Lancet 2015

Treatment


1. Lancet. 2015 Sep 26;386(10000):1299-310. doi: 10.1016/S0140-6736(15)00277-9.

Diagnosis and treatment of acute extremity compartment syndrome.

von Keudell AG(1), Weaver MJ(2), Appelton PT(3), Bae DS(4), Dyer GS(5), Heng
M(6), Jupiter JB(6), Vrahas MS(5).

Author information: 
(1)Orthopedic Trauma Initiative at Harvard Medical School, Boston, MA, USA.
Electronic address: avonkeudell@mgh.harvard.edu. (2)Orthopedic Trauma Initiative
at Harvard Medical School, Boston, MA, USA; Department of Orthopedic Surgery,
Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
(3)Orthopedic Trauma Initiative at Harvard Medical School, Boston, MA, USA;
Department of Orthopedic Surgery, Beth Israel Deaconess Hospital, Harvard Medical
School, Boston, MA, USA. (4)Orthopedic Trauma Initiative at Harvard Medical
School, Boston, MA, USA; Department of Orthopedic Surgery, Boston Children's
Hospital, Harvard Medical School, Boston, MA, USA. (5)Orthopedic Trauma
Initiative at Harvard Medical School, Boston, MA, USA; Department of Orthopedic
Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA;
Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical
School, Boston, MA, USA. (6)Orthopedic Trauma Initiative at Harvard Medical
School, Boston, MA, USA; Department of Orthopedic Surgery, Massachusetts General
Hospital, Harvard Medical School, Boston, MA, USA.

Acute compartment syndrome of the extremities is well known, but diagnosis can be
challenging. Ineffective treatment can have devastating consequences, such as
permanent dysaesthesia, ischaemic contractures, muscle dysfunction, loss of limb,
and even loss of life. Despite many studies, there is no consensus about the way
in which acute extremity compartment syndromes should be diagnosed. Many surgeons
suggest continuous monitoring of intracompartmental pressure for all patients who
have high-risk extremity injuries, whereas others suggest aggressive surgical
intervention if acute compartment syndrome is even suspected. Although surgical
fasciotomy might reduce intracompartmental pressure, this procedure also carries
the risk of long-term complications. In this paper in The Lancet Series about
emergency surgery we summarise the available data on acute extremity compartment
syndrome of the upper and lower extremities in adults and children, discuss the
underlying pathophysiology, and propose a clinical guideline based on the
available data.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID: 26460664  [PubMed - indexed for MEDLINE]


2. Lancet. 2015 Oct 7. pii: S0140-6736(15)00391-8. doi:
10.1016/S0140-6736(15)00391-8. [Epub ahead of print]

High-sensitivity cardiac troponin I at presentation in patients with suspected
acute coronary syndrome: a cohort study.

Shah AS(1), Anand A(2), Sandoval Y(3), Lee KK(2), Smith SW(4), Adamson PD(2),
Chapman AR(2), Langdon T(2), Sandeman D(2), Vaswani A(2), Strachan FE(2), Ferry
A(2), Stirzaker AG(2), Reid A(5), Gray AJ(6), Collinson PO(7), McAllister DA(8), 
Apple FS(9), Newby DE(2), Mills NL(2); High-STEACS investigators.

Author information: 
(1)BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
Electronic address: anoop.shah@ed.ac.uk. (2)BHF Centre for Cardiovascular
Science, University of Edinburgh, Edinburgh, UK. (3)Division of Cardiology,
Department of Medicine, Hennepin County Medical Center, Minneapolis, MN, USA.
(4)Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis,
MN, USA; Department of Laboratory Medicine and Pathology, University of
Minnesota, Minneapolis, MN, USA. (5)Department of Biochemistry, Queen Elizabeth
University Hospital, Glasgow, UK. (6)Department of Emergency Medicine, Royal
Infirmary of Edinburgh, Edinburgh, UK. (7)Division of Clinical Sciences, St
George's, University of London, London, UK. (8)Centre for Population Health
Sciences, University of Edinburgh, Edinburgh, UK. (9)Department of Laboratory
Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.

