A Morris

A Zolopa

Acute Respiratory Distress Network

B Vincent

E Rivers

FJ Palella Jr

G Berghe van den

G Nickas

H Khouli

J Croda

JL Davis

JM Wallace

JR Curtis

K Powell

Krista Powell

L Huang

Laurence Huang

M Narasimhan

MW Fei

RF Miller

SJ Dickson

English

PubMed

Springer - Publisher Connector

The ART of caring for patients with HIV infection in the ICU

Crossref

Powell, Krista

Huang, Laurence

eScholarship - University of California

eScholarshipTitleThe ART of caring for patients with HIV infection in the ICUPermalinkhttps://escholarship.org/uc/item/7zk1f20nJournalIntensive Care Medicine, 35(10)ISSN1432-1238AuthorsPowell, KristaHuang, LaurencePublication Date2009-10-01DOI10.1007/s00134-009-1578-1 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaKrista PowellLaurence HuangThe ART of caring for patients with HIVinfection in the ICUReceived: 26 June 2009Accepted: 27 June 2009Published online: 28 July 2009 The Author(s) 2009. This article is published with open access atSpringerlink.comThis editorial refers to the article available at:doi:10.1007/s00134-009-1559-4Present Address:K. Powell ())Centers for Disease Control and Prevention,1600 Clifton Road, MS E-10, Atlanta, GA 30333, USAe-mail: kpow05@gmail.comTel.: ?1-404-6395337Fax: ?1-404-6398959K. PowellDepartment of Medicine, University of California,San Francisco, CA, USAL. HuangDivision of Pulmonary and Critical Care Medicine and the HIV/AIDS Division, San Francisco General Hospital,University of California, San Francisco, CA, USAWilliam Osler once wrote, ‘‘The practice of medicine is anart, based on science.’’ Never is this statement truer than inthe care of patients with HIV infection in the intensive careunit (ICU) in the current era of combination antiretroviraltherapy (ART). In this issue of Intensive Care Medicine,Barbier and colleagues describe the etiologies and outcomesof acute respiratory failure in patients with HIV infectionover the first decade of ART (1996–2000) [1]. Remarkably,the etiology of respiratory failure was identified in [98%of the 145 patients in the retrospective study. Bacterialpneumonia was the most common cause, followed byPneumocystis pneumonia (PCP). Notably, non-invasiveventilation averted the need for endotracheal intubation andmechanical ventilation in 19 of 22 patients. To differentiatebetween patients taking ART and patients only reportingreceipt of ART, the authors considered patients with evi-dence of poor adherence (i.e., patients for whom medicalchart review indicated non-adherence with prescription ofART, patients with stationary viral loads and no evidence ofviral resistance, or patients who had not received therapy for[6 months) in the non-treatment group. Almost one-thirdof patients were considered in the ART treatment group atthe time of ICU admission. Although not a statisticallysignificant difference, patients receiving ART actually hadhigher mortality (30%) compared to those not receiv-ing ART (15%) (p = 0.07), despite having higher CD4lymphocyte counts, lower HIV viral loads, and feweropportunistic infections. Overall hospital survival was 80%,was stable across the study period, and was not statisticallydifferent across different etiologic groups.The current study adds to the growing number ofstudies of the critical care of patients with HIV infectionin the ART era. Following the introduction of HIV pro-tease inhibitors and their use in combination with HIVreverse transcriptase inhibitors in 1996, improved out-comes were documented with ART among outpatients[2]. A study from San Francisco General Hospital in theearly years of the ART era (1996–1999) providedencouraging evidence that the protective influence ofART might be extended to critically ill patients with HIVinfection [3]. The potential lifesaving role of ART led tothe consideration of its use during the period of acuteillness in the ICU, though this practice has remainedcontroversial [4]. At least one retrospective study inves-tigated the effect of continuation of ART during ICU stayand the effect of initiation of ART on ICU and 6-monthoutcome; the authors concluded that 6-month survivalwas associated with ART [5]. In addition, a recent multi-center randomized controlled trial found that initiation ofART during an acute opportunistic infection, rather thandeferring