[PDF] Journals in Aging, Geriatrics, and Gerontology: A Survey - medRxiv

76479_719012278v1_full.pdf

Article

Journals in Aging, Geriatrics, and Gerontology: A Survey

Robert J. Wolff

1 and Hannah L. Bowser 2 1 Professor of Science and Health Science, South University; rwolff@southuniversity.edu 2 Virtual Services Librarian, New Hanover County Public Library; hbowser@nhcgov.com Abstract: Aging, geriatrics, gerontology, and related areas are important areas of research as the population of older people increases in relationship to the total population. Researchers in these fields would benefit from guidance regarding sources for publishing and finding relevant

scholarly journals and articles. Multiple database sites of journals were searched to provide a list

of relevant publications. This list was expanded via perusal of published citation lists and searches in general search engines. A total of 243 journals were identified and examined. Of those journals, 198 journals are currently publishing and 45 journals have ceased publication. In terms of publication medium, 39% of the currently publishing journals are online-only, 4% are print-only and 59% of the journals publish both online and in print. Journals with aging in the title represent 36%, geriatrics 30% and gerontology 23%. Less than 10% have been identified as predatory journals. An expected increase in journals in the broad field of aging is indicated by the 49% of listed titles beginning in 2000 or later. This recent increase in available journals provides a need for the information listed in this paper. Keywords: Aging; Ageing; Geriatric; Gerontology; Medical journals; Medical publishing;

Predatory journals; dementia; nursing research.

1. Introduction

Not only is the population of elderly people rapidly increasing as a demographic, so is the number and variety of journals that publish research in the areas of aging, geriatrics and gerontology. Researchers are now finding it difficult to determine what journals they can find, which are appropriate, and how to easily access their websites. While there are some listings of journals that can be found using search engines, none of these are very complete, nor do they provide easy access to the journals. Having a greater knowledge of, and access to, the wide variety of publishing options can make it easier for researchers and librarians to advance their professional endeavors. The purposes of this paper include the following:

1. To document the variety of journals available in the professional areas of aging, geriatrics

and gerontology.

2. To provide a list of journals that is as comprehensive as possible.

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

3. To help researchers and graduate students find appropriate journals in which to publish

their work.

4. To open up options for other sources for publication of their research and commentaries.

5. To examine various issues in the diversity of journals in these areas.

6. To provide some warning about journals that are possibly predatory and therefore need to be avoided by serious researchers, and whose articles may be of poor quality.

2. Materials and Methods

The Scimago Journal website [1], the Clarivate Analytics (Web of Science) [2], JenAge Information Center [3], and PubMed (NLM) [4] were used to access lists of journals related to aging. To these we added journals found in citation listings, on publisher websites, and from internet searches. Listings of the A-Z journal titles found in the South University library system were also searched, using keywords such as "age," "aging," "gerontology," etc. The website of each journal was searched and checked for publication status and information about online and open access features, and if available, the article processing charges were determined. Our listing of predatory journals is based on Beall's List of Predatory Journals and Publishers, which can now be accessed in several internet sites. We used an anonymous Weebly blog [5] that was last updated 4 July 2018.

2.1 A Note on Predatory Publishing

Predatory journals are defined by the authors as journals that seek submissions at a high price but generally publish low quality information and often under false pretenses. Predatory journals are

included in our list for three reasons. First, because they exist, it is important to list and identify

them. Second, they are included so their listing can be found and avoided, by those seeking a reputable journal in which to publish. Third, we want them identified as predatory journals so

that their status is clearly noted and so their published articles may be carefully analyzed as they

are often of poor quality. The problems of predatory journals and publishers have been clearly documented, though not without conflict. Warnings about predatory journals have been sounded as a threat to and an undermining of confidence in scholarly research [6-8]. Criteria are available for recognition of legitimate or predatory journals [9-11]. However, it is worth noting that the open access model of publishing does not automatically denote a predatory journal, nor are all predatory journals open access publishers and journals. Although the authors used Beall's List as a convenient listing of

predatory journals, it is important to note that this list has its critics [12,13] and that the best

methods of recognizing a predatory publisher or journal are through each author's own research [9,10].

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

3. Results

The number of currently publishing journals in the broad fields of aging, geriatrics and gerontology that is we focused on is 198, and we found 45 titles that have ceased publication. Table 1 provides basic information about the content of the journals, and the use of common terms or prefixes in journal titles. Age or Aging, with the spelling variant of Ageing, and the Portuguese Envelhecimento, were the most common descriptors used in journal titles at 70 (36%). This was followed by Geri- or Geriatric, or the Dutch Ouderengeneeskunde, with 59 (30%) uses. The journals were categorized as Print (only), Online, or Both. Only 7 of the currently publishing journals were print only (4%), while 5 of the 45 journals that have ceased publication (11%) were print only, which may represent the slow demise of print journals. Of the currently publishing journals, 76 (39%) were online only, and 115 (59%) were published both online and in print form. One journal was considered to be a print publication, with only society members having access to the online version. Journals with 19 or less volumes published as of September 2018 numbered 98 (50%), indicating the rapid expansion of journals since 2000. Of the journals that have ceased publication, 29 (65%) began in 2000 or after, and if 1998-99 are included, the number jumps to 34 (76%), indicating the difficulty of journal start-ups to maintain publication during the move to open access publishing. Nineteen of the currently publishing journals were identified as potentially predatory journals or

publishers, just less than 10% of all available journals in the broad area of aging. We did not find

any hijacked journals (where websites or branding were coopted by a predatory publisher), but the similarity of some journal names may be a form of hijacking by attempting to create confusion. The complete list of journals that are currently being published may be found in Table 2 and the complete list of journals that have ceased publication is in Table 3.

-§³"Ɏµ¬)µµ»¸´²Ƀ§"µ§²Ɏ§(µ¸2µȘ¸Ƀ/ɎɃ/µ¯º´²²ɎɃ/"ȏµ.´³"ș(¨șɃ¹®3

)µ»¸´§²Ɏ3¯º²"¹ Ŵ Ɏ-»³¨"¸Ɏ/"¸©"´ºɎȘµ¬ɎŴżŸșɎ

"ȍɎ ¯´ȍɎ "¯´ȍɎ$´¼"²®"©¯³"´ºµɎźųɎɎ

ŶŹƳ

ŵɎ

Ɏ &"¸µɉȍɎ&"¸µ´ºµ²µ¿ɎŷŸɎɎ

ŵŶƳɎ

Ɏ

&"¸¯ɉȍɎ&"¸¯§º¸¯©ȍɎ.»ª"¸"´"´""¹±»´ª"ɎŸżɎŶųƳɎ

Ɏ

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

-¸´³µɃ³ș""Ɏ1³Ƀ³¬(µ5Ɏ¿±Ɏ±±ȏɎ Ɏ ȵ2²¨"Ɏȵ2²µ5¸ɎªɎ®ȏɎ Ɏ ¼³¶ș2¨"Ɏȍ³¬(5¸Ɏ±¿ɎºȏɎ Ɏ

Ȋ"¹²´¨ɎɎ

Ɏ±®ɎªȏɎ

¼¶ș"¨"Ɏ¼¶ș"µ¬§ɎȘɎ®ȏɎ Ɏ )¸ ³ș"Ɏ)¸ ³ș¸¹"ɎȒ¸ ³șɎȘɎ®ȏɎ Ȋ5șǻµ¬"2¬¨ɎȘɎ®ȏɎ 1 Some titles included more than one of the words or prefixes. 2

Percentages were rounded up to the whole number.

4. Discussion

The list provides clear indication that the print only journal is on its way out, with 7 currently published journals in print only, compared to 115 journals in both print and online formats, and

76 online only journals. We expect to see many of the journals still in print or both formats to

move to online only within the next few years. We are requesting that journal editors and publishers send updated information to the senior author to help improve the list and information about the journals. Missing journals need to be

added to the list after they are identified. It is our expectation that updated versions of this paper

may be published in a preprint form in the future. This can more easily be updated on a regular basis, or made available in some other format. Of interest is the apparently low number of journals focusing on nursing in the field of gerontology. Only 7 of the 195 (4%) currently published journals specifically refer to nursing, a low number as it seems that most nurses do work with aging patients. Those in fields of sociology and social work as well as psychology seem under-represented. Another area of concern is the lack of journals publishing research focusing on caregiving, with the only journal we found in this area having ceased publication. The area of caregiving currently has an emphasis on problems of the health of caregivers and the problems associated with poor (even abusive) quality of care for the aged. This is also a field often staffed by a nonacademic populace who would not have easy access to the wealth of information potentially available on current gerontology and caregiving research.

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

It is apparent from a librarian's point of view that it is difficult for the average researcher to find

and compile a complete list of potential publishing outlets, and it would be helpful to the scholarly community to have an easily searchable database, preferably not behind a firewall. This could increase the diversity of journal articles being published and help researchers find more appropriate choices for article submission, as well as increasing the diversity of authors who are submitting works for publication. With the rise in predatory publishing, we consider that having only 10% of the journals a low number, though there should be careful evaluation of all journals including newly launched titles. Additional journal titles are expected to be found as many of the predatory journals/publishers are not found in searches. More research could be done in specific scholarly fields as to the perceptions of predatory journals as well as how the rise of the open access movement has affected fields of research for better or for worse.

5. Conclusions

This paper provides a current update on journals being published in the broad disciplines of aging, geriatrics and gerontology and providing a broad view of research being published in the area. It is expected that this will be a useful resource to researchers who are considering publishing their research, to those trying to make sure they find all relevant articles in their searches, and for those looking at the discipline of aging, geriatrics and gerontology as a whole. The data provide a view of the wide areas covered within the broad disciplines involved in aging, and the increasing numbers of journals does indicate both an increased focus on aging as well as the dynamic nature of the expanding aspects of aging. While many general journals publish articles on areas of aging, these specific journals are important as a way to view the activity and interests in these fields. While the increase in journal numbers and types is not a direct concern, it is critical that the field note the quality of journals, and that efforts are made to help other researchers avoid predatory journals where there are high costs but the quality of the reviews and papers are very low. This not only hurts the field and is a waste of money, but also undermines the research and medical communities and confidence in them. This compiled list of data will hopefully be a jumping off point for other fields of research to compile lists and bibliographies of available journals for publication and their potential value or

risk. It will be especially helpful to students and new researchers in the field as a starting point

for their projects and careers.

Author Contributions:

Conceptualization, R.W.; methodology, R.W.; investigation, H.B.; data curation, H.B.; writing - original draft preparation, H.B. and R.W.; writing - review and editing, H.B. and R.W.; visualization, H.B.; supervision, R.W.; project administration, R.W. Funding: This research received no external funding. Acknowledgments: Thanks for support and editing to Donna Wolff. Conflicts of Interest: The authors declare no conflict of interest.

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

-§³"Ɏµ¬µ

)»¸´²§"Ƀµ(¸´´Ɏ²-"2µȘ²µ/¸³"Ș(§-Ș»²µ

¯µ3 !+$Ɏŵ$)Ɏ.41 -$2"883$

(/4Ǹ1ŴȌ$Ŷ1-Ǹ1+ŷ$/.Ÿ-ǸŹź+428ɎŻǸ+Ŵż$3.!Ÿ+4$Ɏŵ$

ųɎ-.!+Ź$/4Ǹ1Ŵ$Ɏ4$

Ŷ1-Ǹ1+ȵ$Ŷ®+1$"ŻŻ+ŹŹȵ$"/¯$(³ŷ$"!® ŻŴ$¶ ŻŴɎ42$8ŻǸ! §Ɏ$© 1º¬$/4+µ ŴɎ4ż$/.Ÿ-ǸŹź+4ȵ$

ºȏ

µ"ŻŴǸ¸ǸŴǸ+Ź°$"µ ®Ŵ ŴǸɎ1$»$2"§Ǹ1§$$

´²½¹ª¼¨Ȍ$²±¼¼ª¼¿·$' ż-Ɏ4$»$¶4 1ŻǸŹ$Ŷ1-Ǹ1+$

$¼²$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -$´#¼¼ $$

¬ȏ

µ"µ¸ 1Ż+Ź$Ǹ1$"§Ǹ1§$©+Ź+ 4Żź$ ¹²·½ª´¼½½Ȍ$¹²·½ª´±´¹ $8ŻǸ+1ŴǸŵǸŻ$©+Ź+ 4Żź$ /.Ÿ-ǸŹźǸ1§°$"1Ż#$$$¨$Ŷ1- Ǹ1+$Ƀ+ŹȌ$"/¯$ ³±½½$$Ƀ+Ź$(5+ --ȒŹ$%ǸŹŴŷ$ .ȏ µ"µ¸ 1Ż+Ź$Ǹ1$"-<ź+Ǹ!+4ȒŹ$=ǸŹ+ Ź+$ ¹²·½ª¹¼±½Ȍ$¹²·½ª¹¼·¨ $8ŻǸ+1ŴǸŵǸŻ$©+Ź+ 4Żź$ /.Ÿ-ǸŹźǸ1§°$"1Ż#$$¨$Ŷ1- Ǹ1+$Ƀ+ŹȌ$"/¯$ ³±½½$$Ƀ+Ź$(5+ --ȒŹ$%ǸŹŴŷ$