BACKGROUND: Suspected acute coronary syndrome is the commonest reason for
emergency admission to hospital and is a large burden on health-care resources.
Strategies to identify low-risk patients suitable for immediate discharge would
have major benefits.
METHODS: We did a prospective cohort study of 6304 consecutively enrolled
patients with suspected acute coronary syndrome presenting to four secondary and
tertiary care hospitals in Scotland. We measured plasma troponin concentrations
at presentation using a high-sensitivity cardiac troponin I assay. In derivation
and validation cohorts, we evaluated the negative predictive value of a range of
troponin concentrations for the primary outcome of index myocardial infarction,
or subsequent myocardial infarction or cardiac death at 30 days. This trial is
registered with ClinicalTrials.gov (number NCT01852123).
FINDINGS: 782 (16%) of 4870 patients in the derivation cohort had index
myocardial infarction, with a further 32 (1%) re-presenting with myocardial
infarction and 75 (2%) cardiac deaths at 30 days. In patients without myocardial
infarction at presentation, troponin concentrations were less than 5 ng/L in 2311
(61%) of 3799 patients, with a negative predictive value of 99·6% (95% CI
99·3-99·8) for the primary outcome. The negative predictive value was consistent
across groups stratified by age, sex, risk factors, and previous cardiovascular
disease. In two independent validation cohorts, troponin concentrations were less
than 5 ng/L in 594 (56%) of 1061 patients, with an overall negative predictive
value of 99·4% (98·8-99·9). At 1 year, these patients had a lower risk of
myocardial infarction and cardiac death than did those with a troponin
concentration of 5 ng/L or more (0·6% vs 3·3%; adjusted hazard ratio 0·41, 95% CI
0·21-0·80; p<0·0001).
INTERPRETATION: Low plasma troponin concentrations identify two-thirds of
patients at very low risk of cardiac events who could be discharged from
hospital. Implementation of this approach could substantially reduce hospital
admissions and have major benefits for both patients and health-care providers.
FUNDING: British Heart Foundation and Chief Scientist Office (Scotland).

Copyright © 2015 Shah et al. Open Access article distributed under the terms of
CC BY-NC-ND. Published by Elsevier Ltd.. All rights reserved.

PMID: 26454362  [PubMed - as supplied by publisher]


3. Lancet. 2015 Sep 12;386(9998):1041-8. doi: 10.1016/S0140-6736(15)00163-4.

Oxygen saturation targets in infants with bronchiolitis (BIDS): a double-blind,
randomised, equivalence trial.

Cunningham S(1), Rodriguez A(2), Adams T(3), Boyd KA(4), Butcher I(2), Enderby
B(5), MacLean M(6), McCormick J(7), Paton JY(8), Wee F(6), Thomas H(9), Riding
K(10), Turner SW(11), Williams C(12), McIntosh E(4), Lewis SC(2); Bronchiolitis
of Infancy Discharge Study (BIDS) group.

Collaborators: Murray C, Powell C, Shields M, Gamble C, McKean M, McKenzie S,
Boyd KA, Butcher I, Cunningham S, Lewis SC, MacLean M, McIntosh E, Rodriguez A,
Tonner S, Wee F, Boyd KA, McIntosh E, Turner S, Cameron L, Nelson D, Paxton J,
Thomson V, Thomas H, Bingham T, Clark H, Clifford L, Lyttle M, Parham A, Potter
S, Robinson N, Spires H, McCormick J, MacFarlane S, Treanor F, Cunningham S,
Carson E, Gould V, Miller D, Duncan O, Riding K, Devon R, Enderby B, Harrill C,
Wilkins S, Paton J, Beattie J, Milne C, Waxman E, Adams T, Bell C, Henry M,
Williams C, Prendiville A, Craig G, Solomon H, Worrin N, Harkness R, Thomas S,
Walker A.

Author information: 
(1)Department of Child Life and Health, University of Edinburgh, Edinburgh, UK.
Electronic address: steve.cunningham@nhs.net. (2)Centre for Population Health
Sciences, University of Edinburgh, Edinburgh, UK. (3)Department of Paediatrics,
Crosshouse Hospital, Kilmarnock, UK. (4)Health Economics & Health Technology
Assessment, Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK. 
(5)The Royal Devon and Exeter Hospital, Exeter, UK. (6)Edinburgh Clinical Trials
Unit, University of Edinburgh, Edinburgh, UK. (7)Department of Paediatrics,
Ninewells Hospital and Medical School, Dundee, UK. (8)School of Medicine,
University of Glasgow, Glasgow, UK. (9)Department of Respiratory Medicine,
Bristol Children's Hospital, Bristol, UK. (10)Department of Child Life and
Health, University of Edinburgh, Edinburgh, UK. (11)Royal Aberdeen Children's
Hospital, Aberdeen, UK. (12)Royal Cornwall Hospital, Truro, UK.

Comment in
    Lancet. 2015 Sep 12;386(9998):1016-8.