treatment, reduces progression of HIV diseaseand mortality, although the study was not designed spe-cifically to study critical illness [6].Intensive Care Med (2009) 35:1659–1661DOI 10.1007/s00134-009-1578-1 EDITORIALDespite the immunologic and virologic advantagesconferred by ART, several recent studies have found noimprovement in hospital or short-term survival betweenpatients receiving or not receiving ART at the time ofICU admission [7–11]. Even when authors have notattempted to define treatment adherence as in the currentstudy, investigators have noted higher CD4 lymphocytecounts and lower viral loads among ART recipients [11].Nevertheless, the current study and these prior studiesdemonstrate the improved survival of critically ill patientswith HIV infection in the ART era.Although ART has not been associated consistentlywith this improved survival, one possible explanation isthe decreased percentage of patients admitted to the ICUwith PCP, a recognized risk factor for in-hospital mor-tality among critically ill patients with HIV infection,compared to the pre-ART era [12–14]. In the most recentstudies in a continuing series out of San Francisco Gen-eral Hospital, ongoing since 1981, respiratory failure hasremained the most common indication for ICU admission,and PCP has remained the most frequent etiology ofrespiratory failure [3, 11]. However, the percentages havedecreased throughout the study period, presumably in partdue to prophylactic therapy and ART. In addition, severalstudies have found that patients on ART were more likelyto have non-AIDS-related admissions, which has beenassociated with improved survival [3, 7, 10, 11].Nonetheless, the changing etiology of respiratory fail-ure fails to explain completely the improved survival. Thecurrent study and other ART era studies have demon-strated improved survival even among patients with PCP[9, 15–17]. Although infection with Pneumocystis was arisk factor for in-hospital mortality in the current study,survival exceeded 85%, similar to that in other recentstudies, and a striking improvement compared with theearliest studies from the beginning of the HIV epidemic.Advancements in ICU care that are unrelated to HIV caremay also explain the survival gains in the care of criticallyill patients with HIV infection, though studies designed todetermine the individual effects of these interventions havebeen limited. For example, the current ART era has coin-cided with the adoption of low tidal volume ventilation[18], intensive insulin therapy [19], and early goal-directedtherapy for sepsis [20]. In the current study, the authorshypothesized that early transfer of patients to the ICU, non-invasive ventilation for PCP, and aggressive managementof sepsis contributed to the high in-hospital survival,independent of ART or its effects (i.e., ICU admissiondiagnosis or CD4 cell count). Therefore, improvements inICU practice remain a plausible contributing factor.Unfortunately, the current study and many of its con-temporary comparisons have considered only hospitalsurvival, not longer term survival. Therefore, the well-recognized benefits that ART exerts over periods longerthan typical ICU stays cannot be excluded.Regardless, in the absence of prospective, ICU-basedrandomized clinical trials, retrospective observationalstudies such as the current study can provide usefulclinical information to inform clinicians. Despite theinconsistent findings of the influence of ART on theoutcome of critically ill patients with HIV infection, thisstudy and others reinforce key points. First, in-hospitalsurvival for these critically ill patients has improved in thecurrent ART era. Second, the etiologic spectrum ofrespiratory failure, as well as indication for ICU admis-sion, has shifted. Therefore, clinicians should remainvigilant for both non-HIV-associated and HIV-associatedconditions, including the side effects of ART (such asdrug interactions or immune reconstitution syndrome)among critically ill patients with HIV infection.Open Access This article is distributed under the terms of theCreative Commons Attribution Noncommercial License whichpermits any noncommercial use, distribution, and reproduction inany medium, provided the original author(s) and source arecredited.References1. Barbier F, Coquet I, Legriel S, Pavie