șȏ

µ"µ¸ 1Ż+Ź$Ǹ1$>+4Ɏ1ŴɎ-Ɏ§ż $

¹´¨½ª´±¨´Ȍ$¹´¨½ª´±½$8®4Ǹ1§+4$3 Ŵ.4+$$¨$5ɎŴź$ 3Ɏ$´#¿¹$ $

¨ȏ

µ"µ¸ 1Ż+Ź$Ǹ1$%Ǹŵ+$¯Ɏ.4Ź+$

©+Ź+ 4Żź$

²±·½ª¼½´½Ȍ$²¨½ª

·½¨¼2²´¼´ª¹·´$?-Ź+¸Ǹ+4$$¿¨$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³²²´´$²#¹´´$$

¹ȏ

µ"µ¸ 1Ż+Ź$Ǹ1$/ 4ºǸ1ŹɎ1ȒŹ$=ǸŹ+ Ź+$ ¹²·½ª½¨²¹Ȍ$¹²·½ª½¨¹´ $8ŻǸ+1ŴǸŵǸŻ$

©+Ź+ 4Żź$

/.Ÿ-ǸŹźǸ1§°$"1Ż#$$¨$Ŷ1- Ǹ1+$Ƀ+ŹȌ$"/¯$ ³¼½½$$Ƀ+Ź$(5+ --ȒŹ$%ǸŹŴŷ$

®ȏ

µ"§+$ 1µ$"§+Ǹ1§ $

´´´¹ª´¨¹½Ȍ$²¼·ª¹¿¼$Ŷ@ŵɎ4µ$"Ż µ+!ǸŻ$$¼·$ 5ɎŴź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³¿¼´´$¼#¹¹$$

©ȏ

µ"§+°$¯.-Ŵ.4+°$A.! 1ǸŴǸ+Ź$

¹¿¨±ª±·Ȍ$¹¿¨¿ª±¼²$"Ŵź+1 +.!$/4+ŹŹ$$¿$5ɎŴź$ 3Ɏ$$$

¿ȏ

µ"§+Ǹ1§$"1Ŵ+41 ŴǸɎ1 - $

´²·¿ª±²±Ȍ$²½¿·ª·´·B$8®4Ǹ1§+4$3 Ŵ.4+$$¼¹$5ɎŴź$ Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³¿´´´$´#¿½$$

º5ȏ

µ"§+Ǹ1§$©+Ź+ 4Żź$©+¸Ǹ+CŹ$

²±·ª²·¿¨$?-Ź+¸Ǹ+4$$¼·$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³¿´´´$¨#¼±¹$$

ººȏ

µ"§+Ǹ1§$»$8ɎŻǸ+Ŵż $

´²¼¼ª··BȌ$²¼·½ª²¨¨½$¯ !Ÿ4Ǹµ§+$D1Ǹ¸+4ŹǸŴż$/4+ŹŹ$$¿¨$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³¹¿±$²#¿·$$

º¬ȏ

µ"§Ǹ1§ $

²½¼±ª¼±½

$"!® ŻŴ$)Ɏ.41 -Ź°$

%%¯$$½$Ŷ1- Ǹ1+$Ƀ+ŹȌ$"/¯$³¹½´´$¼#·¨$Ƀ+Ź$(5+ --ȒŹ$

%ǸŹŴŷ$

º.ȏ

µ"§Ǹ1§$¯+-- $

²¼¨¼ª½¨¹·$)Ɏź1$EǸ-+ż$»$8Ɏ1Ź$$²¨$Ŷ1-Ǹ1+$ Ƀ+ŹȌ$"/¯$³¹½´´$·#¨²¼$$

ºșȏ

µ"§Ǹ1§$¯-Ǹ1ǸŻ -$ 1µ$?@®+4Ǹ!+1Ŵ -$©+Ź+ 4Żź$

²¨¹´ª¿²½$8®4Ǹ1§+4$3 Ŵ.4+$$¿´$Ŷ1- Ǹ1+$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³¿´´´$²#¿½¼$$

º¨ȏ

µ"§Ǹ1§$ 1µ$=ǸŹ+ Ź+ $

¹²±¹ª±¹±´$5+ǸFǸ1§$G §Ŵ+Żź$¯Ɏ#$%Ŵµ$$$Ŷ1- Ǹ1+$Ƀ+ŹȌ$"/¯$³·´´ª¹´´´$±#´±$$

º¹ȏ

µ"§Ǹ1§$G -+°$'ź+ $

²¿·ª±±¿Ȍ$²¼¨¿ª´¨½´$' ż-Ɏ4$»$¶4 1ŻǸŹ$Ŷ1-Ǹ1+$$¹´$5Ɏ Ŵź$Ƀ+Ź$

(Ŷ®ŴǸɎ1 -ŷ$¹#²´$$

º®ȏ

µ"§Ǹ1§$»$G+1Ŵ -$A+ -Ŵź $

²¿·´ª¨·¿Ȍ$²¿·¼ª·½²±$' ż-Ɏ4$»$¶4 1ŻǸŹ$

Ŷ1-Ǹ1+$$¹²$5Ɏ Ŵź$Ƀ+Ź$

(Ŷ®ŴǸɎ1 -ŷȌ$ "/¯$³¹½±´$¹#·±$ $$

º©ȏ

µ"§Ǹ1§°$3+.4Ɏ®ŹżŻźɎ-Ɏ§ż°$ 1µ$ ¯Ɏ§1ǸŴǸɎ1$' ż-Ɏ4$»$¶4 1ŻǸŹ$Ŷ1-Ǹ1+$ $¹±$5Ɏ Ŵź$Ƀ+Ź$ (Ŷ®ŴǸɎ1 -ŷȌ$ "/¯$³¹½±´$²#¨·¿$$

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

ŴŶŻŵɉŸŸŻŸȏɎŴźŷŷɉŷŴŵŻɎ

ŴżȌ

Ɏ ¯´ɉ42 Ɏ

ŴżŷŸɉŷŸŻżɎ(³¶§©ºɎ)µ»¸´§²¹ɎɎŴųɎ.´²¯´"Ɏ8"¹ȏɎ /"Ɏ

ǻŵżųųɎŷȌŻŹźɎ8"¹ɎȘ!"§²²ȟ¹Ɏ +¯¹ºșɎ

ŵųȌ

Ɏ &2Ɏ-"½¹²"ºº"¸

Ɏ ³"¸¯©§´Ɏ

&"¸¯§º¸¯©¹Ɏ2µ©¯"º¿ɎɎŷŻɎ.´²¯´"Ɏ 8"¹Ɏ ɎɎ

ŵŴȌ

Ɏ ²À®"¯³"¸Ɏ#¯¹"§¹"Ɏ§´ªɎ ¹¹µ©¯§º"ªɎ#¯¹µ¸ª"¸¹Ɏ

ųŻżŶɉųŶŷŴȏɎŴŸŷŹɉŷŴŸŹɎ6µ²º"¸¹Ɏ*²»½"¸ɎɎŶŵɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŵŻųųɎŵȌŶżŸɎɎ

ŵŵȌ

Ɏ ²À®"¯³"¸ȟ¹Ɏ§´ªɎ#"³"´º¯§Ɏ

ŴŸŸŵɉŸŵŹųɎ$²¹"¼¯"¸ɎɎŴŶɎ!µ º®Ɏ8"¹Ɏ

Ș.¶º¯µ´§²șȏɎ

/"ɎǻŶųųųɎżȌŷźŻɎɎ

ŵŶȌ

Ɏ ²À®"¯³"¸ȟ¹Ɏ§´ªɎ #"³"´º¯§ȎɎ#¯§´µ¹¯¹ȍɎ ¹¹"¹¹³"´ºɎȊɎ#¯¹"§¹"Ɏ ,µ´¯ºµ¸¯´Ɏ

ŵŶŸŵɉŻźŵżɎ$²¹"¼¯"¸ɎɎŴųɎ.´ ²¯´"Ɏ8"¹ȏɎ /"ɎǻŵųųųɎŴȌźżŹɎɎ

ŵŷȌ

Ɏ ²À®"¯³"¸ȟ¹Ɏ§´ªɎ #"³"´º¯§ȎɎ3¸§´¹²§º¯µ´§²Ɏ

1"¹"§¸©®ɎȊɎ"²¯´¯©§²Ɏ

(´º"¸¼"´º¯µ´¹Ɏ

ŵŶŸŵɉŻźŶźɎ$²¹"¼¯"¸ɎɎŶɎ.´ ²¯´"Ɏ8"¹ȏɎ /"ɎǻŵųųųɎŴȌŴųŻɎɎ

ŵŸȌ

Ɏ ²À®"¯³"¸ȟ¹Ɏ§´ªɎ/§¸±¯´¹µ´¯¹³ȎɎ1"¹"§¸©®Ɏ

ȊɎ3®"¸§¶¿Ɏ2,Ɏ.´²¯´"ɎɎ ŴɎ.´²¯´"Ɏ8"¹ȏɎ /"Ɏ´µºɎ¯¼"´ɎɎ 8"¹ɎȘ!"§²²ȟ¹Ɏ

+¯¹ºșɎ

ŵŹȌ

Ɏ ²À®"¯³"¸ȟ¹Ɏ1"¹"§¸©®ɎȊɎ3®"¸§¶¿Ɏ

ŴźŸŻɉżŴżŶɎ!¯µ,"ªɎ""´º¸§²ɎɎżɎ .´²¯´"Ɏ8"¹ȏɎ /"ɎǻŵŴźŸɎŹȌŴŸŷɎɎ

ŵźȌ

Ɏ ³"¸¯©§´Ɏ)µ»¸´§²Ɏµ¬Ɏ ²À®"¯³"¸ȟ¹Ɏ#¯¹"§¹"Ɏ§´ªɎ .º®"¸Ɏ#"³"´º¯§¹Ɏ ŴŸŶŶɉŶŴźŸȏɎŴżŶŻɉŵźŶŴɎ2 &$Ɏ

/»¨²¯©§º¯µ´¹ɎɎŶŵɎ!µ º®Ɏ-µɎŴȌŻŹŷ ɎɎ

ŵŻȌ

Ɏ ³"¸¯©§´Ɏ)µ»¸´§²Ɏµ¬Ɏ&"¸¯§º¸¯©Ɏ/¹¿©®¯§º¸¿ȍɎ3®"Ɏ

ŴųŹŷɉźŷŻŴɎ$²¹"¼¯"¸ɎɎŵŸɎ!µ º®Ɏ8"¹Ɏ

Ș.¶º¯µ´§²șȏɎ

/"ɎǻŶŶųųɎŵȌŻŹŻɎɎ

ŵżȌ

Ɏ ´§²"¹Ɏ"´Ɏ&"¸µ´ºµ²µä§ Ɏ Ș ´´§²¹Ɏ¯´Ɏ&"¸µ´ºµ²µ¿șɎ

ŴŹŸżɉųŻŴŶȏɎŵŵŴŸɉŷŹŷźɎ4´¯¼"¸¹¯º¿Ɏµ¬Ɏ

"µ¹º§Ɏ1¯©§ɎɎŻɎ.´² ¯´"Ɏ8"¹Ɏ ɎɎ

ŶųȌ

Ɏ ´´§²¹Ɏµ¬Ɏ&"¸¯§º¸¯©Ɏ ,"ª¯©¯´"Ɏ§´ªɎ1"¹"§¸©®Ɏ Ș¬µ¸³"¸²¿Ɏ)µ»¸´§²Ɏµ¬Ɏº®"Ɏ *µ¸"§´Ɏ&"¸¯§º¸¯©¹Ɏ