BACKGROUND: The American Academy of Pediatrics recommends a permissive hypoxaemic
target for an oxygen saturation of 90% for children with bronchiolitis, which is
consistent with the WHO recommendations for targets in children with lower
respiratory tract infections. No evidence exists to support this threshold. We
aimed to assess whether the 90% or higher target for management of oxygen
supplementation was equivalent to a normoxic 94% or higher target for infants
admitted to hospital with viral bronchiolitis.
METHODS: We did a parallel-group, randomised, controlled, equivalence trial of
infants aged 6 weeks to 12 months of age with physician-diagnosed bronchiolitis
newly admitted into eight paediatric hospital units in the UK (the Bronchiolitis
of Infancy Discharge Study [BIDS]). A central computer randomly allocated (1:1)
infants, in varying length blocks of four and six and without stratification, to
be clipped to standard oximeters (patients treated with oxygen if pulse oxygen
saturation [SpO2] <94%) or modified oximeters (displayed a measured value of 90% 
as 94%, therefore oxygen not given until SpO2 <90%). All parents, clinical staff,
and outcome assessors were masked to allocation. The primary outcome was time to
resolution of cough (prespecified equivalence limits of plus or minus 2 days) in
the intention-to-treat population. This trial is registered with ISRCTN, number
ISRCTN28405428.
FINDINGS: Between Oct 3, and March 30, 2012, and Oct 1, and March 29, 2013, we
randomly assigned 308 infants to standard oximeters and 307 infants to modified
oximeters. Cough resolved by 15·0 days (median) in both groups (95% CI for
difference -1 to 2) and so oxygen thresholds were equivalent. We recorded 35
serious adverse events in 32 infants in the standard care group and 25 serious
adverse events in 24 infants in the modified care group. In the standard care
group, eight infants transferred to a high-dependency unit, 23 were readmitted,
and one had a prolonged hospital stay. In the modified care group, 12 infants
were transferred to a high-dependency unit and 12 were readmitted to hospital.
Recorded adverse events did not differ significantly.
INTERPRETATION: Management of infants with bronchiolitis to an oxygen saturation
target of 90% or higher is as safe and clinically effective as one of 94% or
higher. Future research should assess the benefits and risks of different oxygen
saturation targets in acute respiratory infection in older children, particularly
in developing nations where resources are scarce.
FUNDING: National Institute for Health Research, Health Technology Assessment
programme.

Copyright © 2015 Cunningham et al. Open Access article distributed under the
terms of CC BY-NC-ND. Published by Elsevier Ltd.. All rights reserved.

PMID: 26382998  [PubMed - indexed for MEDLINE]


4. Lancet. 2015 Feb 26;385 Suppl 1:S79. doi: 10.1016/S0140-6736(15)60394-4.

Cannabis use and treatment resistance in first episode psychosis: a natural
language processing study.

Patel R(1), Wilson R(2), Jackson R(3), Ball M(3), Shetty H(4), Broadbent M(4),
Stewart R(3), McGuire P(2), Bhattacharyya S(2).

Author information: 
(1)King's College London, Department of Psychosis Studies, Institute of
Psychiatry, London, UK. Electronic address: acmedsci@rpatel.co.uk. (2)King's
College London, Department of Psychosis Studies, Institute of Psychiatry, London,
UK. (3)King's College London, Department of Psychological Medicine, Institute of
Psychiatry, London, UK. (4)South London and Maudsley NHS Foundation Trust,
Biomedical Research Centre Nucleus, London, UK.

BACKGROUND: Cannabis is frequently used among individuals with first episode
psychosis and is associated with poor clinical outcomes. However, little is known
about the effect of cannabis use on the response to antipsychotic medications and
how use could affect outcomes. Using natural language processing on clinical data
from a large electronic case register, we sought to investigate whether
resistance to antipsychotic treatment mediated poor clinical outcomes associated
with cannabis use.
METHODS: Data were obtained from 2026 people with first episode psychosis in
south London, UK. Cannabis use documented in free text clinical records was
identified with natural language processing. Data for age, sex, ethnicity,
marital status, psychotic disorder diagnosis, subsequent hospital admission, and
number of unique antipsychotic medications prescribed were obtained using the
Clinical Record Interactive Search instrument. The association of these variables
with cannabis use was analysed with multivariable regression and mediation
analysis.
FINDINGS: 939 people (46·3%) with first episode psychosis were using cannabis at
first presentation. Cannabis use was most strongly associated with being 16-25
years old, male, and single, and was also associated with an increase in number
of hospital admissions (incidence rate ratio 1·50, 95% CI 1·25-1·80), compulsory
hospital admission (odds ratio 1·55, 1·16-2·08), and number of days spent in
hospital (β coefficient 35·1 days, 12·1-58·1) over 5 years' follow-up. An
increase in number of unique antipsychotic medications mediated an increase in
number of hospital admissions (natural indirect effect 1·11, 1·04-1·17; total
effect 1·41, 1·22-1·64), compulsory hospital admission (1·27, 1·10-1·45; 1·71,
1·05-2·78), and number of days spent in hospital (16·1, 6·7-25·5; 19·9,
2·5-37·3).
INTERPRETATION: We showed that a substantial number of people with first episode
psychosis used cannabis and that its use was associated with increased likelihood
of hospital admission and number of days spent in hospital. These associations
were partly mediated by an increase in number of unique antipsychotic medications
prescribed. These findings suggest that cannabis might reduce response to
conventional antipsychotic treatment and highlight the importance of strategies
to reduce its use.
FUNDING: National Institute for Health Research, UK Medical Research Council.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID: 26312901  [PubMed - in process]


5. Lancet. 2015 Feb 26;385 Suppl 1:S41. doi: 10.1016/S0140-6736(15)60356-7.

Emergency department attendance by patients with cancer in the last month of
life: a systematic review and meta-analysis.

