical change, the paradigm of radical structuralism (Critical Management Studies), formed at the meeting point of objectivism and radical change. Theories in the sciences of management may be based on different paradigms, which can be seen in the elements, results, key topics and the attitude of the researcher and the preferred methodology. (original abstract
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No full textPAGE FOUR
DAILY PALO ALTO TIMES, MONUAY. JUNK 17. 191Z
Dalit) Palo Hlto tttmee
■nn st lUmUton atttiuc sod Ksmum sliest.
*r ifcc
TIMKS I'UHLISHISC COMPANY
MAIL SUBSCRIPTION RATE.
iPaiiLlc is sdvaacc.)
Do-Dcxtic Ratc
9m. Y-*» , U-t»
•ts Slonth. i.t.
fw* Wests i-ss
fast Month .,0
flsis W-*k is
Adiltiit all ro-nutunicAlHiu to THE DAILY
TIMK... PaW. Alto. CaL News item sbout
~llo Alto or Stanford imiplc anywhere in tbe
-rU wLci-vl Till. TIMES i. not
kst for the opinion! of c«( teapot, dent*. AT-
im mint be ■J|ni-il by the true nam*' of the
er. not for publication, but aa a susrwile-:
jaf nod faith Nothing of s tst^naalouai or
tBMlou* natutr -.ill be publiihed.
gnt-f-il at It.e I'.-iKimt-r. f.lo Alto, Ca.i-
■Warnts. .1 **«ontlcli-a) mailer.
at W. SIMKINS W. H. KELLY
EDITORS
MONDAY. J I'NE 17. 1912.
MR SWELL DRE5SEK
ARE YDU READY
FOR YOUR
TRIP?/
Fine Old Comedy
to Be Revived
Hll.-ll SCHOOL SIM..IIS Mill'
READY T<) GIVE I ill.-UN'S
"HEIR AT LAW."
Special Hammock
Sale
<JFor the next ten days we are going to
have a special sale on bed and porch
hammocks, so as to make room for our
fall shipments which will arrive very soon
Palo Alto Furniture Co.
222 University Ave.
PlioneP. A. 12
CLASSIFIED
CLASSIFIED
We are Sole Agents for the
Pilling and Madeley Guaranteed
Hose - 6 pair 1.25
Otto Wideman
FOR BALK.
FOB RENT.
Far Sale—An auto-plano, in fins!
condition, almost new; reasonable
pries, with records Included. Party
to make change. Box L, Times office.
6-7-tf !
For Rent—Armory Hall; rent
reduced. Available for mestlnga,
shows, dances. Apply F. J. Drisooll.
303 University avenue. 1-22-ti
PROFESSIONAL
ATTORNEY*
NORMAN E. MALCOLM
ATTORNEY AT LAW
.NOTARY PUBLIC
First National Bank bollcllasj.
Pals AJto. on-* psoas tiiii
rssldsnos pbons HIK.
Dr. THOMAS f. HAMMOND
DBNTI8T
Hours I ts 12 I
1 la t p. m. Ledyard balli
I 415K.
-/
•taaj. #
.al
I'l.-IIMIIVARIAM.
1'ul.t AJto 1'rtirlnarj HoapltaJ
Dr. R. M. Olsson-Seffer
Thoroughly equipped to bsndls tbs
smaller snlmals. Separate manga
and distemper wsrda.
Phone- Its. 817 Alma Stress.
NEW RAILROAD IFR1ENDS OF RUEF
IS COMPLETED TRY NEW SCHEME
One of thu moat Interesting
evenl* of il.ii. graduation week will
bo tho presentation or '"The Heir at
Law" by the high school senior
class In tbe Armory Wednesday
night. Manager Walter Dlngley reports a brisk a'-at ualc at Weingart-
ner's. where the tickets are on aale
at "<0 and 3& cents.
"The Heir at l-aw." written by
Thomas Colman the younger. In
1B02. Is s singular pln> Although
written In a classical age, when
long aod formal moralizing Bpeechep
were cuatomary. tbo author managed lo Inject considerable live action Into his work, nnd becauae of
tbo true picture of life It presents,
and bcesusv of Its Interesting cbar-|
actors, the play bss survived'
throuRb a century's teat. At the
tin;-- when this comedy-drama was
placed before the publlc tbe author
found It necessary to apologize for, . _ # .. , _. *■ — .grain
certain characters, which might bfl »**• "' lh* lhrowln-- of *• J"? association on record as demanding |1 ,„
. " .. , ahnv.'ll.il ttt hsllast on ibe roadbed, nj..-.-. 1- -j_ -> . •-« -.-I —- -
For Hale—Or exchange for acreage property, a bouas and lot. Apply :;.'■;: Melville avenue. r.-7-tf
| RIU>AIHMl'Gr. LINE CONSTRUCT- RESOLUTION I-KMANlJlM.