2µ©¯"º¿șɎ

ŵŸųŻɉŷźżŻȏɎŵŸųŻɉŷżųż Ɏ3®"Ɏ*µ¸"§´Ɏ&"¸¯§º¸¯©¹Ɏ2µ©¯"º¿Ɏ ɎŵŵɎ!µ º®Ɏ8"¹ɎɎɎ

ŶŴȌ

Ɏ ´´§²¹Ɏµ¬Ɏ+µ´ɉ3"¸³Ɏ"§¸"Ɏ

ŴŸŵŷɉźżŵżɎ',/Ɏ

"µ³³»´¯©§º¯µ´¹ɎɎŵŸɎ!µ º®Ɏ8"¹ɎųȌŴŷɎ Ɏ

ŶŵȌ

Ɏ ´´»§²Ɏ1"¼¯"½Ɏµ¬Ɏ &"¸µ´ºµ²µ¿Ɏ§´ªɎ &"¸¯§º¸¯©¹Ɏ

ųŴżŻɉŻźżŷȏɎŴżŷŷɉŷųŶŹɎ2¶¸¯´"¸Ɏ

/»¨²¯¹®¯´Ɏ

"µ³¶§´¿ɎɎŶźɎ!µ º®Ɏ-µɎųȌŵŵŵ ɎɎ

ŶŶȌ

Ɏ ´º®¸µ¶µ²µ¿ɎȊɎ ¯´ Ɏ

Ș¬µ¸³"¸²¿Ɏ ´º®¸µ¶µ²µ¿Ɏ4´¯¼"¸¹¯º¿Ɏµ¬Ɏ/¯ºº¹¨»¸®ɎɎŶŻɎ.´²¯´"Ɏ 8"¹ȏɎ &$Ɏ,"³¨"¸¹®¯¶ɎɎɎ

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

ȊɎ ¯´Ɏ0»§¸º"¸²¿șɎ ŵŶźŷɉŵŵŹźɎ¸"·»¯¸"ªɎ

ŶŷȌ

Ɏ ¸©®¯¼"¹Ɏµ¬Ɏ&"¸µ´ºµ²µ¿Ɏ§´ªɎ&"¸¯§º¸¯©¹Ɏ

ųŴŹźɉŷżŷŶɎ$²¹"¼¯"¸ɎɎźŷɎ!µ º®Ɏ8"¹ɎŵȌųŻŹɎ Ɏ

ŶŸȌ

Ɏ ¹¯§´Ɏ)µ»¸´§²Ɏµ¬Ɏ

&"¸µ´ºµ²µ¿ɎȊɎ&"¸¯§º¸¯©Ƀ¹Ɏ'µ´Ɏ*µ´Ɏ

&"¸¯§º¸¯©¹Ɏ2µ©¯"º¿Ɏ

ȊɎ'µ´Ɏ*µ´Ɏ

¹¹µ©¯§º¯µ´Ɏµ¬Ɏ

&"¸µ´ºµ²µ¿ɎɎŴŵɎ/¸¯ ´ºɎ-µɎųȌŶŶɎ Ɏ

ŶŹȌ

Ɏ »¹º¸§²§¹¯§´Ɏ)µ»¸´§²Ɏµ´Ɏ "¯´Ɏ

ŴźŷŴɉŹŹŴŵɎ6¯²"¿ɉ!²§©±½"²²ɎɎŶŹɎ!µº®Ɏ .¶º¯µ´§²ȏɎ

/"ɎǻŵźųųɎųȌŻŵŸɎɎ

ŶźȌ

Ɏ!¯µ"¸µ´ºµ²µ¿ Ɏ

ŴŶŻżɉŸźŵżȏɎŴŸźŶɉŹźŹŻɎ2¶¸¯´"¸ɎɎŴżɎ.´ ²¯´"Ɏ8"¹ȏɎ /"ɎǻŶųųųɎŶȌŵŶŴɎɎ

ŶŻȌ

Ɏ!,"Ɏ&"¸¯§º¸¯©¹ Ɏ

ŴŷźŴɉŵŶŴŻɎ2¶¸¯´"¸Ɏ-§º»¸"ɎɎŴźɎ.´² ¯´"Ɏ8"¹ȏɎ /"ɎǻŵŴŷŸɎŵȌŹŴŴɎɎ

ŶżȌ

Ɏ"§´§ª¯§´Ɏ&"¸¯§º¸¯©¹Ɏ)µ»¸´§²Ɏ

ŴżŵŸɉŻŶŷŻɎ"§´§ª¯§´Ɏ

&"¸¯§º¸¯©¹Ɏ2µ©¯"º¿ɎɎŵųɎ.´²¯´"Ɏ 8"¹ȏɎ /"ɎǻżŸųɎȘ" #șɎųȌŷżŷɎɎ

ŷųȌ

Ɏ"§´§ª¯§´Ɏ)µ»¸´§²Ɏµ´Ɏ ¯´Ɏ

ųźŴŷɉżŻųŻȏɎŴźŴųɉŴŴųźɎ"§³¨¸¯ª"Ɏ4´¯¼"¸¹¯º¿Ɏ/¸"¹¹Ɏ

ɎŶźɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŴųżŸɎųȌźŶŷɎɎ

ŷŴȌ

Ɏ"²¯´¯©§²Ɏ&"¸µ´ºµ²µ¯¹º Ɏ

ųźŶŴɉźŴŴŸȏɎŴŸŷŸɉŵŶųŴɎ3§¿²µ¸ɎȊɎ%¸§´©¯¹Ɏ.´²¯´"ɎɎŷųɎ!µ º®Ɏ

Ș.´²¯´"șɎ.¶º¯µ´§²ɎųȌŸżŶ ɎɎ

ŷŵȌ

Ɏ"²¯´¯©§²Ɏ(´º"¸¼"´º¯µ´¹Ɏ¯´Ɏ ¯´Ɏ

ŴŴźŻɉŴżżŻɎ#µ¼"Ɏ/¸"¹¹ɎɎŴŶ Ɏ.´²¯´"Ɏ8"¹ȏɎ /"ɎǻŵŶŴųɎŵȌŸŻŴɎɎ

ŷŶȌ

Ɏ"²¯´¯©¹Ɏ¯´Ɏ&"¸¯§º¸¯©Ɏ,"ª¯©¯´"Ɏ

ųźŷżɉųŹżųɎ$²¹"¼¯"¸ɎɎŶŷɎ.´ ²¯´"Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŶųųųɎŵȌųŴųɎɎ

ŷŷȌ

Ɏ"µ´´"©º¯µ´¹ Ɏ

ŵŵųŹɉŷŷŴżȏɎŵŵųŹɉŷŷŵźɎ/§¸±¯´¹µ´ȟ¹Ɏ0»""´¹²§´ªɎɎŴŶɎȘ(¹¹»"¹șɎ.´²¯´"Ɏ8"¹Ɏ ɎɎ

ŷŸȌ

Ɏ"»¸¸"´ºɎ ¯´Ɏ2©¯"´©" Ɏ

ŴŻźŷɉŹųżŻȏɎŴŻźŷɉŹŴŵŻɎ!"´º®§³Ɏ2©¯"´©"ɎɎŴŴɎ!µ º®Ɏ.¶º¯µ´§²ɎŴȌŸŴ ɎɎ

ŷŹȌ

Ɏ"»¸¸"´ºɎ ²À®"¯³"¸Ɏ1"¹"§¸©®Ɏ

ŴŸŹźɉŵųŸųȏɎŴŻźŸɉŸŻŵŸɎ!"´º®§³Ɏ2©¯"´©"ɎɎŴŸɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŵżųųɎŵȌżŸŵɎɎ

ŷźȌ

Ɏ"»¸¸"´ºɎ&"¸¯§º¸¯©¹Ɏ1"¶µ¸º¹Ɏ

ŵŴżŹɉźŻŹŸɎ2¶¸¯´"¸Ɏ-§º»¸"ɎɎŹɎ.´² ¯´"Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŶųųųɎųȌŵżŻɎɎ

ŷŻȌ

Ɏ"»¸¸"´ºɎ&"¸µ´ºµ²µ¿Ɏ§´ªɎ&"¸¯§º¸¯©¹Ɏ1"¹"§¸©®Ɏ

ŴŹŻźɉźųŹŶȏɎŴŹŻźɉźųźŴɎ'¯´ª§½¯Ɏ+¯³¯º"ªɎɎŴųɎ !µº®Ɏ8"¹ȏɎ /"Ɏ

ǻźŸųɎųȌŷźŵɎɎ

ŷżȌ

Ɏ"»¸¸"´ºɎ.¶¯´¯µ´Ɏ¯´Ɏ

2»¶¶µ¸º¯¼"Ɏ§´ªɎ/§²²¯§º¯¼"Ɏ

"§¸"Ɏ

ŴźŸŴɉŷŵŸŻȏɎŴźŸŴɉŷŵŹŹɎ6µ²º"¸¹Ɏ*²»½"¸ɎɎŴŵɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŵŷųųɎŵȌųŷŸɎɎ

ŸųȌ

Ɏ#"³"´º¯§ Ɏ

ŴŷźŴɉŶųŴŵȏɎŴźŷŴɉŵŹŻŷɎ2 &$Ɏ/»¨²¯©§º¯µ´¹ɎɎŴŹɎ!µ º®Ɏ-µɎŴȌźŹŻ ɎɎ

ŸŴȌ

Ɏ#"³"´º¯§Ɏ§´ªɎ&"¸¯§º¸¯©Ɏ

"µ´¯º¯¼"Ɏ#¯¹µ¸ª"¸¹Ɏ2ȌɎ*§¸"¸Ɏ &Ɏ ɎŷŷɎ!µº®Ɏ .¶º¯µ´§²ȏɎ

/"ɎŶųųųɎŵȌŹŸɎɎ

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

ŴŷŵųɉŻųųŻȏɎŴŷŵŴɉżŻŵŷɎȘ"'%șɎ

ŸŵȌ

Ɏ#"³"´º¯§Ɏ§´ªɎ&"¸¯§º¸¯©Ɏ "µ´¯º¯¼"Ɏ#¯¹µ¸ª"¸¹Ɏ $¾º¸§Ɏ

ŴŹŹŷɉŸŷŹŷɎ2ȌɎ*§¸"¸Ɏ &Ɏ ɎźɎ.´² ¯´"Ɏ8"¹ȏɎ /"Ɏ

ŴŻųųɎȘ"'%șɎųȌŹŶŵɎɎ

ŸŶȌ

Ɏ#"³"´º¯§Ɏ§´ªɎ -"»¸µ©µ´¯º¯¼"Ɏ #¯¹µ¸ª"¸¹Ɏ ŴźŶŻɉŴŷżŸȏɎŵŶŻŷɉųźŸź Ɏ*µ¸"§´Ɏ#"³"´º¯§Ɏ ¹¹µ©¯§º¯µ´Ɏ ɎŴźɎ!µ º®Ɏ8"¹ɎɎɎ

ŸŷȌ

Ɏ#"³"´º¯§Ɏ"Ɏ -"»¸µ¶¹¿©®µ²µ¯§Ɏ Ɏ

ŴżŻųɉŸźŹŷɎ ¹¹µ©¯§ÐŵɎ-"»¸µ²µ¯§Ɏ

"µ´¯º¯¼§Ɏ"ɎªµɎ

"µ³¶µ¸º§³"´ºµɎɎŴŵɎ.´²¯´"Ɏ -µɎųȌŷŷɎɎ

ŸŸȌ

Ɏ#¸»¹Ɏ§´ªɎ ¯´ Ɏ

ŴŴźųɉŵŵż7ȏɎŴŴźżɉŴżŹżɎ2¶¸¯´"¸Ɏ-§º»¸"ɎɎŶŷɎ!µº®Ɏ .¶º¯µ´§²ȏɎ

/"ɎǻŶųųųɎŵȌźŹżɎɎ

ŸŹȌ

Ɏ$ª»©§º¯µ´§²Ɏ&"¸µ´ºµ²µ¿ Ɏ

ųŶŹųɉŴŵźźȏɎŴŸŵŴɉųŷźŵɎ3§¿²µ¸ɎȊɎ%¸§´©¯¹Ɏ

.´²¯´"ɎɎŷŷɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŵżŸųɎųȌŹźŷɎɎ

ŸźȌ

Ɏ$²ª"¸²¿Ɏ'"§²º®Ɏ)µ»¸´§² Ɏ ŵŷŵŶɉŹŴźżɎ2®§®¯ªɎ2§ªµ»®¯Ɏ

4´¯¼"¸¹¯º¿Ɏµ¬Ɏ

,"ª¯©§²Ɏ2©¯"´©"¹Ɏ

§´ªɎ'"§²º®Ɏ

2"¸¼¯©"¹ɎɎŷɎ.´² ¯´"Ɏ8"¹Ɏ ɎɎ

ŸŻȌ

Ɏ$»¸µ¶"§´Ɏ&"¸¯§º¸¯©Ɏ,"ª¯©¯´"Ɏ ŴŻźŻɉźŹŸźɎ2¶¸¯´"¸Ɏ-§º»¸"Ɏ

Ș¬µ¸³"¸²¿Ɏ

$²¹"¼¯"¸șɎɎŻɎ.´² ¯´"Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŶųųųɎŴȌŶŶŹɎɎ

ŸżȌ

Ɏ$»¸µ¶"§´Ɏ)µ»¸´§²Ɏµ¬Ɏ "¯´Ɏ

ŴŹŴŶɉżŶźŵȏɎŴŹŴŶɉżŶŻųɎ2¶¸¯´"¸Ɏ-§º»¸"ɎɎŴŸɎ!µº®Ɏ 4´±´µ½´Ɏ ŴȌŴźźɎɎ

ŹųȌ

Ɏ$»¸µ¶"§´Ɏ1"¼¯"½Ɏµ¬Ɏ ¯´Ɏ§´ªɎ/®¿¹¯©§²Ɏ ©º¯¼¯º¿Ɏ

ŴŻŹŴɉŹżųżɎ2¶¸¯´"¸Ɏ-§º»¸"ɎɎŴŷɎ.´² ¯´"Ɏ8"¹ȏɎ /"Ɏ

ǻŵŴŷŸɎŵȌŴŸŷɎɎ

ŹŴȌ

Ɏ$¾¶"¸¯³"´º§²Ɏ ¯´Ɏ1"¹"§¸©®Ɏ

ųŶŹŴɉųźŶ7ȏɎŴųżŹɉŷŹŸźɎ3§¿²µ¸ɎȊɎ%¸§´©¯¹Ɏ

.´²¯´"ɎɎŷŶɎ!µ º®Ɏ.¶º¯µ´§²ɎŴȌŶŷŸ ɎɎ

ŹŵȌ

Ɏ$¾¶"¸¯³"´º§²Ɏ&"¸µ´ºµ²µ¿Ɏ

ųŸŶŴɉŸŸŹŸɎ$²¹"¼¯"¸ɎɎŴųŴɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŵźŸųɎŶȌŶŷųɎɎ

ŹŶȌ

Ɏ%µ©»¹Ɏµ´Ɏ'"§²º®¿Ɏ ¯´ Ɏ Ș,µ»´ºɎ2¯´§¯Ɏ2©®µµ²Ɏµ¬Ɏ ,"ª¯©¯´"șɎ!"²¼µ¯¸Ɏ,"ª¯§Ɏ &¸µ»¶Ɏ++"ɎɎŵųɎ!µ º®Ɏ-µɎɎ Ɏ