Henson L(1), Gao W(2), Higginson I(2), Smith M(2), Davies J(2), Ellis-Smith C(2),
Daveson B(2).

Author information: 
(1)King's College London, London, UK. Electronic address:
lesley.henson@kcl.ac.uk. (2)King's College London, London, UK.

BACKGROUND: Emergency department visits towards the end of life by people with
cancer are increasing over time. This increase has occurred despite evidence of
an association with poor patient outcomes, the majority of patients preferring
home-based care, and significant overcrowding and capacity concerns for many
emergency departments. We aimed to explore factors associated with emergency
department attendance by cancer patients in the last month of life.
METHODS: We searched Medline, Embase, CINAHL, PsychINFO, and the Cochrane Library
from inception to February, 2014, for studies investigating emergency department
attendances by adult cancer patients (≥18 years) towards the end of life. No time
or language limitations were applied. We performed meta-analysis of factors using
a random-effects model, with results expressed as odds ratios (OR) for emergency
department attendance. Sensitivity analysis explored heterogeneity.
FINDINGS: 30 studies were identified, reporting three demographic, five clinical,
and 13 environmental factors; they included data from five countries and
1 181 842 patients. An increased likelihood of emergency department attendance
was found for men versus women (OR 1·24, 95% CI 1·19-1·29), black versus white
race (1·45, 1·40-1·50), patients with lung cancer versus other cancers (1·17,
1·10-1·23), and those of lowest versus highest socioeconomic status (1·15,
1·10-1·19). Patients receiving palliative care were less likely than those not
receiving palliative care to attend the emergency department in the last month of
life (OR 0·43, 95% CI 0·36-0·51).
INTERPRETATION: We have identified demographic (men, black race), clinical (lung
cancer), and environmental (low socioeconomic status, no palliative care) factors
associated with an increased risk of emergency department attendance. These
findings could be used to develop screening interventions and assist policy
makers in directing limited resources. Future studies should also investigate
previously neglected areas of research, including psychosocial factors, and the
emergency care preferences of patients and caregivers.
FUNDING: LH is a PhD clinical training fellow and funded through project
BuildCARE which is supported by Cicely Saunders International and The Atlantic
Philanthropies, and led by King's College London, Cicely Saunders Institute of
Palliative Care, Policy & Rehabilitation, UK.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID: 26312863  [PubMed - in process]


6. Lancet. 2015 Aug 1;386(9992):469-78. doi: 10.1016/S0140-6736(15)61167-9.

Long-term effects of radiation exposure on health.

Kamiya K(1), Ozasa K(2), Akiba S(3), Niwa O(4), Kodama K(5), Takamura N(6),
Zaharieva EK(7), Kimura Y(6), Wakeford R(8).

Author information: 
(1)Department of Experimental Oncology, Research Institute for Radiation Biology
and Medicine, Hiroshima University, Hiroshima, Japan. Electronic address:
kkamiya@hiroshima-u.ac.jp. (2)Department of Epidemiology, Hiroshima, Japan.
(3)Epidemiology and Preventive Medicine, Kagoshima University Graduate School of
Medical and Dental Sciences, Kagoshima, Japan. (4)Fukushima Global Medical
Science Center, Fukushima Medical University, Fukushima, Japan. (5)Radiation
Effects Research Foundation, Hiroshima, Japan. (6)Department of Global Health,
Medicine and Welfare, Atomic Bomb Disease Institute, Nagasaki University,
Nagasaki, Japan. (7)Department of Genetics and Cell Biology, Research Institute
for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
(8)Centre for Occupational and Environmental Health, Institute of Population
Health, The University of Manchester, Manchester, UK.

Comment in
    Lancet. 2015 Oct 31;386(10005):1737-8.