J,Darmon M, Mayaux J, Molina J-M,Schlemmer B, Azoulay E (2009)Etiologies and outcome of acuterespiratory failure in HIV-infectedpatients. J Intensive Care Med.doi:10.1007/s00134-009-1559-42. Palella FJ Jr, Delaney KM, MoormanAC, Loveless MO, Fuhrer J, Satten GA,Aschman DJ, Holmberg SD (1998)Declining morbidity and mortalityamong patients with advanced humanimmunodeficiency virus infection: HIVoutpatient study investigators. N Engl JMed 338:853–8603. Morris A, Creasman J, Turner J, LuceJM, Wachter RM, Huang L (2002)Intensive care of humanimmunodeficiency virus-infectedpatients during the era of highly activeantiretroviral therapy. Am J Respir CritCare Med 166:262–2674. Huang L, Quartin A, Jones D, HavlirDV (2006) Intensive care of patientswith HIV infection. N Engl J Med355:173–1815. Croda J, Croda MG, Neves A, SousaDe, dos Santos S (2009) Benefit ofantiretroviral therapy on survival ofhuman immunodeficiency virus-infected patients admitted to anintensive care unit. Crit Care Med37:1605–16116. Zolopa A, Andersen J, Powderly W,Sanchez A, Sanne I, Suckow C, HoggE, Komarow L (2009) Earlyantiretroviral therapy reduces AIDSprogression/death in individuals withacute opportunistic infections: amulticenter randomized strategy trial.PLoS One 5:e557516607. Narasimhan M, Posner AJ, DePalo VA,Mayo PH, Rosen MJ (2004) Intensivecare in patients with HIV infection inthe era of highly active antiretroviraltherapy. Chest 125:1800–18048. Khouli H, Afrasiabi A, Shibli M, HajalR, Barrett CR, Homel P (2005)Outcome of critically ill humanimmununodeficiency virus-infectedpatients in the era of highly activeantiretroviral therapy. J Intensive CareMed 20:327–3339. Miller RF, Allen E, Copas A, Singer M,Edwards SG (2006) Improved survivalfor HIV infected patients with severePneumocystis jirovecii pneumonia isindependent of highly activeantiretroviral therapy. Thorax 61:716–72110. Dickson SJ, Batson S, Copas AJ,Edwards SG, Singer M, Miller RF(2007) Survival of HIV-infectedpatients in the intensive care unit in theera of highly active antiretroviraltherapy. Thorax 62:964–96811. Powell K, Davis JL, Morris A, Chi A,Bensley MR, Huang L (2009) Survivalfor patients with HIV admitted to theICU continues to improve in the currentera of combination antiretroviraltherapy. Chest 139:11–1712. Wallace JM, Hansen NI, Lavange L,Glassroth J, Browdy BL, Rosen MJ,Kvale PA, Mangura BT, Reichman LB,Hopewell PC (1997) Respiratorydisease trends in the pulmonarycomplications of HIV infection studycohort. Pulmonary complications ofHIV infection study group. Am J RespirCrit Care Med 155:72–8013. Nickas G, Wachter RM (2000)Outcomes of intensive care for patientswith human immunodeficiency virusinfection. Arch Intern Med 160:541–54714. Vincent B, Timsit JF, Auburtin M,Schortgen F, Bouadma L, Wolff M,Regnier B (2004) Characteristics andoutcomes of HIV-infected patients inthe ICU: impact of the highly activeantiretroviral treatment era. J IntensiveCare Med 30:859–86615. Curtis JR, Yarnold PR, Schwartz DN,Weinstein RA, Bennett CL (2000)Improvements in outcomes of acuterespiratory failure for patients withhuman immunodeficiency virus-relatedPneumocystis carinii pneumonia. Am JRespir Crit Care Med 162:393–39816. Davis JL, Morris A, Kallet RH, PowellK, Chi AS, Bensley M, Luce JM,Huang L (2008) Low tidal volume isassociated with reduced mortality inHIV-infected patients with acute lunginjury. Thorax 63:988–99317. Fei MW, Sant CA, Kim EJ, SwartzmanA, Davis JL, Jarlsberg LG, Huang L(2009) Severity and outcomes ofpneumocystis pneumonia in patientsnewly diagnosed with HIV infection: anobservational cohort study. Scand JInfect Dis 11:1–718. Acute Respiratory Distress Network(2000) Ventilation with lower tidalvolumes as compared with traditionaltidal volumes for acute lung injury andthe acute respiratory distress syndrome.N Engl J Med 342:1301–130819. Rivers E, Nguyen B, Havstad S, ResslerJ, Muzzin A, Knoblich B, Peterson E,Tomlanovich M (2001) Early goal-directed therapy collaborative group.Early goal-directed therapy in thetreatment of severe sepsis and septicshock. N Engl J Med 345:1368–137720. van den Berghe G, Wouters P, WeekersF, Verwaest C, Bruyninckx F, SchetzM, Vlasselaers D, Ferdinande P,Lauwers P, Bouillon R (2001) Intensiveinsulin therapy in the critically illpatients. N Engl J Med 345:1359–13671661