ŹŷȌ

Ɏ%¸µ´º¯"¸¹Ɏ¯´Ɏ ¯´Ɏ-"»¸µ¹©¯"´©"Ɏ

ŴŹŹŶɉŷŶŹŸɎ%¸µ´º¯"¸¹Ɏ,"ª¯§Ɏ

2 ɎɎŴŹżųɎɎ§¸º¯©²"¹Ɏ.´²¯´"Ɏ8"¹ȏɎ /"ɎǻŵżŸųɎŴȌŹŶŻɎɎ

ŹŸȌ

Ɏ&"´"¸§º¯µ´¹ Ɏ

ųźŶŻɉźŻųŹɎ ³"¸¯©§´Ɏ2µ©¯"º¿Ɏµ´Ɏ ¯´ɎɎŷŵɎ/¸¯ ´ºɎ

Ș.´²¯´"Ɏ¬µ¸Ɏ

³"³¨"¸¹șɎ-µɎųȌŶŴ ɎɎ

ŹŹȌ

Ɏ&Ô¸¯§º¸¯"Ɏ"ºɎ/¹¿©®µ²µ¯"Ɏ -"»¸µ¶¹¿©®¯§º¸¯"Ɏª»Ɏ

5¯"¯²²¯¹¹"³"´ºɎ

ŵŴŴŸɉŻźŻżȏɎŵŴŴŸɉźŻŹŶɎ)µ®´Ɏ+¯¨¨"¿Ɏ

$»¸µº"¾ºɎɎŴŹɎ!µ º®Ɏ-µɎųȌŶŶ ɎɎ

ŹźȌ

Ɏ&"¸¯§º¸¯©Ɏ"§¸"Ɏ/ &$/¸"¹¹ɎɎŷ Ɏ.´²¯´"Ɏ8"¹Ɏ ɎɎ

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

ŵŷŹŸɉŴŴųżȏɎŵŷŹŸɉŴŶżźɎ

ŹŻȌ

Ɏ&"¸¯§º¸¯©Ɏ-»¸¹¯´ Ɏ

ųŴżźɉŷŸźŵɎ$²¹"¼¯"¸ɎɎŶŻɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŵųųųɎŴȌŴŷŵɎɎ

ŹżȌ

Ɏ&"¸¯§º¸¯©Ɏ.¸º®µ¶§"ª¯©Ɏ2»¸"¸¿ɎȊɎ1"®§¨¯²¯º§º¯µ´Ɏ

ŵŴŸŴɉŷŸżŶȏɎŵŴŸŴŷŸżŶɎ2 &$Ɏ /»¨²¯©§º¯µ´¹ɎɎŻɎ!µ º®Ɏ8"¹ȏɎ /"Ɏ ǻŴŵųųɎųȌŵżŴɎɎ

źųȌ

Ɏ&"¸¯§º¸¯©¹ Ɏ

ŵŶųŻɉŶŷŴźɎ,#/(ɎɎŵɎ.´² ¯´"Ɏ8"¹ȏɎ-µɎ /"Ɏ¯´ɎŵųŴŻɎɎ/µ¹¹¯¨²¿ɎȘ!"§²²ȟ¹Ɏ+¯¹ºșɎ

źŴȌ

Ɏ&"¸¯§º¸¯©¹Ɏ§´ªɎ &"¸µ´ºµ²µ¿Ɏ (´º"¸´§º¯µ´§²Ɏ

ŴŷŷźɉųŸżŷɎ6¯²"¿ɎɎŴŻɎ.´²¯´"Ɏ .¶º¯µ´§²ȏɎ /"ɎǻŶųųųɎŵȌŶŸŴɎɎ

źŵȌ

Ɏ&"¸µªµ´ºµ²µ¿ Ɏ

ŴźŷŴɉŵŶŸŻɎ6¯²"¿ɎɎŶŸɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŵŸųųɎŴȌŹŻŴɎɎ

źŶȌ

Ɏ&"¸µ(´¬µ Ɏ

ŴŻŴŹɉŻŷŸųɎ,"ª¯¸§¶®¯©ɎɎŴŶɎ.´²¯´"Ɏ 8"¹Ɏ ɎɎ

źŷȌ

Ɏ&"¸µ±µ³µ¹ Ɏ

ŴŴŶŷɉżŵŻ7Ɏ1µ´ª§Ɏª"Ɏ2§´ºɎ/"¸"ɎɎŵŻɎ!µ º®Ɏ8"¹ɎųȌŷɎ Ɏ

źŸȌ

Ɏ&"¸µ´º"©®´µ²µ¿ Ɏ ŴŸŹżɉŴŴųŴɎ(´º"¸´§º¯µ´§²Ɏ

2µ©¯"º¿Ɏ¬µ¸Ɏ

&"¸µ´º"©®´µ²µ¿ɎɎŴźɎ!µ º®Ɏ8"¹ȏɎŴɉ¿"§¸Ɏ

"³¨§¸µɎųȌŵɎɎ

źŹȌ

Ɏ&"¸µ´ºµ²µ¯¹ºȍɎ3®" Ɏ

ųųŴŹɉżųŴŶȏɎŴźŸŻɉŸŶŷŴɎ.¾¬µ¸ªɎ ©§ª"³¯©ɎɎŸźɎ!µ º®Ɏ-µɎŶȌŸųŸ ɎɎ

źźȌ

Ɏ&Ô¸µ´ºµ²µ¯"Ɏ"ºɎ¹µ©¯ÔºÔ Ɏ

ųŴŸŴɉųŴżŶȏɎŵŴųŴɉųŵŴŻɎ"§¯¹¹"Ɏ´§º¯µ´§²"Ɏ

ªȤ§¹

¹»¸§

´©"Ɏ

¼¯"¯²²"¹¹"ɎɎŷųɎ!µ º®Ɏ-µɎųɎ Ɏ

źŻȌ

Ɏ&"¸µ´ºµ²µ¿ Ɏ

ųŶųŷɉŶŵŷ7ȏɎŴŷŵŶɉųųųŶɎ2ȌɎ*§¸"¸Ɏ &ɎɎŹŶɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎŶųųųɎ

Ș"'%șɎŷȌŵŸŵɎɎ

źżȌ

Ɏ&"¸µ´ºµ²µ¿Ɏ§´ªɎ&"¸¯§º¸¯©Ɏ,"ª¯©¯´"Ɏ

ŵŶŶŶɉźŵŴŷɎ2 &$Ɏ

/»¨²¯©§º¯µ´¹ɎɎŶɎ.´² ¯´"Ɏ8"¹ȏɎǻŴŵųųɎɎ Ɏ

ŻųȌ

Ɏ&"¸µ´ºµ²µ¿Ɏ§´ªɎ&"¸¯§º¸¯©¹Ɏ

ųųŴŷɉŷŵŷ7Ɏ$¾©"¸¶º§Ɏ,"ª¯©§Ɏ%µ»´ª§º¯µ´Ɏ

ɎŹŴɎ/¸¯ ´ºɎ4´±´µ½´Ɏ ɎɎ

ŻŴȌ

Ɏ&"¸µ´ºµ²µ¿ɎȊɎ&"¸¯§º¸¯©Ƀ¹Ɏ$ª»©§º¯µ´Ɏ

ųŵźųɉŴżŹųȏɎŴŸŷŸɉŶŻŷźɎ3§¿²µ¸ɎȊɎ%¸§´©¯¹Ɏ

.´²¯´"ɎɎŶŻɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŵżŸųɎųȌŹŶɎɎ

ŻŵȌ

Ɏ&"¸µ´ºµ²µ¿ɎȊɎ

&"¸¯§º¸¯©¹ȎɎ1"¹"§¸©®Ɏ »¹º¯´Ɏ/»¨²¯¹®¯´Ɏ&¸µ»¶ɎɎŵɎ.´² ¯´"Ɏ8"¹ȏɎ /"ɎǻŴŻųųɎɎ 8"¹ɎȘ!"§²²ȟ¹Ɏ

+¯¹ºșɎ

ŻŶȌ

Ɏ&"¸µ/¹¿©®ȎɎ3®"Ɏ)µ»¸´§²Ɏ µ¬Ɏ&"¸µ´ºµ¶¹¿©®µ²µ¿Ɏ §´ªɎ&"¸¯§º¸¯©Ɏ/¹¿©®¯§º¸¿Ɏ

ŴŹŹŵɉżŹŷźȏɎŴŹŹŵɉżźŴ7Ɏ'µ¸"¬"Ɏ &ɎɎŶųɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŶųųųɎųȌŶŹɎɎ

ŻŷȌ

Ɏ&"¸µ2©¯"´©"ȎɎ.¬¬¯©¯§²Ɏ )µ»¸´§²Ɏµ¬Ɏº®"Ɏ ³"¸¯©§´Ɏ ¯´Ɏ ¹¹µ©¯§º¯µ´Ɏ

Ș¬µ¸³"¸²¿Ɏ &$șɎ

ŵŸųżɉŵźŴŸȏɎŵŸųżɉŵźŵŶɎ2¶¸¯´"¸Ɏ-§º»¸"ɎɎŶżɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŶųųųɎŵȌŴŵŶɎɎ

ŻŸȌ

Ɏ&²µ¨§²Ɏ "¯´Ɏ)µ»¸´§² Ɏ

ŴźŵżɉŶŷźŵɎ(´º"¸´§º¯µ´§²Ɏ%"ª"¸§º¯µ´Ɏµ´Ɏ

"¯´ɎɎżɎ.´² ¯´"Ɏ4´±´µ½´ɎɎɎ

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

©¹ȏ µ>-ɎŸ -$)Ɏ.41 -$Ɏŵ$>+4Ǹ Ŵ4ǸŻŹ$3.4ŹǸ1§$ ¹¿´½ª¿´¿BȌ$¹¿¨±ª¼´¨½$3+C$¯+1Ŵ.4ż$

8ŻǸ+1Ż+$/4+ŹŹ$%%¯$$±$Ŷ1- Ǹ1+$Ƀ+ŹȌ$"/¯$³²·´$$Ƀ+Ź$(5+ --ȒŹ$%ǸŹŴŷ$

©®ȏ

µ>G $ ´¹·ª¹´²B$/ ¸Ǹ-ǸɎ1$/.Ÿ-ǸŹźǸ1§$ 1µ$ G+µǸ $$¼¨$5Ɏ Ŵź$Ƀ+Ź$$$

©©ȏ

µA+ -Ŵźż$"§Ǹ1§$©+Ź+ 4Żź $

¹¹·²ª¨¼¿¼$EɎ-Ŵ+4Ź$H-.C+4$$¨$Ŷ1- Ǹ1+$Ƀ+ŹȌ$"/¯$³²±´´$$$

©¿ȏ

µA+ -Ŵźż$Ƀ+ 4Ź$(D¯%"$ G+µǸŻ -$¯+1Ŵ+4ŷ$5+-¸ɎǸ4$G+µǸ $ >4Ɏ.®$%%¯$$²¼$5Ɏ Ŵź$3Ɏ$$ $

¿5ȏ

µ"!!.1ǸŴż$»$"§+Ǹ1§I$"$»$"$

²¨¼¹ª¼½¿¿$"¶/$G+µǸ $$²¼$Ŷ1-Ǹ1+$ Ƀ+ŹȌ$"/¯$

³¹²¼±$¹#¹²·$$

¿ºȏ

µ"1µǸ 1$)Ɏ.41 -$Ɏŵ $ >+4Ǹ Ŵ4ǸŻ$¯ 4+ $

´½¨¼ª¿¼´±Ȍ$´½¨¼ª¹¼¼$>+4Ǹ Ŵ4ǸŻ$8ɎŻǸ+Ŵż$

Ɏŵ$"1µǸ $$±$/4Ǹ 1Ŵ$3Ɏ$$$

¿¬ȏ

µ"1µǸ 1$)Ɏ.41 -$Ɏŵ$>+4Ɏ1ŴɎ-Ɏ§ż$ ´½¨²ª¼²½$>+4Ɏ1ŴɎ-Ɏ§ż$"1µǸ $ $¿¹$5Ɏ Ŵź$3Ɏ$$ $

¿.ȏ

µ"11Ɏ¸ ŴǸɎ1$Ǹ1$"§Ǹ1§ $

¹¿½½ª±¿´´$Ŷ@ŵɎ4µ$"Ż µ+!ǸŻ$$²$Ŷ1- Ǹ1+$Ƀ+ŹȌ$"/¯$³¹±´´$$$

¿șȏ

µ"1Ŵ+4µǸŹŻǸ®-Ǹ1 4ż$'Ɏ®ǸŻŹ$

Ǹ1$>+4Ɏ1ŴɎ-Ɏ§ż$ 1µ$

>+4Ǹ Ŵ4ǸŻŹ$

¹¹½¨ª¿±´Ȍ$¹¹½¨ª¿¼·$H 4§+4$$¼¹$5Ɏ Ŵź$3Ɏ$¹$ $

¿¨ȏ

µ"1Ŵ+41 ŴǸɎ1 -$)Ɏ.41 -$Ɏŵ$"§+Ǹ1§$ 1µ$% Ŵ+4$%Ǹŵ+$ ²·±¹ª·¨´$%Ǹ1ºQ®Ǹ1§$

D1Ǹ¸+4ŹǸŴż$

?-+ŻŴ4Ɏ1ǸŻ$/4+ŹŹ$$²²$Ŷ1-Ǹ1+$ Ƀ+Ź$ ´#¼¿$$

¿¹ȏ

µ"1Ŵ+41 ŴǸɎ1 -$)Ɏ.41 -$Ɏŵ$ "§Ǹ1§$ 1µ$A.! 1$ =+¸+-Ɏ®!+1Ŵ°$'ź+$ ´´½²ª¼²±´Ȍ$²±¼²ª¿±¿±$8">?$ /.Ÿ-ǸŻ ŴǸɎ1Ź$$±$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$ "/¯$³¿´´´$´#²$$