Late-onset effects of exposure to ionising radiation on the human body have been
identified by long-term, large-scale epidemiological studies. The cohort study of
Japanese survivors of the atomic bombings of Hiroshima and Nagasaki (the Life
Span Study) is thought to be the most reliable source of information about these
health effects because of the size of the cohort, the exposure of a general
population of both sexes and all ages, and the wide range of individually
assessed doses. For this reason, the Life Span Study has become fundamental to
risk assessment in the radiation protection system of the International
Commission on Radiological Protection and other authorities. Radiation exposure
increases the risk of cancer throughout life, so continued follow-up of survivors
is essential. Overall, survivors have a clear radiation-related excess risk of
cancer, and people exposed as children have a higher risk of radiation-induced
cancer than those exposed at older ages. At high doses, and possibly at low
doses, radiation might increase the risk of cardiovascular disease and some other
non-cancer diseases. Hereditary effects in the children of atomic bomb survivors
have not been detected. The dose-response relation for cancer at low doses is
assumed, for purposes of radiological protection, to be linear without a
threshold, but has not been shown definitively. This outstanding issue is not
only a problem when dealing appropriately with potential health effects of
nuclear accidents, such as at Fukushima and Chernobyl, but is of growing concern
in occupational and medical exposure. Therefore, the appropriate dose-response
relation for effects of low doses of radiation needs to be established.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID: 26251392  [PubMed - indexed for MEDLINE]


7. Lancet. 2015 Sep 5;386(9997):974-81. doi: 10.1016/S0140-6736(15)61137-0. Epub
2015 Jun 28.

Oral versus intravenous high-dose methylprednisolone for treatment of relapses in
patients with multiple sclerosis (COPOUSEP): a randomised, controlled,
double-blind, non-inferiority trial.

Le Page E(1), Veillard D(2), Laplaud DA(3), Hamonic S(2), Wardi R(4), Lebrun
C(5), Zagnoli F(6), Wiertlewski S(7), Deburghgraeve V(1), Coustans M(8), Edan
G(9); COPOUSEP investigators; West Network for Excellence in Neuroscience.

Collaborators: Lallement F, Cohen M, Blanchard C, Sartori E, Demarco O, Rouhart
F, Papeix C, Taurin G, Anani T, Kassiotis P, Hamon C, Lester MA, Merienne M,
Coustans M, Javaudin L, Hamon C, Rouhart F, Zagnoli F, Lallement F, Taurin G,
Kassiotis P, Sartori E, Massengo S, Anani T, Laplaud D, Wiertlewski S, De Marco
O, Papeix C, Lubetski C, Lebrun Frenay C.

Author information: 
(1)Clinical Neuroscience Centre, CIC-P 1414 INSERM, Rennes University Hospital,
Rennes, France. (2)Epidemiology and Public Health Department, Rennes University
Hospital, Rennes, France. (3)UMR1064, INSERM, and CIC015, INSERM, Nantes, France.
(4)Neurology Department, Saint Brieuc Hospital, Saint-Brieuc, France.
(5)Neurology Department, Nice University Hospital, Nice, France. (6)Neurology
Department, Military Hospital, Brest, France. (7)Neurology Department, Nantes
University Hospital, Nantes, France. (8)Neurology Department, Quimper Hospital,
Quimper, France. (9)Clinical Neuroscience Centre, CIC-P 1414 INSERM, Rennes
University Hospital, Rennes, France. Electronic address:
gilles.edan@chu-rennes.fr.

Comment in
    Lancet. 2015 Sep 5;386(9997):937-9.

BACKGROUND: High doses of intravenous methylprednisolone are recommended to treat
relapses in patients with multiple sclerosis, but can be inconvenient and
expensive. We aimed to assess whether oral administration of high-dose
methylprednisolone was non-inferior to intravenous administration.
METHODS: We did this multicentre, double-blind, randomised, controlled,
non-inferiority trial at 13 centres for multiple sclerosis in France. We enrolled
patients aged 18-55 years with relapsing-remitting multiple sclerosis who
reported a relapse within the previous 15 days that caused an increase of at
least one point in one or more scores on the Kurtzke Functional System Scale.
With use of a computer-generated randomisation list and in blocks of four, we
randomly assigned (1:1) patients to either oral or intravenous
methylprednisolone, 1000 mg, once a day for 3 days. Patients, treating physicians
and nurses, and data and outcome assessors were all masked to treatment
allocation, which was achieved with the use of saline solution and placebo
capsules. The primary endpoint was the proportion of patients who had improved by
day 28 (decrease of at least one point in most affected score on Kurtzke
Functional System Scale), without need for retreatment with corticosteroids, in
the per-protocol population. The trial was powered to assess non-inferiority of
oral compared with intravenous methylprednisolone with a predetermined
non-inferiority margin of 15%. This trial is registered with ClinicalTrials.gov, 
number NCT00984984.
FINDINGS: Between Jan 29, 2008, and June 14, 2013, we screened 200 patients and
enrolled 199. We randomly assigned 100 patients to oral methylprednisolone and 99
patients to intravenous methylprednisolone with a mean time from relapse onset to
treatment of 7·0 days (SD 3·6) and 7·4 days (3·9), respectively. In the
per-protocol population, 66 (81%) of 82 patients in the oral group and 72 (80%)
of 90 patients in the intravenous group achieved the primary endpoint (absolute
treatment difference 0·5%, 90% CI -9·5 to 10·4). Rates of adverse events were
similar, but insomnia was more frequently reported in the oral group (77 [77%])
than in the intravenous group (63 [64%]).
INTERPRETATION: Oral administration of high-dose methylprednisolone for 3 days
was not inferior to intravenous administration for improvement of disability
scores 1 month after treatment and had a similar safety profile. This finding
could have implications for access to treatment, patient comfort, and cost, but
indication should always be properly considered by clinicians.
FUNDING: French Health Ministry, Ligue Française contre la SEP, Teva.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID: 26135706  [PubMed - indexed for MEDLINE]