ED BY RAVENSWOOD PEO- HOLE IS PRESENTED PRISON
MOO FEET LONG.
! For Sale—At a bargain, fine initio burtlnoaa. well established; clean
outside work, borse and buggy Included. Only S300 caah If taken at
once, flood reason for selling.
• Look thla up Box 8, Times office.
PA- 6-8-3w»
For Rsnt —- Alts Hall, os ths
third floor of tbs Simklns building,
la arallable ror smalt meetings at a
rental of fl.60 par msstlng. Enquire Times office. 6-7-tf
For Rent—Furnished flat with
largo sleeping porch, reasonable; all
modern conveniences. Inquire 487
Kipling atreet. 6-2»-tf
Dr. E. C. Zickenclrath
GRADUATE \ IM KRENARIAN
(California Suts License.)
l-f-.itl-.iry. Snrgt-ry, Medicine.
Phrne Olli. Office. 428 Hamilton Ava.
PLB is '
For Sale—Baby buggy. Apply
1446 Bryant street. 6-11-lw
'S I'.iM' ;.'.!.i: of
M.-.tl.-. an Imimrt.nit
District Prom Agricultural to
Manufacturing Center.
The Ravenswood railroad
.150 feet long. we>s finished yester
ia> wltb
REFORM MEETING
. Sor Sslo—At a bargain, New 5-
'room cement bungalow, strictly
The Progressive Prison Reform, modern; built-in bookcases, cblnel
Association, organized by women! clo>et"< ahower bath, etc: cabinet;
' sociological workers of San Fran-! kitchen: chicken yard; one block to
.elsco. held Ita drat publlc meeting *"■"- 3-7 Kamona atreet. Palo Alto.
> nt tho Valencia Theater yesterday
about I nnd In the middle of the meeting a
number of Abraham Ruef's old
too "rough" for the classical, aodl-i
saees. But. strange to say. It ls tbe
natural and appealing humor of
these very chnraetera rather than
tbe "beautiful" apeeches which ban
made "The Heir at Law." In fact,
the long t-oHlonuiea have been cut
considerably- Three famous nctora
—JoSSph Jefferson aa Doctor Pan-
gloss. YVIlltnm J. Florence aa Zek-
lel. and Viola Allen as Cicely—all
playing In the name cont puny, first
brought otit the real mem* of Col-
man's character creations.
Miss E L Buckingham of the
Stanford English department. a*-alst-
ed by Miss B K Freeman. English
instructor at the high school. 11 - ■
coached thr .:,:>:: Following It:
the east which will appear In the
dress rehearsal tonight; t
\*ot€\ Duberly Waldron Green.
Dr. Pai.gloaH—Wesley Templeton.
Zeklc] Homespun- John Norton.
Dirk Dowlnss—Leslie Miller
' Steadfast Byron Fox.
Henry Morlnnd—Robert Bleecker.
Kcndrlck—Walter Dlngley.
I-ady Duberly—Inez Shone
Lady Caroline Dormer—B'-rtha
Knag.
Cicely—Olive Croaby.
6-17-6t* |
A-l stock ranch, foothills in San'
Joaquin valley near Patterson, Cal,
the drawing of tbe tallES. JS*- W **.*"***!! P*-°" 700° "c** 50° °r 6°° ■*"* SOOd
lutlon. which would place tbo new -^ ,.„„_ j^y Urmn. PrlcgJ
. per acre. See S. 0. Wood-
l>anclseo ^^rooi.^g^. ufTCm&oUm street, Palo Alto.
ward. 327 Ramona street. Palo Alto.
The move was not expected by' 6-i6-6t* |"
the uoiiii-il. who In their association —,__—. i
and work had not entered Into tho For Bale—Cbsrrles and fruit tor
propaganda to secure the liberation "n,c ftt the George Meeklns ranch.;
For Rent—Two housekeeping
rooms wltb sleeping porch; all conveniences; 111. 436 Florence St.
6-1-tf
For Rent—Two flats of 3 rooms
each, completely fnmlsbed. 813.50
and 814. Apply 311 Alma at. 5-31-Sw
Rooms furnished ror housekeeping: rates reasonable. The Hamilton. it>i Hamilton ave. Pbone 488K.