¿®ȏ

µ"1Ŵ+41 ŴǸɎ1 -$)Ɏ.41 -$Ɏŵ$"§Ǹ1§$ 1µ$8ɎŻǸ+Ŵż$

¹²·´ª²½´½Ȍ$¹²·´ª²½²¨$¯Ɏ!!Ɏ1$>4Ɏ.1µ$

©+Ź+ 4Żź$

3+ŴCɎ4ºŹ$$¨$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³¹±´$$$

¿©ȏ

µ"1Ŵ+41 ŴǸɎ1 -$)Ɏ.41 -$Ɏŵ$ "-<ź+Ǹ!+4Ź$»$

3+.4Ɏ-Ɏ§ǸŻ -$=ǸŹɎ4µ+4Ź$

$5ǸɎ"ŻŻ+1Ŵ$$²$Ŷ1- Ǹ1+$Ƀ+ŹI$$"/¯$³¨±´2³±´´$$ Ƀ+ŹI$(5+ --ȒŹ$

%ǸŹŴŷ$

¿¿ȏ

µ"1Ŵ+41 ŴǸɎ1 -$)Ɏ.41 -$Ɏŵ$"-<ź+Ǹ!+4ȒŹ$=ǸŹ+ Ź+$

¹´½´ª´¹¼Ȍ$¹´½´ª´¹±¹$AǸ1µ CǸ$%Ǹ!ǸŴ+µ$$½$5Ɏ Ŵź$Ƀ+ŹȌ$"/¯$

³¨±´$´#¨¨$$

º55ȏ

µ"1Ŵ+41 ŴǸɎ1 -$)Ɏ.41 -$Ɏŵ$?µ.Ż ŴǸɎ1$ 1µ$"§+Ǹ1§$ ¹´¼¼ª±¼±$"ŹŹɎŻǸ ŴǸɎ1$ŵɎ4$ ?µ.Ż ŴǸɎ1$»$ "§+Ǹ1§$("?"ŷ$$¼$/4Ǹ 1Ŵ$3Ɏ$$$

º5ºȏ

µ"1Ŵ+41 ŴǸɎ1 -$)Ɏ.41 -$Ɏŵ$>+4Ǹ Ŵ4ǸŻ$/ŹżŻźǸ Ŵ4ż$

²´½½ª²²··$EǸ-+ż$$¿¹$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³¿±±´$¿#´²$$

º5¬ȏ

µ"1Ŵ+41 ŴǸɎ1 -$)Ɏ.41 -$Ɏŵ$>+4Ɏ1ŴɎ-Ɏ§ż$

²¨¿ª½±½$?-Ź+¸Ǹ+4$$²²$Ŷ1-Ǹ1+$ Ƀ+ŹȌ$"/¯$³¹´´ª¨´´$´#¿½·$$

º5.ȏ

µ"1Ŵ+41 ŴǸɎ1 -$)Ɏ.41 -$Ɏŵ$EǸ-+ż$$²¿$Ŷ1-Ǹ1+$ Ŷ®ŴǸɎ1 -Ȍ$ ²#¿¿¿$$

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

.²ª"¸Ɏ/"µ¶²"Ɏ-»¸¹¯´Ɏ

ŴźŷŻɉŶźŶŸȏɎŴźŷŻɉŶźŷŶɎ /"ɎǻŵŸųųɎ

ŴųŷȌ

Ɏ(´º"¸´§º¯µ´§²Ɏ/¹¿©®µ"¸¯§º¸¯©¹Ɏ

ŴųŷŴɉŹŴųŵȏɎŴźŷŴɉŵųŶ7Ɏ"§³¨¸¯ª"Ɏ

4´¯¼"¸¹¯º¿Ɏ/¸"¹¹ɎɎŵżɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŵŻŶŸɎŵȌŷŵŶɎɎ

ŴųŸȌ

Ɏ(´º"¸´"ºɎ)µ»¸´§²Ɏµ¬Ɏ &"¸¯§º¸¯©¹Ɏ§´ªɎ &"¸µ´ºµ²µ¿ȍɎ3®"Ɏ

ŴżŶźɉŻŵŴŴɎ(´º"¸´"ºɎ2©¯"´º¯¬¯©Ɏ

/»¨²¯©§º¯µ´¹ɎɎżɎ.´² ¯´"Ɏ8"¹ȏɎ/»¨²¯©§º¯µ´Ɏ

¬""ɎǻŵźŸɎɎ 8"¹ɎȘ!"§²²ȟ¹Ɏ +¯¹ºșɎ

ŴųŹȌ

Ɏ)§¶§´"¹"Ɏ)µ»¸´§²Ɏµ¬Ɏ&"¸¯§º¸¯©¹Ɏ

ųŶųųɉżŴźŶɎ3®"Ɏ)§¶§´"¹"Ɏ&"¸¯§º¸¯©¹Ɏ2µ©¯"º¿Ɏ

ɎŸŸɎ.´²¯´"Ɏ 8"¹Ɏ ųȌŴŵɎɎ

ŴųźȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ¯´Ɏ§´ªɎ&"¸¯§º¸¯©Ɏ,"ª¯©¯´"Ɏ

ŵŸźŹɉŶżŷŹɎ2©¯3"©®´µ²ɎɎŴɎ.´² ¯´"Ɏ8"¹ȏɎ /"ɎǻżŷżɎɎ 8"¹ɎȘ!"§²²ȟ¹Ɏ

+¯¹ºșɎ

ŴųŻȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ¯´Ɏ§´ªɎ

&"¸¯§º¸¯©Ɏ/¹¿©®¯§º¸¿Ɏ ²²¯"ªɎ ©§ª"³¯©¹ɎɎŴɎ.´² ¯´"Ɏ8"¹ȏɎ /"Ɏ

ǻźŴżɎɎɎ

ŴųżȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ¯´Ɏ§´ªɎ'"§²º®Ɏ ųŻżŻɉŵŹŷŶȏɎŴŸŸŵɉŹŻŻźɎ2 &$Ɏ

/»¨²¯©§º¯µ´¹ɎɎŵżɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŶųųųɎŵȌŴŹŻɎɎ

ŴŴųȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ¯´Ɏ+¯¬"Ɏ

"§¸"Ɏ ¯´Ɏ+¯¬"Ɏ"§¸"Ɏ ¹¹µ©¯§º¯µ´ɎɎŴŵɎ.´²¯´"Ɏ 4´±´µ½´ɎɎɎ

ŴŴŴȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ¯´Ɏ§´ªɎ +µ´ɉ3"¸³Ɏ"§¸"Ɏ ŵŹŴżɉżųŴźȏɎŵŹŴŻɉŹŸŶŸ

Ɏ-§º¯µ´§²Ɏ

¹¹µ©¯§º¯µ´Ɏµ¬Ɏ

2µ©¯§²Ɏ§´ªɎ

¶¶²¯"ªɎ &"¸µ´ºµ²µ¿ɎɎŴɎ!µ º®Ɏ-µɎɎ Ɏ

ŴŴŵȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ¯´Ɏ§´ªɎ/®¿¹¯©§²Ɏ ©º¯¼¯º¿Ɏ

ŴųŹŶɉŻŹŸŵȏɎŴŸŷŶɉŵŹź7Ɏ º¿¶µ´Ɏ+¯º"¸§º»³ɎɎŵŸɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŵųųųɎŴȌżŶźɎɎ

ŴŴŶȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ¯´Ɏ1"¹"§¸©®Ɏ

ŵųżųɉŵŵųŷɎ'¯´ª§½¯Ɏ+¯³¯º"ªɎɎŻɎ!µ º®Ɏ8"¹ȏɎ /"Ɏ

ǻźŸųɎųȌźŹżɎɎ

ŴŴŷȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ¯´Ɏ

1"¹"§¸©®ɎȊɎ"²¯´¯©§²Ɏ

/¸§©º¯©"Ɏ

ŵŵźŶɉŷŵŴ7Ɏ( &&ɎȊɎ& 1-ɎɎŹɎ.´² ¯´"Ɏ8"¹ȏɎ /"Ɏ4´±´µ½´ɎɎɎ

ŴŴŸȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ¯´Ɏ1"¹"§¸©®Ɏ§´ªɎ'"§²º®©§¸"Ɏ

ŵŷźŷɉźźŻŸɎ.¶"´Ɏ ©©"¹¹Ɏ/»¨ɎɎŵɎɎ.´²¯´"Ɏ 8"¹ȍɎ /"Ɏ

ǻŴȍŵųųɎɎ8"¹ɎȘ!"§²²ȟ¹Ɏ+¯¹ºșɎ

ŴŴŹȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ¯´Ɏ2©¯"´©" Ɏ

ŵŶŵżɉŻŻŷźɎ.,("2Ɏ

(´º"¸´§º¯µ´§²ɎɎŸɎ.´² ¯´"Ɏ8"¹ȏɎ /"ɎǻŴųųųɎųȌŸųɎ8"¹ɎȘ!"§²²ȟ¹Ɏ

+¯¹ºșɎ

ŴŴźȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ¯´Ɏ§´ªɎ2µ©¯§²Ɏ/µ²¯©¿Ɏ

ųŻżŸɉżŷŵųȏɎŴŸŷŸɉųŻŵŴɎ3§¿²µ¸ɎȊɎ%¸§´©¯¹Ɏ

.´²¯´"ɎɎŵżɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŵżŸųɎŴȌŵŸŹɎɎ

ŴŴŻȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ¯´Ɏ2º»ª¯"¹ Ɏ

ųŻżųɉŷųŹŸɎ$²¹"¼¯"¸ɎɎŷŷɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŴŻųųɎŴȌŵŷŻɎɎ

ŴŴżȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ²À®"¯³"¸ȟ¹Ɏ #¯¹"§¹"Ɏ

ŴŶŻźɉŵŻźźȏɎŴŻźŸɉŻżųŻɎ(.2Ɏ/¸"¹¹ɎɎŹŷɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŴŷŸųɎ

Ș¶²»¹ɎǻźųųɎ

©®§¸"șɎŶȌźŶŴɎɎ

ŴŵųȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ²À®"¯³"¸ȟ¹Ɏ.,("2ɎɎźɎ.´² ¯´"Ɏ8"¹ȏɎ /"Ɏ ŶȌųŶɎ8"¹ɎȘ!"§²²ȟ¹Ɏ

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

#¯¹"§¹"Ɏ§´ªɎ /§¸±¯´¹µ´¯¹³Ɏ

ŵŴŹŴɉųŷŹųɎ(´º"¸´§º¯µ´§²ɎǻŶŴŹŵɎ+¯¹ºșɎ

ŴŵŴȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ²À®"¯³"¸ȟ¹Ɏ #¯¹"§¹"Ɏ1"¶µ¸º¹Ɏ

ŵŸŷŵɉŷŻŵŶɎ(.2Ɏ/¸"¹¹ɎɎŵɎ.´² ¯´"Ɏ8"¹ȏɎ /"Ɏ

ǻźŵŸɎ¬µ¸Ɏ¬¯¸¹ºɎ

º½µɎ¿"§¸¹Ɏµ¬Ɏ

¶»¨²¯©§º¯µ´ɎɎɎ

ŴŵŵȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ ¶¶²¯"ªɎ&"¸µ´ºµ²µ¿Ɏ

ųźŶŶɉŷŹŷŻȏɎŴŸŸŵɉŷŸŵŶɎ2 &$Ɏ/»¨²¯©§º¯µ´¹Ɏ

ɎŶŹɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŶųųųɎŴȌŹŶŻɎɎ

ŴŵŶȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ"²¯´¯©§²Ɏ &"¸µ´ºµ²µ¿Ɏ§´ªɎ &"¸¯§º¸¯©¹Ɏ

ŵŵŴųɉŻŶŶŸɎ"µ´º"´ºɎ$ªɎ-"ºɎ3§¯½§´Ɏ+¯³¯º"ªɎ

Ș¬µ¸³"¸²¿Ɏ

$²¹"¼¯"¸șɎɎŻɎ.´² ¯´"Ɏ8"¹Ɏ ųȌŻŵɎɎ

ŴŵŷȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ"¸µ¹¹ɉ"»²º»¸§²Ɏ&"¸µ´ºµ²µ¿Ɏ

ųŴŹżɉŶŻŴŹȏɎŴŸźŶɉųźŴżɎ2¶¸¯´"¸Ɏ-§º»¸"ɎɎŶŵɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŶųųųɎųȌźŶŷɎɎ

ŴŵŸȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ#"³"´º¯§Ɏ"§¸" Ɏ ŴŶŸŴɉŻŶźŵɎ'§½±"¸Ɏ