8. Lancet. 2015 Jul 25;386(9991):341-9. doi: 10.1016/S0140-6736(15)60933-3. Epub
2015 May 18.

Medical expulsive therapy in adults with ureteric colic: a multicentre,
randomised, placebo-controlled trial.

Pickard R(1), Starr K(2), MacLennan G(2), Lam T(3), Thomas R(2), Burr J(4),
McPherson G(2), McDonald A(2), Anson K(5), N'Dow J(3), Burgess N(6), Clark T(7), 
Kilonzo M(8), Gillies K(2), Shearer K(2), Boachie C(2), Cameron S(2), Norrie
J(2), McClinton S(9).

Author information: 
(1)Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
(2)Centre for Healthcare Randomised Trials, Health Services Research Unit,
University of Aberdeen, Aberdeen, UK. (3)Academic Urology Unit, University of
Aberdeen, Aberdeen, UK. (4)School of Medicine, University of St Andrews, St
Andrews, UK. (5)St Georges Healthcare NHS Trust, London, UK. (6)Norfolk and
Norwich University Hospitals NHS Foundation Trust, Norwich, UK. (7)Stone Patient
Advisory Group, Section of Endourology, British Association of Urological
Surgeons, London, UK. (8)Health Economics Research Unit, University of Aberdeen, 
Aberdeen, UK. (9)Academic Urology Unit, University of Aberdeen, Aberdeen, UK;
Aberdeen Royal Infirmary, NHS Grampian, Aberdeen, UK. Electronic address:
smcclinton@nhs.net.

Comment in
    Lancet. 2015 Jul 25;386(9991):315-6.
    Nat Rev Urol. 2015 Jul;12(7):357.

BACKGROUND: Meta-analyses of previous randomised controlled trials concluded that
the smooth muscle relaxant drugs tamsulosin and nifedipine assisted stone passage
for people managed expectantly for ureteric colic, but emphasised the need for
high-quality trials with wide inclusion criteria. We aimed to fulfil this need by
testing effectiveness of these drugs in a standard clinical care setting.
METHODS: For this multicentre, randomised, placebo-controlled trial, we recruited
adults (aged 18-65 years) undergoing expectant management for a single ureteric
stone identified by CT at 24 UK hospitals. Participants were randomly assigned by
a remote randomisation system to tamsulosin 400 μg, nifedipine 30 mg, or placebo
taken daily for up to 4 weeks, using an algorithm with centre, stone size (≤5 mm
or >5 mm), and stone location (upper, mid, or lower ureter) as minimisation
covariates. Participants, clinicians, and trial personnel were masked to
treatment assignment. The primary outcome was the proportion of participants who
did not need further intervention for stone clearance within 4 weeks of
randomisation, analysed in a modified intention-to-treat population defined as
all eligible patients for whom we had primary outcome data. This trial is
registered with the European Clinical Trials Database, EudraCT number
2010-019469-26, and as an International Standard Randomised Controlled Trial,
number 69423238.
FINDINGS: Between Jan 11, 2011, and Dec 20, 2013, we randomly assigned 1167
participants, 1136 (97%) of whom were included in the primary analysis (17 were
excluded because of ineligibility and 14 participants were lost to follow-up).
303 (80%) of 379 participants in the placebo group did not need further
intervention by 4 weeks, compared with 307 (81%) of 378 in the tamsulosin group
(adjusted risk difference 1·3% [95% CI -5·7 to 8·3]; p=0·73) and 304 (80%) of 379
in the nifedipine group (0·5% [-5·6 to 6·5]; p=0·88). No difference was noted
between active treatment and placebo (p=0·78), or between tamsulosin and
nifedipine (p=0·77). Serious adverse events were reported in three participants
in the nifedipine group (one had right loin pain, diarrhoea, and vomiting; one
had malaise, headache, and chest pain; and one had severe chest pain, difficulty
breathing, and left arm pain) and in one participant in the placebo group
(headache, dizziness, lightheadedness, and chronic abdominal pain).
INTERPRETATION: Tamsulosin 400 μg and nifedipine 30 mg are not effective at
decreasing the need for further treatment to achieve stone clearance in 4 weeks
for patients with expectantly managed ureteric colic.
FUNDING: UK National Institute for Health Research Health Technology Assessment
Programme.