Krista Powell
Laurence Huang
The ART of caring for patients with HIV
infection in the ICU
Received: 26 June 2009
Accepted: 27 June 2009
Published online: 28 July 2009
 The Author(s) 2009. This article is published with open access at
Springerlink.com
This editorial refers to the article available at:
doi:10.1007/s00134-009-1559-4
Present Address:
K. Powell ())
Centers for Disease Control and Prevention,
1600 Clifton Road, MS E-10, Atlanta, GA 30333, USA
e-mail: kpow05@gmail.com
Tel.: ?1-404-6395337
Fax: ?1-404-6398959
K. Powell
Department of Medicine, University of California,
San Francisco, CA, USA
L. Huang
Division of Pulmonary and Critical Care Medicine and the HIV/
AIDS Division, San Francisco General Hospital,
University of California, San Francisco, CA, USA
William Osler once wrote, ‘‘The practice of medicine is an
art, based on science.’’ Never is this statement truer than in
the care of patients with HIV infection in the intensive care
unit (ICU) in the current era of combination antiretroviral
therapy (ART). In this issue of Intensive Care Medicine,
Barbier and colleagues describe the etiologies and outcomes
of acute respiratory failure in patients with HIV infection
over the first decade of ART (1996–2000) [1]. Remarkably,
the etiology of respiratory failure was identified in [98%
of the 145 patients in the retrospective study. Bacterial
pneumonia was the most common cause, followed by
Pneumocystis pneumonia (PCP). Notably, non-invasive
ventilation averted the need for endotracheal intubation and
mechanical ventilation in 19 of 22 patients. To differentiate
between patients taking ART and patients only reporting
receipt of ART, the authors considered patients with evi-
dence of poor adherence (i.e., patients for whom medical
chart review indicated non-adherence with prescription of
ART, patients with stationary viral loads and no evidence of
viral resistance, or patients who had not received therapy for
[6 months) in the non-treatment group. Almost one-third
of patients were considered in the ART treatment group at
the time of ICU admission. Although not a statistically
significant difference, patients receiving ART actually had
higher mortality (30%) compared to those not receiv-
ing ART (15%) (p = 0.07), despite having higher CD4
lymphocyte counts, lower HIV viral loads, and fewer
opportunistic infections. Overall hospital survival was 80%,
was stable across the study period, and was not statistically
different across different etiologic groups.
The current study adds to the growing number of
studies of the critical care of patients with HIV infection
in the ART era. Following the introduction of HIV pro-
tease inhibitors and their use in combination with HIV
reverse transcriptase inhibitors in 1996, improved out-
comes were documented with ART among outpatients
[2]. A study from San Francisco General Hospital in the
early years of the ART era (1996–1999) provided
encouraging evidence that the protective influence of
ART might be extended to critically ill patients with HIV
infection [3]. The potential lifesaving role of ART led to
the consideration of its use during the period of acute
illness in the ICU, though this practice has remained
controversial [4]. At least one retrospective study inves-
tigated the effect of continuation of ART during ICU stay
and the effect of initiation of ART on ICU and 6-month
outcome; the authors concluded that 6-month survival
was associated with ART [5]. In addition, a recent multi-
center randomized controlled trial found that initiation of
ART during an acute opportunistic infection, rather than
deferring treatment, reduces progression of HIV disease
and mortality, although the study was not designed spe-
cifically to study critical illness [6].
Intensive Care Med (2009) 35:1659–1661
DOI 10.1007/s00134-009-1578-1 EDITORIAL
Despite the immunologic and virologic advantages
conferred by ART, several recent studies have found no
improvement in hospital or short-term survival between
patients receiving or not receiving ART at the time of
ICU admission [7–11]. Even when authors have not
attempted to define treatment adherence as in the current
study, investigators have noted higher CD4 lymphocyte
counts and lower viral loads among ART recipients [11].
Nevertheless, the current study and these prior studies
demonstrate the improved survival of critically ill patients