/»¨²¯©§º¯µ´¹Ɏ+ºªȌɎɎɎŵŸɎ!µ º®Ɏ-µɎųȌųŸ ɎɎ

ŴŵŹȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ$²ª"¸Ɏ ¨»¹"ɎȊɎ -"²"©ºɎ

ųŻżŷɉŹŸŹŹȏɎŴŸŷųɉŷŴŵżɎ3§¿²µ¸ɎȊɎ%¸§´©¯¹Ɏ.´²¯´"Ɏ

ɎŵżɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŵżŸųɎŴȌŶŹɎɎ

ŴŵźȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ%¸§¯²º¿ɎȊɎ ¯´ȍɎ3®"Ɏ

ŵŵŹųɉŴŶŷŴȏɎŵŵźŶɉŷŶųżɎ3µ»²µ»¹"ɎȎɎ2"¸ª¯Ɏ$ª¯º¯µ´Ɏ

ɎźɎ!µ º®Ɏ2µ³"Ɏ%¸""Ɏ ©©"¹¹Ɏ ¼§¯²§¨²"ȏɎ /%ɎǻŶŵŻɃ¶Ɏ §¬º"¸ɎŵɎ¶§"¹ɎųȌŸźŶɎɎ

ŴŵŻȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ&"¸¯§º¸¯©Ɏ "§¸ª¯µ²µ¿Ɏ

ŴŹźŴɉŸŷŴŴɎ2©¯"´©"Ɏ/¸"¹¹ɎɎŴŷɎ.´²¯´"Ɏ 8"¹ȏɎ /"Ɏ

ǻŴŹŸųɎŴȌŻųŹɎɎ

ŴŵżȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ&"¸¯§º¸¯©Ɏ ,"´º§²Ɏ'"§²º®Ɏ

ŵŶŷŻɉżżżŸȏɎŵŶżŸɉŶŶŵŵɎ(´ª¯§´Ɏ ¹¹µ©¯§º¯µ´Ɏ¬µ¸Ɏ

&"¸¯§º¸¯©Ɏ,"´º§²Ɏ '"§²º®ɎɎŷɎ!µ º®Ɏ8"¹ɎɎɎ

ŴŶųȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ&"¸¯§º¸¯©Ɏ .´©µ²µ¿Ɏ

ŴŻźżɉŷųŹŻɎ$²¹"¼¯"¸ɎɎżɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŴźųųɎŵȌŻŸŵɎɎ

ŴŶŴȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ&"¸¯§º¸¯©Ɏ /®¿¹¯©§²Ɏ3®"¸§¶¿Ɏ

ŴŸŶżɉŻŷŴŵȏɎŵŴŸŵɉųŻżŸɎ6µ²º"¸¹Ɏ*²»½"¸ɎɎŷųɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŵźųųɎŴȌŻŶŶɎɎ

ŴŶŵȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ&"¸¯§º¸¯©Ɏ /¹¿©®¯§º¸¿Ɏ§´ªɎ -"»¸µ²µ¿Ɏ

ųŻżŴɉżŻŻźȏɎŴŸŸŵɉŸźųŻɎ2 &$Ɏ/»¨²¯©§º¯µ´¹Ɏ

ɎŶųɎ!µ º®Ɏ-µɎŵȌŴųż ɎɎ

ŴŶŶȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ&"¸µ´ºµ²µ¯©§²ɎɃ -»¸¹¯´Ɏ

ųųżŻɉżŴŶŷȏɎŴżŶŻɉŵŷŶ7Ɏ'"§²¯µɎɎŷŶɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŴŸųųɎųȌŻŵźɎɎ

ŴŶŷȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ&"¸µ´ºµ²µ¯©§²ɎɃ2µ©¯§²Ɏ6µ¸±Ɏ

ųŴŹŶɉŷŶźŵȏɎŴŸŷųɉŷųŷŻɎ3§¿²µ¸ɎȊɎ%¸§´©¯¹Ɏ.´²¯´"Ɏ

ɎŹųɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŵżŸųɎųȌŸŴŶɎɎ

ŴŶŸȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ&"¸µ´ºµ²µ¿Ɏ

§´ªɎ&"¸¯§º¸¯©¹ɎȘ¬µ¸³"¸²¿Ɏ/§©¯´¯Ɏ$ª¯ºµ¸"Ɏ21+ɎɎŹŹɎ.´²¯´"Ɏ 8"¹Ɏ ųȌŴŵŴɎɎ

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

&¯µ¸´§²"Ɏª¯Ɏ&"¸µ´ºµ²µ¯§șɎ

ŵŷżżɉŹŸŹŷɎ

ŴŶŹȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ&"¸µ´ºµ²µ¿Ɏ §´ªɎ&"¸¯§º¸¯©Ɏ1"¹"§¸©®Ɏ

ŵŴŹźɉźŴŻŵɎ.,("2Ɏ

(´º"¸´§º¯µ´§²ɎɎŹɎ.´² ¯´"Ɏ8"¹ȏɎ /"ɎǻŵźŴżɎųȌżŵɎ8"¹ɎȘ!"§²²ȟ¹Ɏ

+¯¹ºșɎ

ŴŶźȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ'"§²º®Ɏ§´ªɎ2µ©¯§²Ɏ!"®§¼¯µ¸Ɏ

ųųŵŵɉŴŷŹŸȏɎŵŴŸųɉŹųųųɎ2 &$Ɏ

/»¨²¯©§º¯µ´¹ɎɎŸżɎ!µ º®Ɏ-µɎŴȌżŷż ɎɎ

ŴŶŻȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ'µ»¹¯´Ɏ¬µ¸Ɏº®"Ɏ$²ª"¸²¿Ɏ

ųŵźŹɉŶŻżŶȏɎŴŸŷųɉŶŸŶ7 Ɏ3§¿²µ¸ɎȊɎ%¸§´©¯¹Ɏ.´²¯´"Ɏ ɎŶŵɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŵżŸųɎųȌŴŻŹɎɎ

ŴŶżȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ (´º"¸"´"¸§º¯µ´§²Ɏ

1"²§º¯µ´¹®¯¶¹Ɏ

ŴŸŶŸɉųźźųȏɎŴŸŶŸɉųżŶŵɎ3§¿²µ¸ɎȊɎ%¸§´©¯¹Ɏ.´²¯´"ɎɎ

ɎŴŹɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŵżŸųɎųȌŷŷɎɎ

ŴŷųȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ*µ¸"§´Ɏ &"¸¯§º¸¯©Ɏ/¹¿©®¯§º¸¿Ɏ

ŴŵŵŹɉŹŶŵżɎ2Ă»²ɎȎɎ3§"®§´Ɏ-µ¯´Ɏ"®Ă´¹¯´Ɏ“¯®§±®µ"ɎɎŵŵɎ/¸¯ ´ºɎ-µɎɎɎ

ŴŷŴȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ,"´º§²Ɏ'"§²º®ɎɃ

§´ªɎ ¯´Ɏ ²²¯"ªɎ ©§ª"³¯"¹ɎɎŵɎ.´² ¯´"Ɏ8"¹ȏɎɎ /"ɎǻŸŴżɎɎ 8"¹ȍɎȘ!"§²²ȟ¹Ɏ

+¯¹ºșɎ

ŴŷŵȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ,¯ªɉ+¯¬"Ɏ'"§²º®Ɏ

ųżźŹɉźŻųųȏɎųżźŹɉźŻŴżɎ,"ª±´µ½Ɏ

/»¨²¯©§º¯µ´¹ɎɎżɎ!µ º®Ɏ8"¹ɎųȌŶųŻɎ Ɏ

ŴŷŶȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ-»º¸¯º¯µ´ȍɎ '"§²º®ɎȊɎ ¯´ȍɎ3®"Ɏ

ŴŵźżɉźźųźȏɎŴźŹųɉŷźŻŻɎ2¶¸¯´"¸Ɏ-§º»¸"ɎɎŵŴɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŶųųųɎŵȌŻŹŻɎɎ

ŴŷŷȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ-»º¸¯º¯µ´Ɏ¯´Ɏ &"¸µ´ºµ²µ¿Ɏ§´ªɎ &"¸¯§º¸¯©¹Ɏ

ŵŴŸŸɉŴŴżźȏɎŵŴŸŸɉŴŵųųɎ3§¿²µ¸ɎȊɎ%¸§´©¯¹Ɏ

.´²¯´"ɎɎŶŹɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŵżŸųɎŴȌŴŹɎɎ

ŴŷŸȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ/§¸±¯´¹µ´¯¹³Ɏ §´ªɎ1"¹º²"¹¹Ɏ+"¹Ɏ

2¿´ª¸µ³"Ɏ

ŴżŵźɉźźŶŶɎ#µ¼"¶¸"¹¹ɎɎŻɎ.´² ¯´"Ɏ /"ɎǻŴȍźŻųɎ ɎɎ

ŴŷŹȌ

Ŵ )µ»¸´§²Ɏµ¬Ɏ/§¸±¯´¹µ´ȟ¹Ɏ #¯¹"§¹"Ɏ

ŴŻźźɉźŴźŴɎ(.2Ɏ/¸"¹¹ɎɎźɎ.´² ¯´"Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŴŷŸųɎŴȌŴŸŴɎ8"¹ɎȘ!"§²²ȟ¹Ɏ

+¯¹ºșɎ

ŴŷźȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ/µ¶»²§º¯µ´Ɏ "¯´Ɏ

ŴŻźŷɉźŻŻŷȏɎŴŻźŷɉźŻźŹɎ2¶¸¯´"¸Ɏ-§º»¸"ɎɎŴųɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ

/"ɎǻŶųųųɎɎɎ

ŴŷŻȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ1"²¯¯µ´ȍɎ

2¶¯¸¯º»§²¯º¿ɎȊɎ ¯´Ɏ

Ș¬µ¸³"¸²¿Ɏ)µ»¸´§²Ɏµ¬Ɏ

1"²¯¯µ»¹Ɏ&"¸µ´ºµ²µ¿șɎ

ŴŸŸŵɉŻųŶųȏɎŴŸŸŵɉŻųŷżɎ3§¿²µ¸ɎȊɎ%¸§´©¯¹Ɏ

.´²¯´"ɎɎŵżɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŵżŸųɎųȌŴźżɎɎ

ŴŷżȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ2µ©¯§²Ɏ6µ¸±Ɏ¯´Ɏ $´ªɉµ¬ɉ+¯¬"ɎȊɎ/§²²¯§º¯¼"Ɏ "§¸"Ɏ

ŴŸŸŵɉŷŵŸŹȏɎŴŸŸŵɉŷŵŹŷɎ3§¿²µ¸ɎȊɎ%¸§´©¯¹Ɏ.´²¯´"Ɏ

ɎŴŶɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŵżŸųɎųȌŶŷŸɎɎ

ŴŸųȌ

Ɏ)µ»¸´§²Ɏµ¬Ɏ6µ³"´ɎȊɎ ¯´Ɏ

ųŻżŸɉŵŻŷŴȏɎŴŸŷųɉźŶŵŵɎ3§¿²µ¸ɎȊɎ%¸§´©¯¹Ɏ

.´²¯´"ɎɎŵżɎ!µ º®Ɏ.¶º¯µ´§²ȏɎ /"ɎǻŵżŸųɎųȌźŷɎɎ

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

º¨ºȏ µ)Ɏ.41 -$Ɏŵ$Ŵź+$"!+4ǸŻ 1$>+4Ǹ Ŵ4ǸŻŹ$8ɎŻǸ+Ŵż$

´´´¹ª·²¼Ȍ$²±¿¹ª±¼²± $EǸ-+ż$$··$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$ "/¯$³¼¿´´$¼#¿$$

º¨¬ȏ

µ)Ɏ.41 -$Ɏŵ$Ŵź+$"!+4ǸŻ 1$

G+µǸŻ -$=Ǹ4+ŻŴɎ4Ź$

"ŹŹɎŻǸ ŴǸɎ1$()"G="ŷ°$ 'ź+Ȍ$'ź+$)Ɏ.41 -$Ɏŵ$/ɎŹŴª "Ż.Ŵ+$ 1µ$%Ɏ1§ª'+4!$

¯ 4+$G+µǸŻǸ1+$

²±¹±ª·²´Ȍ$²±¿ª½¿¨± $?-Ź+¸Ǹ+4$$²½$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$ "/¯$³¿·´´$±#¿¹±$$

º¨.ȏ

µ)Ɏ.41 -$Ɏŵ$Ŵź+$?ŻɎ1Ɏ!ǸŻŹ$Ɏŵ$"§+Ǹ1§$ ¹¹²¹ª¹B$?-Ź+¸Ǹ+4$$²´$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$ "/¯$³²²´´$´#·¿²$$

º¨șȏ

µ)Ɏ.41 -$Ɏŵ$Ŵź+$"1µǸ 1$"Ż µ+!ż$Ɏŵ$>+4Ǹ Ŵ4ǸŻŹ$ ´½¨¼ª¹¼¼$"1µǸ 1$"Ż µ+!ż$ Ɏŵ$>+4Ǹ Ŵ4ǸŻŹ$$²¿$Ŷ1-Ǹ1+$ Ƀ+Ź$ ´#²²²$$

º¨¨ȏ

µ)Ɏ.41 -Ź$Ɏŵ$>+4Ɏ1ŴɎ-Ɏ§ż°$ 'ź+#$8+4Ǹ+Ź$"°$5ǸɎ-Ɏ§ǸŻ2 -$

8ŻǸ+1Ż+Ź$ 1µ$G+µǸŻ -$

8ŻǸ+1Ż+Ź$

²´¨½ª±´´·Ȍ$²¨±ª±¿±B$Ŷ@ŵɎ4µ$"Ż µ+!ǸŻ$$¨¹$5Ɏ Ŵź$3Ɏ$¼#½´¹ $$

º¨¹ȏ

µ)Ɏ.41 -Ź$Ɏŵ$>+4Ɏ1ŴɎ-Ɏ§ż°$ 'ź+#$8+4Ǹ+Ź$5°$ /ŹżŻźɎ-Ɏ§ǸŻ -$8ŻǸ+1Ż+Ź$ 1µ$8ɎŻǸ -$8ŻǸ+1Ż+Ź$$