Copyright © 2015 Pickard et al. Open Access article distributed under the terms
of CC BY. Published by Elsevier Ltd.. All rights reserved.

PMID: 25998582  [PubMed - in process]


9. Lancet. 2015 May 2;385(9979):1758-66. doi: 10.1016/S0140-6736(14)62285-6. Epub
2015 Apr 1.

Oral amoxicillin compared with injectable procaine benzylpenicillin plus
gentamicin for treatment of neonates and young infants with fast breathing when
referral is not possible: a randomised, open-label, equivalence trial.

African Neonatal Sepsis Trial (AFRINEST) group, Tshefu A(1), Lokangaka A(1),
Ngaima S(1), Engmann C(2), Esamai F(3), Gisore P(3), Ayede AI(4), Falade AG(4),
Adejuyigbe EA(5), Anyabolu CH(6), Wammanda RD(7), Ejembi CL(8), Ogala WN(7), Gram
L(9), Cousens S(9).

Author information: 
(1)Department of Community Health, Kinshasa School of Public Health, Kinshasa, DR
Congo. (2)Departments of Pediatrics and Maternal Child Health, Schools of
Medicine and Public Health, University of North Carolina, Chapel Hill, NC, USA.
(3)Department of Child Health and Paediatrics, School of Medicine, Moi
University, Eldoret, Kenya. (4)Department of Paediatrics, College of Medicine,
University of Ibadan, and University College Hospital, Ibadan, Nigeria.
(5)Department of Paediatrics and Child Health, Obafemi Awolowo University,
Ile-Ife, Nigeria. Electronic address: ebunadejuyigbe@hotmail.com. (6)Department
of Paediatrics and Child Health, Obafemi Awolowo University, Ile-Ife, Nigeria.
(7)Department of Paediatrics, Ahmadu Bello University Teaching Hospital, Ahmadu
Bello University, Zaria, Nigeria. (8)Department of Community Medicine, Ahmadu
Bello University Teaching Hospital, Ahmadu Bello University, Zaria, Nigeria.
(9)Department of Infectious Disease Epidemiology, Faculty of Epidemiology and
Population Health, London School of Hygiene & Tropical Medicine, London, UK.

Comment in
    J Pediatr. 2015 Sep;167(3):778-9.
    Lancet. 2015 May 2;385(9979):1706-9.
    Lancet. 2015 Oct 3;386(10001):1339.
    Lancet. 2015 Oct 3;386(10001):1338-9.

BACKGROUND: WHO recommends referral to hospital for possible serious bacterial
infection in young infants aged 0-59 days. We aimed to assess whether oral
amoxicillin treatment for fast breathing, in the absence of other signs, is as
efficacious as the combination of injectable procaine
benzylpenicillin-gentamicin.
METHODS: In a randomised, open-label, equivalence trial at five sites in DR
Congo, Kenya, and Nigeria, community health workers followed up all births in the
community, identified unwell young infants, and referred them to study nurses. We
randomly assigned infants with fast breathing as a single sign of illness or
possible serious bacterial infection, whose parents did not accept referral to
hospital, to receive either injectable procaine benzylpenicillin-gentamicin once
per day or oral amoxicillin treatment twice per day for 7 days. A person who was
off-site generated randomisation lists using computer software. Trained health
professionals gave injections, but outcome assessors were masked to group
allocations. The primary outcome was treatment failure by day 8 after enrolment, 
defined as clinical deterioration, development of a serious adverse event
including death, persistence of fast breathing on day 4, or recurrence up to day
8. The primary analysis was per protocol and we used a prespecified similarity
margin of 5% to assess equivalence between regimens. This study is registered
with the Australian New Zealand Clinical Trials Registry, number
ACTRN12610000286044.
FINDINGS: From April 4, 2011, to March 29, 2013, we enrolled 2333 infants aged
0-59 days with fast breathing as the only sign of possible serious bacterial
infection at the five study sites. We assigned 1170 infants to receive injectable
procaine benzylpenicillin-gentamicin and 1163 infants to receive oral
amoxicillin. In the per-protocol analysis, from which 137 infants were excluded, 
we included 1061 (91%) infants who fulfilled predefined criteria of adherence to
treatment and adequate follow-up in the injectable procaine
benzylpenicillin-gentamicin group and 1145 (98%) infants in the oral amoxicillin
group. In the procaine benzylpenicillin-gentamicin group, 234 infants (22%)
failed treatment, compared with 221 (19%) infants in the oral amoxicillin group
(risk difference -2·6%, 95% CI -6·0 to 0·8). Four infants died within 15 days of
follow-up in each group. We detected no drug-related serious adverse events.
INTERPRETATION: Young infants with fast breathing alone can be effectively
treated with oral amoxicillin on an outpatient basis when referral to a hospital
is not possible.
FUNDING: Bill & Melinda Gates Foundation grant to WHO.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID: 25842223  [PubMed - indexed for MEDLINE]


10. Lancet. 2015 May 2;385(9979):1767-76. doi: 10.1016/S0140-6736(14)62284-4. Epub
2015 Apr 1.

Simplified antibiotic regimens compared with injectable procaine benzylpenicillin
plus gentamicin for treatment of neonates and young infants with clinical signs
of possible serious bacterial infection when referral is not possible: a
randomised, open-label, equivalence trial.