6-10-lm
Shampooing
Manicuring, Scalp Treatment, Fa-aad
Trratmrut, Hair Work.
Mill. G. MALCOLM WADI
Room No. 1 MadJaoD-TbolU Block.
Phone 23fiX.
For Runt- Completely furnished
five-room bungalow; gas range,
porches, oak tree. Pbone 493X.
«-14-lt"
Bbovei'ul of ballast on the roadbed. Iflwtri paroiu «„.
This marked an Important transition' presided
in the Ravenswood property from
an agricultural to a manufacturing j
dlBtrlct. Tho new road is broad-1
gaugt. and cost approximately 810.*
••'■
It was built to develop and nc-j
commodate new factories nnd IikIuh-! . .
trial en.erprl.es of all kinds In Ra-- "'"0,,,, ,'" "»■ «»«'
I (.'>iuiiml in atam-ba-ts; tb
For Rent—€-room cottage completely furnished: 825 a month.
Apply Box 15, Times. 6-15-lw
vcBSwood The Reed Zinc Work;
ami the Lubrleatlng Products Company worki. are now In course of
construction, nnd others are to follow aoon. Tratbr experts are unanimous In predicting a rapid increase
ln tr.i- population of Rovenawood
and also of I'alo Alto. Tbe new
lownslte etnlirareit !>fUi aerep of for-
tile land
j of Ituef A tiii'tuber of the audl-
|sncs asked to be allowed to road a
resolution. Then Ituef's friends al-
! tempted to Ktaiiipede the meeting by
' forcing it Into the position of ft
' delegate body by making motions,
< discussing the resolutions and en-
I deavorlng to rush It through.
Professor I. B. Cross of Stanford
University, wbo was present as an
Interested worker In prison reform.
made n speech by
ed In bringing the
without a voti
V. 0. Bordreaux.
6-15-ls
For 8alo—1319 Bryant street.
new bungalow: monthly payment
6-15-lw"
f0T gjitvi—jlo. 5 Underwood typewriter. Al condition, used very little. Box R, Times. 6-l7-6t«
For Rent—Dntll September lat.
completely furnished five-room cottage at 1229 Webster. 0. R. Slo-
cum. agent Phone 665 or 19.
6-15-31
MISCELLANEOUS
Whitewashing and housedeaolog.
J. C ("anion. Redwood City, will
tskc orders snd guarantee satisfaction Phone Redwood 111. 5-25-lm
WANTRD.
Bicycle Taker Arrested,
Joseph Murphy, a 13-year-old
boy of Los Altos, was arrested yesterday In Snn Joae thefts committed hero on June 5th. One of
the wheel*, belonging to Frank Car-!
doi.t. was recovered. The boy had'
Wanted—Apricot cutters. Good
hlch he succeed- campgrounds, pleasant surround-
iCetlng to a close Ings: wood and water free. Apply
on Ruef In the name James J. Dale, frultdrler. Mountain
SQUABS
Los Altos Pigeon Lofts
Finest squsbs for table dellvsrsd
st your door. Prices on application,
Ring Palo Alto 14-17—ring 5.
Regular delivery on Wednssdays
and Saturdays. Orders of half do-ten
or more st any time. Orders most
be in before 5 p. m. tbe day befors
delivery.
L- T. LENOX
P. L. SEAMANS
THE LEADING JEWELER
r-srgest and Most Complete Stock
Ever Brought to Palo AltO.
Only Engraver Is Palo Alto.
What We Say It U It Is.
All Goods Engraved Free.
REGISTERED OPTICIAN.
of the new association.
Tbe meeting was the first of tbo
Progresslvo Prison Reform Association which was organized about two
months ngo for the purpose of taking up aoclologlcal work and bettering prison conditions as well sa
View.
Phone Suburban 17X-1.
6-7-lm« I
Wantod — Gardening, painting,
whitewashing or general work. Ad-
dresa Box 213. Phone 539L.
5-29-lm*
PALO ALTO VACTJUM CARPET
CLEANING CO. Carpet laying and
remodeling. 8. C. Gibson, res. l€7
Lytton avs. Phons 430T. ll-81tf
PALMISTRY AND PSYCH ICj
READER—Best on tbe penlnBula.j
Mrs. Van Baker; full readings 21.00.j
817 Kipling street, off Homer avenue. Reads for Society affairs, 26
an afternoon or evening. Telephone
4»7L. 6-11-tf
C. R. BASOM
BICYCLES, M.WIM. MACHINES.