with HIV infection in the ART era.
Although ART has not been associated consistently
with this improved survival, one possible explanation is
the decreased percentage of patients admitted to the ICU
with PCP, a recognized risk factor for in-hospital mor-
tality among critically ill patients with HIV infection,
compared to the pre-ART era [12–14]. In the most recent
studies in a continuing series out of San Francisco Gen-
eral Hospital, ongoing since 1981, respiratory failure has
remained the most common indication for ICU admission,
and PCP has remained the most frequent etiology of
respiratory failure [3, 11]. However, the percentages have
decreased throughout the study period, presumably in part
due to prophylactic therapy and ART. In addition, several
studies have found that patients on ART were more likely
to have non-AIDS-related admissions, which has been
associated with improved survival [3, 7, 10, 11].
Nonetheless, the changing etiology of respiratory fail-
ure fails to explain completely the improved survival. The
current study and other ART era studies have demon-
strated improved survival even among patients with PCP
[9, 15–17]. Although infection with Pneumocystis was a
risk factor for in-hospital mortality in the current study,
survival exceeded 85%, similar to that in other recent
studies, and a striking improvement compared with the
earliest studies from the beginning of the HIV epidemic.
Advancements in ICU care that are unrelated to HIV care
may also explain the survival gains in the care of critically
ill patients with HIV infection, though studies designed to
determine the individual effects of these interventions have
been limited. For example, the current ART era has coin-
cided with the adoption of low tidal volume ventilation
[18], intensive insulin therapy [19], and early goal-directed
therapy for sepsis [20]. In the current study, the authors
hypothesized that early transfer of patients to the ICU, non-
invasive ventilation for PCP, and aggressive management
of sepsis contributed to the high in-hospital survival,
independent of ART or its effects (i.e., ICU admission
diagnosis or CD4 cell count). Therefore, improvements in
ICU practice remain a plausible contributing factor.
Unfortunately, the current study and many of its con-
temporary comparisons have considered only hospital
survival, not longer term survival. Therefore, the well-
recognized benefits that ART exerts over periods longer
than typical ICU stays cannot be excluded.
Regardless, in the absence of prospective, ICU-based
randomized clinical trials, retrospective observational
studies such as the current study can provide useful
clinical information to inform clinicians. Despite the
inconsistent findings of the influence of ART on the
outcome of critically ill patients with HIV infection, this
study and others reinforce key points. First, in-hospital
survival for these critically ill patients has improved in the
current ART era. Second, the etiologic spectrum of
respiratory failure, as well as indication for ICU admis-
sion, has shifted. Therefore, clinicians should remain
vigilant for both non-HIV-associated and HIV-associated
conditions, including the side effects of ART (such as
drug interactions or immune reconstitution syndrome)
among critically ill patients with HIV infection.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which
permits any noncommercial use, distribution, and reproduction in
any medium, provided the original author(s) and source are
credited.
References
1. Barbier F, Coquet I, Legriel S, Pavie J,
Darmon M, Mayaux J, Molina J-M,
Schlemmer B, Azoulay E (2009)
Etiologies and outcome of acute
respiratory failure in HIV-infected
patients. J Intensive Care Med.
doi:10.1007/s00134-009-1559-4
2. Palella FJ Jr, Delaney KM, Moorman
AC, Loveless MO, Fuhrer J, Satten GA,
Aschman DJ, Holmberg SD (1998)
Declining morbidity and mortality
among patients with advanced human
immunodeficiency virus infection: HIV
outpatient study investigators. N Engl J
Med 338:853–860
3. Morris A, Creasman J, Turner J, Luce
JM, Wachter RM, Huang L (2002)
Intensive care of human
immunodeficiency virus-infected
patients during the era of highly active
antiretroviral therapy. Am J Respir Crit
Care Med 166:262–267
4. Huang L, Quartin A, Jones D, Havlir
DV (2006) Intensive care of patients