²´¨½ª±´²¼Ȍ$²¨±ª±¿·$Ŷ@ŵɎ4µ$"Ż µ+!ǸŻ$$¨¹$5Ɏ Ŵź$3Ɏ$¿#´·¼ $$

º¨®ȏ

µG Ŵ.4ǸŴ Ź $

´¿¨ª±²¹¹$?-Ź+¸Ǹ+4$$²´¨$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³¿¹´´$¿#¹±±$$

º¨©ȏ

µG+Żź 1ǸŹ!Ź$Ɏŵ$"§+Ǹ1§$ 1µ$=+¸+-Ɏ®!+1Ŵ$

´´¼¨ª·¿¨¼$?-Ź+¸Ǹ+4$$²¨¿$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³¹·±´$¿#´¨$$

º¨¿ȏ

µG+µ¯4 ¸+$Ŷ1-Ǹ1+$ )Ɏ.41 -$(GŶ)ŷ$Ɏŵ$ >+4Ɏ1ŴɎ-Ɏ§ż$»$>+4Ǹ Ŵ4ǸŻ2Ź$

¹±¨¼ª²¿´$

$G+µ¯4 ¸+$>4Ɏ.®$$¹$Ŷ1- Ǹ1+$Ƀ+ŹȌ$"/¯$

³¹²½ª½½$

(µ+®+1µ+1Ŵ$ .®Ɏ1$Ǹ1ŻɎ!+$ 1µ$ Ź.Ÿ!ǸŹŹǸɎ1ŷ$$ Ƀ+Ź$(5+ --ȒŹ$ %ǸŹŴŷ$

º¹5ȏ

µGǸµµ-+$? ŹŴ$)Ɏ.41 -$Ɏŵ$"§+$ 1µ$"§+Ǹ1§$ ²¼¼½ª·¨¨$!+µǸTEŶ©%=$"1Ŵ+41 ŴǸɎ1 -$ $²¼$Ŷ1-Ǹ1+$ Ƀ+ŹȌ$"/¯$³¿±´$$$

º¹ºȏ

µGɎ-+Ż.- 4$3+.4Ɏµ+§+1+4 ŴǸɎ1$

²¨±´ª²¿¹·$8®4Ǹ1§+4$3 Ŵ.4+$$²¿$Ŷ1-Ǹ1+$ Ƀ+ŹȌ$"/¯$³¹±´$¿#¼²$$

º¹¬ȏ

µ35?©$5.--+ŴǸ1$Ɏ1$"§Ǹ1§$ 1µ$A+ -Ŵź°$Ŵź+$'ź+$3 ŴǸɎ1 -$5.4+ .$Ɏŵ$ ?ŻɎ1Ɏ!ǸŻ$ ©+Ź+ 4Żź$$¿²$Ŷ1-Ǹ1+$ Ƀ+Ź$ $$

º¹.ȏ

µ3+.4ɎŸǸɎ-Ɏ§ż$Ɏŵ$"§Ǹ1§ $

´²½¨ª¼±´$?-Ź+¸Ǹ+4$$·´$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³¿¿´´$±#²²¨$$

º¹șȏ

µ3+.4Ɏµ+§+1+4 ŴǸ¸+$=ǸŹ+ Ź+Ź$

²··´ª¹±¼Ȍ$²··´ª¹·¹$H 4§+4$$²$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$¯A¶$

¿´´´$¹#¼¹$$

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

º¹¨ȏ µ3/>$3+.4Ɏ-Ɏ§Ǹ+$ª $ /ŹżŻźǸ Ŵ4Ǹ+$ª$>O4Ǹ Ŵ4Ǹ+ $

²·¹¨ª¼¿´$?-Ź+¸Ǹ+4$5ų$$²$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

?D©$¹´´´$´#²½$$

º¹¹ȏ

µ3/)$"§Ǹ1§$ 1µ$G+Żź 1ǸŹ!Ź$Ɏŵ$=ǸŹ+ Ź+$

¹´±·ª¿½¨¿$8®4Ǹ1§+4$3 Ŵ.4+$$±¹$ 4ŴǸŻ-+Ź$ Ŷ1-Ǹ1+$Ƀ+ŹȌ$"/¯$

³¹´´$$$

º¹®ȏ

µ3.4ŹǸ1§$Ŷ-µ+4$/+Ɏ®-+ $ (ŵɎ4!+4-ż$?-µ+4-ż$¯ 4+ŷ$

²¼¨¹ª´¨½±Ȍ$¹´¼¨ª½¼²$©¯3Ǹ$$¹½$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$U²´´´$$$

º¹©ȏ

µ3.Ŵ4ǸŴǸɎ1$ 1µ$A+ -Ŵźż$ "§Ǹ1§$(ŵɎ4!+4-ż$

3.Ŵ4ǸŴǸɎ1$ 1µ$"§Ǹ1§ŷ$

¹¼±²ª½¼´Ȍ$¹¼±²ª½±´¹$"Ŷ8$/4+ŹŹ$$¼$/4Ǹ 1Ŵ$Ƀ+ŹȌ$"/¯$

³²¹±´$$ Ƀ+Ź$(5+ --ȒŹ$

%ǸŹŴŷ$

º¹¿ȏ

µŶG?>"$V$)Ɏ.41 -$Ɏŵ$=+ Ŵź$ 1µ$=żǸ1§$ ´´¿´ª¹¹¹Ȍ$²±¼²ª¿¨·¼$8">?$ /.Ÿ-ǸŻ ŴǸɎ1Ź$$¨·$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$ "/¯$³¿´´´$´#·¨·$$

º®5ȏ

µŶ@Ǹµ ŴǸ¸+$G+µǸŻǸ1+$»$¯+--.- 4$%Ɏ1§+¸ǸŴż$

²½¼¹ª´½´´$AǸ1µ CǸ$%Ǹ!ǸŴ+µ$$²´$5Ɏ Ŵź$Ƀ+ŹȌ$"/¯$

³¹´´´$¼#±½¿$$

º®ºȏ

µ/ 4ºǸ1ŹɎ1ǸŹ!$ 1µ$©+- Ŵ+µ$=ǸŹɎ4µ+4Ź$

²¿±¿ª´¹´$?-Ź+¸Ǹ+4$$¼½$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³$¿¹´´$¼#¼¼$$

º®¬ȏ

µ/ 4ºǸ1ŹɎ1ȒŹ$=ǸŹ+ Ź+ $

¹´½´ª´¿$AǸ1µ CǸ$%Ǹ!ǸŴ+µ$$$5Ɏ Ŵź$Ƀ+ŹȌ$"/¯$

³²±´´$²#¨´¹$$

º®.ȏ

µ/ ŴźɎŸǸɎ-Ɏ§ż$Ɏŵ$"§Ǹ1§$»$"§+ª4+- Ŵ+µ$=ǸŹ+ Ź+Ź$

¹´´²ª´´´²$' ż-Ɏ4$»$¶4 1ŻǸŹ$Ŷ1-Ǹ1+$ $¨$Ŷ1- Ǹ1+$Ƀ+ŹȌ$3Ɏ$"/¯$´#¿¨½$$

º®șȏ

µ/źżŹǸŻ -$»$ŶŻŻ.® ŴǸɎ1 -$'ź+4 ®ż$Ǹ1$>+4Ǹ Ŵ4ǸŻŹ$

´¹¨´ª¿²²Ȍ$²±¼²ª¿²±¹$' ż-Ɏ4$»$¶4 1ŻǸŹ$

Ŷ1-Ǹ1+$$¿±$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$ "/¯$³¹½±´$´#¹·$$

º®¨ȏ

µ/ɎŹŴ$©+®4Ɏµ.ŻŴǸ¸+$

A+ -Ŵź$(ŵɎ4!+4-ż$

G+1Ɏ® .Ź+$

"1Ŵ+41 ŴǸɎ1 -ŷ$ ¹´±¿ª¿·½²Ȍ$¹´±¿ª¿¨´±$8">?$ /.Ÿ-ǸŻ ŴǸɎ1Ź$$¹¿$5Ɏ Ŵź$3Ɏ$´#¹¨ $$

º®¹ȏ

µ/4Ɏµ.ŻŴǸ¸+$"§Ǹ1§$8®+ŻǸ -$ "1Ŵ+4+ŹŴ$8+ŻŴǸɎ1$(ŵɎ4!+4-ż$ >+4Ɏ1ŴɎ-Ɏ§ż$8®+ŻǸ -$ "1Ŵ+4+ŹŴ$8+ŻŴǸɎ1ŷ$'ź+$"!+4ǸŻ 1$ŶŻŻ.® ŴǸɎ1 -$ 'ź+4 ®ż$ "ŹŹɎŻǸ ŴǸɎ1°$"1Ż#$$¼´$(ȵŷ$5ɎŴź$ 3Ɏ$$$

º®®ȏ

µ/ŹżŻźɎ§+4Ǹ Ŵ4ǸŻŹ $

²¿¼·ª¿±´´Ȍ$²¼¨½ª¿´²$EǸ-+ż$$²¨$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³¹¨´´$²#·½¿$$

º®©ȏ

µ/ŹżŻźɎ-Ɏ§ż$ 1µ$"§Ǹ1§ $ ´¹ª¨½¨¼Ȍ$²½¿½ª²¼½$"!+4ǸŻ 1$ /ŹżŻźɎ-Ɏ§ǸŻ -$ "ŹŹɎŻǸ ŴǸɎ1$$¿¹$5Ɏ Ŵź$3Ɏ$¹#²¹ $$

º®¿ȏ

µ/.Ÿ-ǸŻ$/Ɏ-ǸŻż$»$"§Ǹ1§$©+®Ɏ4Ŵ$

²´±±ª¿´¿¨Ȍ$¹´±¿ª¼½¹$Ŷ@ŵɎ4µ$"Ż µ+!ǸŻ$$¹¨$5Ɏ Ŵź$3Ɏ$$ $

º©5ȏ

µK. -ǸŴż$Ǹ1$"§+Ǹ1§$ 1µ$Ŷ-µ+4$"µ.-ŴŹ$ ²¼¨²ª¨¨½¼$?!+4 -µ$/.Ÿ-ǸŹźǸ1§$ %Ǹ!ǸŴ+µ$$²$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$ "/¯$³¹´´´$$$

º©ºȏ

µ©+F.¸+1 ŴǸɎ1$©+Ź+ 4Żź $ ²±¼½ª²·¼Ȍ$²±±¨ª±¨¨$G 4ż$"11$ %Ǹ+Ÿ+4Ŵ°$"1Ż#$$¹²$Ŷ1-Ǹ1+$ Ŷ®ŴǸɎ1 -$¹#¹¨ $$

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

º©¬ȏ µ©+Ź+ 4Żź$Ɏ1$"§Ǹ1§ $ ´²·¼ª´¹¨±Ȍ$²±±¹ª¨±¨¿$8">?$ /.Ÿ-ǸŻ ŴǸɎ1Ź$$¿½$5Ɏ Ŵź$3Ɏ$²#¹²¼ $$

º©.ȏ

µ©+Ź+ 4Żź$Ǹ1$>+4Ɏ1ŴɎ-Ɏ§ǸŻ -$3.4ŹǸ1§$

²½¼´ª¼½¹²Ȍ$²½¿ª¹¼·¼$A+ -ǸɎ$$²´$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³²±´´$´#¨²¨$$

º©șȏ

µ©+¸ǸŹŴ $54 ŹǸ-+Ǹ4 $µ+$

¯ǸW1ŻǸ Ź$µɎ$

?1¸+-ź+ŻǸ!+1ŴɎ$A.! 1Ɏ$ ²·¨½ª¨½¿´Ȍ$¹¿²¨ª··½± $D/¶$?µǸŴɎ4 $$²¼$Ŷ1-Ǹ1+$ D1º1ɎC1$$$

º©¨ȏ

µ©+¸ǸŹŴ $54 ŹǸ-+Ǹ4 $µ+$>+4Ǹ Ŵ4Ǹ $+$>+4Ɏ1ŴɎ-Ɏ§Ǹ $

²½²ª¹¹±·$Ŷ®+1$D1Ǹ¸+4ŹǸŴż$ Ɏŵ$Ŵź+$'źǸ4µ$"§+$$¹²$Ŷ1-Ǹ1+$ Ƀ+Ź$ $$

º©¹ȏ

µ©+¸ǸŹŴ $?Ź® XɎ- $µ+$>+4Ǹ Ŵ4J $ż$>+4Ɏ1ŴɎ-Ɏ§J $

´¹²²ª²¿½B$?-Ź+¸Ǹ+4$?Ź® X $$±¿$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$²ª