VACUUM CLEANERS
Sold, Itettslred, Rented.
Vacuum Cleaners for rent, 91 a day.
l.tH High Street. Phone 81SX
Painted it red and was trying 10 sell. u',nln* ont **• anderlying condi
It. Tbe youngster will probabb be',lon"- -h«; csuse of crimes,
put on probation
Wanted—Cheap for cash, born
for Victor Talking machine. Address
X. Times office. 6-14-4t»
LOANS.
UPHOLSTERING AND RHPAIB2NG
Awnings. Window Shads*. Brass
Rods, Etc. Agency for gas Jean
Rug Works.
A. W. MILLS
819 University Are. Phone MCI
Mr. and Mrs George Brown of j who
Sao Diego, who nro visiting with Mrs.
relatives in I'nlo Alto, apont yester- go to their summer cottage at Fallen
day In Alamertn. j I^caf Lake.
Professor J C L Fish and little son Isavs tomorrow for Ohio,
they will apend the summer.
Fish and little daughter will
FABER TRACT
We have the selling agency for the Faber Tract of SOO
acres, known for yeara as tho Clarke Ranch.
This property adjoins tlte lUvenswood Addition to Palo
Alto and lie* within two bloeko of the ear line. It ls subdivided Into five and ten sere tract*, and is the highest claw
tirr-nsgc close to Palo AlloUuit lias ever been upon the market-
It is rich, level land, especially adapted to alfalfa or vegetable.*. Electric power for pumping.
We will sell yoa flvs or ten seres sod build to suit on s
t.m*ll payment down, the balance In easy terms.
For full partimlars call on
Marshall BlacK tavestment
Company
257 UniveraityAvenue, Palo .AltO, Cal.
"Abe Ruef Is not eligible to parol-.." Professor Cross said. "The
board of prison directors bas acted Wanted—Position to do bouse-
entirely within the law. Ruef Is not *•»*• Apply Mariposa hotel ^ or
being illegally restrained In San Phone 772X. 6-14-St*
Qtientin. Alt your campaigning aod: Wanted—Owner wants a loan of
propaganda for tho parole of Ruef ,B 000 or jg.ooo at 6 per cent on
Is not going to benefit prison reform. flrBt^!llu Unlvoralty avenue busl-
Thla prison refdYm Is greater than npM pr0porty, well rented. Ad-
one man. It la greater than one poll- AfW Box u T,mM offlce 6.i6-«t
tlrlau. It la greater than tbe editor
Notice—Money to loan on real ea-
(ate security. Apply to Rodgcrs A
Smith, attorneys at law. room z{
Madlaon-TholU block, Palo Alto. 1
r-:--im I
Newly Opened
Turkish Baths
Lady attendent for Ladies
UnivKsstTV Rant* Palo alto
Pbone 430K
of ono newiipaper.
"You eannot make this movement for one man. it Is a movement for the benefit of all the people ln the state of California. Are
you going lo wreck this movement
on tho rock of one man?
"You want to treat Ruef as you
would any other prisoner. Give hlm|
the samo deal that you give everybody else. If you adopt this resolution for tho parole of one man youi
will get the condemnation or every |
other prison reform society In the!
state.
"Do you think that tbls sUtsj
will stand for a prison reform association which seeks the parole of,
one man? Do not allow these people, wbo sre not of your association.
to attempt to dominate you"
Wanted—Two Sunny rooms with
bosrd. Addresa Box 66. Menlo Park.
6-15-3t*
Wanted—Place to do gardening,
flowers, milk cow, tend chickens,
horses. Speaks English and French.
Pierre Malbert. Menlo Psrk P. O.
6-15-lw*
FOUND.
Pound—Near Coolers Landing,
Sunday. June 9th, a pair of rimless
eyeglasses. Owner can have same
by identifying them at Times offlcs
and paying for thla ad. 6-9-lw
•SSSSSSSSSS»SSgSSSSSSSS»S4
FOR 8ALR
Stranger—Boy, will you direct
me to tho nearest bank?
Street Oamln—I will for a shilling- Stranger—A shilling! Isn't
that too much?
Street Oamln—Bank directors
always got big pay, mister.—Tld
Bits.
OLD BUILDINGS ON THK
SEALE RANCH
Also second-hand boggles,
sarreys. harness. Apply to
ALFRED SEALE
X Nevada Building. Phone 31SX
Do you Like Good Coffee?
OF COURSE YOU DO.
IK) YOU GET ITT
Not always, unless yoa boy our
Avoca Blent]—* asaaaaasasasss. of old
coffee of detlcloa* flavor, not rank.