with HIV infection. N Engl J Med
355:173–181
5. Croda J, Croda MG, Neves A, Sousa
De, dos Santos S (2009) Benefit of
antiretroviral therapy on survival of
human immunodeficiency virus-
infected patients admitted to an
intensive care unit. Crit Care Med
37:1605–1611
6. Zolopa A, Andersen J, Powderly W,
Sanchez A, Sanne I, Suckow C, Hogg
E, Komarow L (2009) Early
antiretroviral therapy reduces AIDS
progression/death in individuals with
acute opportunistic infections: a
multicenter randomized strategy trial.
PLoS One 5:e5575
1660
7. Narasimhan M, Posner AJ, DePalo VA,
Mayo PH, Rosen MJ (2004) Intensive
care in patients with HIV infection in
the era of highly active antiretroviral
therapy. Chest 125:1800–1804
8. Khouli H, Afrasiabi A, Shibli M, Hajal
R, Barrett CR, Homel P (2005)
Outcome of critically ill human
immununodeficiency virus-infected
patients in the era of highly active
antiretroviral therapy. J Intensive Care
Med 20:327–333
9. Miller RF, Allen E, Copas A, Singer M,
Edwards SG (2006) Improved survival
for HIV infected patients with severe
Pneumocystis jirovecii pneumonia is
independent of highly active
antiretroviral therapy. Thorax 61:716–
721
10. Dickson SJ, Batson S, Copas AJ,
Edwards SG, Singer M, Miller RF
(2007) Survival of HIV-infected
patients in the intensive care unit in the
era of highly active antiretroviral
therapy. Thorax 62:964–968
11. Powell K, Davis JL, Morris A, Chi A,
Bensley MR, Huang L (2009) Survival
for patients with HIV admitted to the
ICU continues to improve in the current
era of combination antiretroviral
therapy. Chest 139:11–17
12. Wallace JM, Hansen NI, Lavange L,
Glassroth J, Browdy BL, Rosen MJ,
Kvale PA, Mangura BT, Reichman LB,
Hopewell PC (1997) Respiratory
disease trends in the pulmonary
complications of HIV infection study
cohort. Pulmonary complications of
HIV infection study group. Am J Respir
Crit Care Med 155:72–80
13. Nickas G, Wachter RM (2000)
Outcomes of intensive care for patients
with human immunodeficiency virus
infection. Arch Intern Med 160:541–
547
14. Vincent B, Timsit JF, Auburtin M,
Schortgen F, Bouadma L, Wolff M,
Regnier B (2004) Characteristics and
outcomes of HIV-infected patients in
the ICU: impact of the highly active
antiretroviral treatment era. J Intensive
Care Med 30:859–866
15. Curtis JR, Yarnold PR, Schwartz DN,
Weinstein RA, Bennett CL (2000)
Improvements in outcomes of acute
respiratory failure for patients with
human immunodeficiency virus-related
Pneumocystis carinii pneumonia. Am J
Respir Crit Care Med 162:393–398
16. Davis JL, Morris A, Kallet RH, Powell
K, Chi AS, Bensley M, Luce JM,
Huang L (2008) Low tidal volume is
associated with reduced mortality in
HIV-infected patients with acute lung
injury. Thorax 63:988–993
17. Fei MW, Sant CA, Kim EJ, Swartzman
A, Davis JL, Jarlsberg LG, Huang L
(2009) Severity and outcomes of
pneumocystis pneumonia in patients
newly diagnosed with HIV infection: an
observational cohort study. Scand J
Infect Dis 11:1–7
18. Acute Respiratory Distress Network
(2000) Ventilation with lower tidal
volumes as compared with traditional
tidal volumes for acute lung injury and
the acute respiratory distress syndrome.
N Engl J Med 342:1301–1308
19. Rivers E, Nguyen B, Havstad S, Ressler
J, Muzzin A, Knoblich B, Peterson E,
Tomlanovich M (2001) Early goal-
directed therapy collaborative group.
Early goal-directed therapy in the
treatment of severe sepsis and septic
shock. N Engl J Med 345:1368–1377
20. van den Berghe G, Wouters P, Weekers
F, Verwaest C, Bruyninckx F, Schetz
M, Vlasselaers D, Ferdinande P,
Lauwers P, Bouillon R (2001) Intensive
insulin therapy in the critically ill
patients. N Engl J Med 345:1359–1367
1661


Early goaldirected therapy collaborative group. Early goal-directed therapy in the treatment of severe sepsis and septic shock.

Etiologies and outcome of acute respiratory failure in HIV-infected patients. J Intensive Care Med. doi:10.1007/s00134-009-1559-4 2. Palella

Intensive care in patients with HIV infection in the era of highly active antiretroviral therapy.

https://link.springer.com/content/pdf/10.1007%2Fs00134-009-1578-1.pdf

The ART of caring for patients with HIV infection in the ICU

Abstract

Similar works

Full text

Available Versions

Springer - Publisher Connector

Crossref

eScholarship - University of California

Springer - Publisher Connector