ż+ 4$

+!Ÿ 4§Ɏ$²#²¹$$

º©®ȏ

µ©+¸ǸŹŴ $"Ÿ+4Ɏª"!+4ǸŻ $µ+$8 Yµ+$+$?1¸+-ź+ŻǸ!+1ŴɎ$

¹²¿ª···¿$'ź+$D1Ǹ¸+4ŹǸŴż$Ɏŵ$Z¸Ɏ4 $ $¼$Ŷ1- Ǹ1+$Ƀ+Ź$ $$

º©©ȏ

µ8+1ǸɎ4Ź$AɎ.ŹǸ1§$»$¯ 4+$ )Ɏ.41 -$ ²½¼²ª¨²¨$3 ŴǸɎ1 -$"1¸+ŹŴ!+1Ŵ$

¯+1Ŵ+4$ŵɎ4$Ŵź+$

8+1ǸɎ4Ź$AɎ.ŹǸ1§$

»$¯ 4+$"1µ.ŹŴ4ż$$¹±$/4Ǹ 1Ŵ$Ƀ+Ź$$$

º©¿ȏ

µ8G$>+4Ɏ1ŴɎ-Ɏ§ż$ 1µ$>+4Ǹ Ŵ4ǸŻ$©+Ź+ 4Żź$

¹±¨·ª±¼¿¼$8G$Ŷ1-Ǹ1+$$¹$Ŷ1- Ǹ1+$Ƀ+ŹI$"/¯$1ɎŴ$§Ǹ¸+1$$Ƀ+ŹI$(5+ --ȒŹ$%ǸŹŴŷ$

º¿5ȏ

µ'ǸFµŹŻź4ǸŵŴ$¸ɎɎ4$>+4Ɏ1ŴɎ-Ɏ§Ǹ+$+1$>+4Ǹ Ŵ24Ǹ+$

´²·¨ª½¹¹Ȍ$²¨±ª·¿¹$8®4Ǹ1§+4$3 Ŵ.4+$$¼½$5Ɏ Ŵź$3Ɏ$´#¹± $$

º¿ºȏ

µ'ǸFµŹŻź4ǸŵŴ$¸ɎɎ4$ Ŷ.µ+4+1§+1++Źº.1µ+$ų+4+1ŹɎ$$$Ŷ1- Ǹ1+$3Ɏ$´$ $

º¿¬ȏ

µ'Ɏµ żȒŹ$>+4Ǹ Ŵ4ǸŻ$G+µǸŻǸ1+$

¹¿¹ª´¨¨Ȍ$¹¿¹ª´¨·$>4+ Ŵ$ų --+ż$/.Ÿ-ǸŹźǸ1§$

$²´$5Ɏ Ŵź$Ƀ+Ź$$$

º¿.ȏ

µ'Ɏ®ǸŻŹ$Ǹ1$>+4Ǹ Ŵ4ǸŻ$©+ź ŸǸ-ǸŴ ŴǸɎ1$

´¹ª¨±¹¼Ȍ$²±±´ª¹¼²¼$%Ǹ®®Ǹ1ŻɎŴŴ°$EǸ--Ǹ !Ź$»$

EǸ-ºǸ1Ź$$¿¿$Ŷ1-Ǹ1+$ Ŷ®ŴǸɎ1 -Ȍ$ "/¯$³¼´´´$´#¿¨$$

º¿șȏ

µ'4 1Ź- ŴǸɎ1 -$G+µǸŻǸ1+$Ɏŵ$"§Ǹ1§$

¹¼·ª±´²²

$H+"Ǹ$¯Ɏ!!.1ǸŻ ŴǸɎ1Ź$ ¯Ɏ#$$$¹$Ŷ1- Ǹ1+$Ƀ+ŹȌ$"/¯$

³½´$$$

º¿¨ȏ

µ'.4ºǸŹź$)Ɏ.41 -$Ɏŵ$ >+4Ǹ Ŵ4ǸŻŹ$('.4º$>+4Ǹ Ŵ4Ǹ$ =+4§ǸŹǸŷ$

²¿´¼ª¹½¼¨Ȍ$²¿´¨ª½½¼$'.4ºǸŹź$>+4Ǹ Ŵ4ǸŻŹ$

8ɎŻǸ+Ŵż$$¹²$Ŷ1-Ǹ1+$ D1º1ɎC1$´#²¨$$

º¿¹ȏ

µEɎ4º°$"§Ǹ1§$ 1µ$©+ŴǸ4+!+1Ŵ$

¹´±¼ª¼·¼¹Ȍ$¹´±¼ª¼·±´$Ŷ@ŵɎ4µ$"Ż µ+!ǸŻ$$¼$5Ɏ Ŵź$3Ɏ$$ $

º¿®ȏ

µEɎ4ºǸ1§$CǸŴź$Ŷ-µ+4$/+Ɏ®-+$

²¿··ª¿···$?!+4 -µ$

/.Ÿ-ǸŹźǸ1§$ %Ǹ!ǸŴ+µ$$¹²$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$ "/¯$³¹´´´$´#²·¹$$

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

º¿©ȏ

µ[+ǸŴŹŻź4ǸŵŴ$ŵ\4$ >+4Ɏ1ŴɎ-Ɏ§Ǹ+$.1µ$ >+4Ǹ Ŵ4Ǹ+$

´½¼ª·¨´¼Ȍ$$

²¼¿±ª²¹·½$8®4Ǹ1§+4$3 Ŵ.4+$$±²$5Ɏ Ŵź$Ŷ®ŴǸɎ1 -Ȍ$

"/¯$³¿´´´$´#±$$

Ȓ-¶ µ"ǻ%1±µȵ1±ª¼µªȵµ±¶ µȍªȊ¼ųŴµżŵµŴ"ŵ± ɉµż¶ ųµŷ"ŴźŴ µªųµ±¶ µȍªȊ¼ųŴµż źŵ"± ȏµ-¶ µɃ1"ǻŻªµ)ªȊ¼ųŴµ´ųŸ"ųŻµżŵµ

Ȋŵ ɉµż¶ ųµ±¶ µ"ǻ%1±µȵ1±ª¼µżŵµųª±µŷ"ŴźŴ µȵ¼ªǻµ±¶ µȍªȊ¼ųŴµż źŵ"± ȏµ-¶ µ"ǻ%1±µȵ1±ª¼µŵ¶ªȊŴɉµųª±µź µȊŵ ɉµŵµ±¶ µ

ªųŴŶµ"ųɉ"1±ª¼µªȵµȍªȊ¼ųŴµŹȊŴ"±Ŷȏµµ

-§³"Ɏµ.µ

)»¸´²§"Ƀµ-3§-µ3§!Ɏµ(Ɏ§ɃɎȌµ/¸³"Ș(§-Ș»²µ

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

¯µ ²ǻ µªȵµ)ªȊ¼ųŴµ/ȊźŴ"ŵ¶ ¼8 Ƀª1" ±Ŷµ2 ¼ŵµªȵµ

/ȊźŴ"1±"ªųµµ/¼"ų±µª¼µ

»ųŴ"ų ȟµ»% ųµ§11 ŵŵȟµȘǻ%1±µ+1±ª¼µ/¼ ɉ±ª¼Ŷµ/ȊźŴ"ŵ¶ ¼ȟµ

ºȏ

µ"µ¸ 1Ż+Ź$Ǹ1$¯+--$ "§Ǹ1§$ 1µ$ >+4Ɏ1ŴɎ-Ɏ§ż$

²±··ª¿²¹¼Ȍ$

$

²¨±ª±¹¹¼

$?-Ź+¸Ǹ+4$²½½·ª¹´´±$5Ɏ Ŵź$3Ɏ$$ $

¬ȏ

µ"µ¸ 1Ż+Ź$Ǹ1$ >+4Ǹ Ŵ4ǸŻŹ$

¹¿²¼ª¨·¨½$AǸ1µ CǸ$%Ǹ!ǸŴ+µ$¹´²¼ª¹´²±$ Ŷ1-Ǹ1+$Ƀ+Ź$ $$

.ȏ µ"§+Ǹ1§$AɎ4Ǹ<Ɏ1Ź$

²¨¼·ª²´¨¿Ȍ$$

²¨¼·ª²´²$'ź+$Ŷ@ŵɎ4µ$"1ŹŴǸŴ.Ŵ+$Ɏŵ$/Ɏ®.- ŴǸɎ1$"§+Ǹ1§$¹´´¼ª¹´²´$5Ɏ Ŵź$Ƀ+Ź$$$

șȏ

µ"§+Ǹ1§$©+Ź+ 4Żź$

¹´¿·ª¨¿¼Ȍ$

¹´¿·ª¨¿¨·$/">?/4+ŹŹ$¹´´½ª¹´²¹ $Ŷ1-Ǹ1+$Ƀ+Ź$ $$

¨ȏ

µ"§Ǹ1§$A+ -Ŵź$

²¨¼±ª±´½BȌ$

²¨¼±ª±²´¿$¶.Ŵ.4+$!+µǸŻǸ1+$ %Ŵµ#$¹´´±ª¹´²¿$5Ɏ Ŵź$Ƀ+Ź$´$$

¹ȏ

µ"-<ź+Ǹ!+4ȒŹ$¯ 4+$ 'Ɏµ ż$

²½¿·ª¿´´²$EɎ-Ŵ+4Ź$H-.C+4$¹´´´ª¹´²´$5Ɏ Ŵź$GɎŹŴ$-Ǹº+-ż$

Ɏ®ŴǸɎ1 -$$$

®ȏ

µ"-<ź+Ǹ!+4ȒŹ$=ǸŹ+ Ź+$

©+Ź+ 4Żź$)

Ɏ.41 -$

²½¿±ª¹±²¼$3Ɏ¸ $8ŻǸ+1Ż+$/.Ÿ-ǸŹź+4Ź$ D1º1ɎC1$/4Ǹ1Ŵ$ 3Ɏ$$/ɎŴ+1ŴǸ --ż$

©ȏ

µ"!+4ǸŻ 1$)Ɏ.41 -$Ɏŵ$ >+4Ǹ Ŵ4ǸŻ$¯ 4µǸɎ-Ɏ§ż°$ 'ź+$

²¨±²ª¨²±B

$EǸ-+ż$²½½¹ª¹´´$ 5ɎŴź$GɎŹŴ$-Ǹº+-ż$

Ɏ®ŴǸɎ1 -$$$

¿ȏ

µ"!+4ǸŻ 1$)Ɏ.41 -$Ɏŵ$ >+4Ǹ Ŵ4ǸŻ$ /ź 4! ŻɎŴź+4 ®ż°$ 'ź+$

²±¼¿ª±½¼·$?-Ź+¸Ǹ+4$¹´´¿ª¹´²¿$/4Ǹ 1Ŵ$D1º 1ɎC1$$$

º5ȏ

µ"®®4Ɏ Żź+Ź$ŴɎ$"§Ǹ1§$2

¯Ɏ1Ŵ4Ɏ-$

²±ª¼´¹$8® 1ǸŹź$8ɎŻǸ+Ŵż$Ɏŵ$"1ŴǸª"§Ǹ1§$

G+µǸŻǸ1+$ 1µ$¹´´ª¹´²±$Ŷ1 -Ǹ1+$Ƀ+Ź$ $$

. CC-BY-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the

preprint in perpetuity. was not certified by peer review)(whichThe copyright holder for this preprint this version posted November 22, 2019. ; https://doi.org/10.1101/19012278doi: medRxiv preprint

+µ´"¼¯º¿Ɏ

ŴŴȌ

Ɏ ¸©®¯¼"¹Ɏµ¬Ɏ &"¸µ´ºµ²µ¿Ɏ§´ªɎ &"¸¯§º¸¯©¹Ɏ2»¶¶²"³"´ºɎ

ųżŵŷɉźżŷźɎ$²¹"¼¯"¸ɎŴżŻżɉŵųųŷɎ/¸¯ ´ºɎ4´± ´µ½´ɎɎɎ

ŴŵȌ

Ɏ »¹º¯´Ɏ ²À®"¯³"¸ȟ¹Ɏ §´ªɎ/§¸±¯´¹µ´ȟ¹Ɏ #¯¹"§¹"Ɏ

ŵŶźźɉŶŸź7Ɏ »¹º¯´Ɏ/»¨²¯¹®¯´Ɏ&¸µ»¶Ɏ

ŵųŴŷɉŵųŴŸɎ.´ ² ¯´"Ɏ8"¹Ɏ Ɏ8"¹ɎȘ!"§²²ȟ¹Ɏ +¯¹ºșɎ

ŴŶȌ

Ɏ!¯µ³"ª¯©¯´"Ɏ§´ªɎ ¯´Ɏ/§º®µ²µ¿Ɏ

ŵŵŴųɉŸŵŵųɎ$²¹"¼¯"¸ɎŵųŴŴɉŵųŴŷɎ.´ ²¯´"Ɏ 4´±´µ½´ɎŴȌŻŹ ɎɎ

ŴŷȌ

Ɏ!¸µ½´Ɏ4´¯¼"¸¹¯º¿Ɏ &"¸¯§º¸¯©Ɏ /¹¿©®µ¶®§¸³§©µ²µ¿Ɏ

4¶ª§º"ȍɎ3®"ɎȘ¬µ¸³"¸²¿Ɏ

3®"Ɏ!¸µ½´Ɏ4´¯¼"¸¹¯º¿Ɏ

&"¸µ/¹¿©®Ɏ1"¶µ¸ºșɎ

ŴŸŸŹɉźŸŷųɎ6¯²"¿Ɏ/"¸¯µª¯©§²¹ȍɎ(´©ȌɎɎ

ŴżżżɉŵųŴŴɎ

Ș³"¸"ªɎ½¯º®Ɏ

3®"Ɏ!¸µ½´Ɏ

4´¯¼"¸¹¯º¿Ɏ

/¹¿©®µ¶®§¸ɉ

³§©µ²µ¿Ɏ

4¶ª§º"șɎ!µº®Ɏ4´ ±´µ½´ɎɎɎ

ŴŸȌ

Ɏ"§®¯"¸¹Ɏª"Ɏ²Ȥ§´´Ô"Ɏ Ô¸µ´ºµ²µ¯·»"ȍɎ+"¹Ɏ

ŴźŹųɉŸŶŷŵȏɎ

ŴźŹųɉŸŶŸųɎ+§¼µ¯¹¯"¸ɎȘ2¶¸