EARLE & CO.
Masonic Temple Building
Phones 837 and 83
The role of conflict & negotiation in the complexity of projects
No full textProjects are pervasive and disparate spanning a plethora of domains. Most projects are unified by certain characteristics regardless of the sector or industry to which they belong i.e. time & budget limitedness, a concern for quality, and a goal orientation. Although, projects have been around for a longtime, the phenomenon of conflict in projects gained interest around the 1960s with the introduction of the matrix form of organization. However, out of all the research papers on project centric conflict between 1960 to 1980 time period, only one is empirically grounded and that too focused on IT projects. Surprisingly, the findings put forward during this time period are to date considered valid and propagated by most project literature as universally true. Several other studies have contributed peripheral contributions to the project conflict literature, however, no study has focused on building an understanding of why and how conflicts arise on projects, how they are managed, and affects they create within projects.Recent concerns pertaining to project failures, despite the existence of well-defined problems and toolsets, gave birth to an ESRC funded research network named `Rethinking Project Management'. Whose members in examining the ontological groundings of project management identified several areas of interest for future research in project management; one of which is complexity. The present study therefore focuses on integrating the concerns of conflict & negotiation within the context of project complexity.Every research has its philosophical bearings. This study is ontologically objectivist and epistemologically subjectivist (consequently the axiology is subjectivist as well). This study accepts a Critical Realist view of the world and perceive the conceivable knowledge about this world to be subjective in nature. As the study is concerned about understanding the processes through which conflict & negotiation reify and interplay within a project the objective is not to find generalizations but rather to seek out patterns of occurrences and to build explanations. The methodology followed in the study is mixed, borrowing from both positivistic and constructivist ideologies. The survey methodology is used to, in loose terms, cast a net and capture the status quo. Results of the survey supplement the literature review driven a priori assumptions and seek out context embedded variables that the literature has not touched upon. Findings from the survey contribute to the succeeding case study methodology, which inquired into their detail through the use of interviews.Data for the study was collected between March through August 2010. During the first phase of the study 86 questionnaires were filled from 73 different projects. The survey data was analyzed using aggregate statistical techniques and a thesaurus based automated coding software named Leximancer. Results of the survey indicate that all projects surveyed had experienced some form of conflict and used at least one type of negotiation technique. A large number of projects faced conflicts related to land access, political pressures, time, interdepartmental relationships, and availability of resources. Project behavior when experiencing conflict exhibits a theme of delay, slowness, and work stoppages; there are also negative effects on group cohesion and productivity. The respondents described projects experiencing conflict as challenging, time consuming, delayed, and difficult. The data also revealed several useful patterns within projects experiencing conflicts. Additionally, baseline data for project complexity was captured using Shenhar and Dvir's Diamond Approach from all the projects surveyed. Findings, from the survey contributed to the study by providing preliminary answers to each of the research questions asked. Data gathered as a result of the survey contributed significantly to the design and orientation of the case study interviews.The second phase of the data collection involved implementation of the case study methodology. Personnel at various levels of nine projects, one government consultant, and a tribal elder were interviewed, for a total of thirty interviews. Additionally, six meetings on one of the projects, and two movie filming sequences were observed. Published and non-published reports on all the projects were examined. Interviews were captured using causal-maps (a cognitive mapping technique) and short notes. The causal-maps were captured using Banxia Decision Explorer and later refined using Cmap (an open-source mapping software). Each project's complexity measurements were taken and compared against the complexity baseline developed as a result of the survey.Results from the case study reveals certain patterns of behavior on the projects, specifically in the interactions taking place between a project and its principle organization, peers, and subordinates. Additionally, I find that quality plays the most active role in project conflict & negotiation and contributes significantly to project complexity because of its interconnection to other concepts and the recursive nature of the connections it spawns. Some factors that were reported by the survey as contributing significantly to project complexity and project conflict & negotiation were disqualified and a foundation laid for further inquiry into the role played by conflict & negotiation in project complexity.In concluding the study the data is first discussed through the lens of Jurgen Habermas' (1984) Theory of Communicative Action (TCA) and is followed by a general discussion on the data. The study concludes with a discussion on the possible future work that could result from this work
Whole-genome sequencing reveals host factors underlying critical COVID-19
No full textAltres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization 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
Stratified analyses refine association between TLR7 rare variants and severe COVID-19
No full textSummary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway
Whole-genome sequencing reveals host factors underlying critical COVID-19
No full textCritical 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