African Neonatal Sepsis Trial (AFRINEST) group, Tshefu A(1), Lokangaka A(1),
Ngaima S(1), Engmann C(2), Esamai F(3), Gisore P(4), Ayede AI(5), Falade AG(5),
Adejuyigbe EA(6), Anyabolu CH(6), Wammanda RD(7), Ejembi CL(8), Ogala WN(7), Gram
L(9), Cousens S(9).

Author information: 
(1)Department of Community Health, Kinshasa School of Public Health, Kinshasa, DR
Congo. (2)Departments of Pediatrics and Maternal Child Health, Schools of
Medicine and Public Health, University of North Carolina, Chapel Hill, NC, USA.
(3)Department of Child Health and Paediatrics, School of Medicine, Moi
University, Eldoret, Kenya. Electronic address: fesamai2007@gmail.com.
(4)Department of Child Health and Paediatrics, School of Medicine, Moi
University, Eldoret, Kenya. (5)Department of Paediatrics, College of Medicine,
University of Ibadan, and University College Hospital, Ibadan, Nigeria.
(6)Department of Paediatrics and Child Health, Obafemi Awolowo University,
Ile-Ife, Nigeria. (7)Department of Paediatrics, Ahmadu Bello University Teaching
Hospital, Ahmadu Bello University, Zaria, Nigeria. (8)Department of Community
Medicine, Ahmadu Bello University Teaching Hospital, Ahmadu Bello University,
Zaria, Nigeria. (9)Department of Infectious Disease Epidemiology, Faculty of
Epidemiology and Population Health, London School of Hygiene & Tropical Medicine,
London, UK.

Comment in
    Lancet. 2015 Oct 3;386(10001):1337.
    Lancet. 2015 Oct 3;386(10001):1339.
    Lancet. 2015 May 2;385(9979):1706-9.
    Lancet. 2015 Oct 3;386(10001):1337-8.
    Lancet. 2015 Oct 3;386(10001):1338-9.

BACKGROUND: WHO recommends hospital-based treatment for young infants aged 0-59
days with clinical signs of possible serious bacterial infection, but most
families in resource-poor settings cannot accept referral. We aimed to assess
whether use of simplified antibiotic regimens to treat young infants with
clinical signs of severe infection was as efficacious as an injectable procaine
benzylpenicillin-gentamicin combination for 7 days for situations in which
hospital referral was not possible.
METHODS: In a multisite open-label equivalence trial in DR Congo, Kenya, and
Nigeria, community health workers visited all newborn babies at home, identifying
and referring unwell young infants to a study nurse. We stratified young infants
with clinical signs of severe infection whose parents did not accept referral to
hospital by age (0-6 days and 7-59 days), and randomly assigned each individual
within these strata to receive one of the four treatment regimens. Randomisation
was stratified by age group of infants. An age-stratified randomisation scheme
with block size of eight was computer-generated off-site at WHO. The outcome
assessor was masked. We randomly allocated infants to receive injectable procaine
benzylpenicillin-gentamicin for 7 days (group A, reference group); injectable
gentamicin and oral amoxicillin for 7 days (group B); injectable procaine
benzylpenicillin-gentamicin for 2 days, then oral amoxicillin for 5 days (group
C); or injectable gentamicin for 2 days and oral amoxicillin for 7 days (group
D). Trained health professionals gave daily injections and the first dose of oral
amoxicillin. Our primary outcome was treatment failure by day 8 after enrolment, 
defined as clinical deterioration, development of a serious adverse event
(including death), no improvement by day 4, or not cured by day 8. Independent
outcome assessors, who did not know the infant's treatment regimen, assessed
study outcomes on days 4, 8, 11, and 15. Primary analysis was per protocol. We
used a prespecified similarity margin of 5% to assess equivalence between
regimens. This study is registered with the Australian New Zealand Clinical
Trials Registry, number ACTRN12610000286044.
FINDINGS: In Kenya and Nigeria, we started enrolment on April 4, 2011, and we
enrolled the necessary number of young infants aged 7 days or older from Oct 17, 
2011, to April 30, 2012. At these sites, we continued to enrol infants younger
than 7 days until March 29, 2013. In DR Congo, we started enrolment on Sept 17,
2012, and continued until June 28, 2013. We randomly assigned 3564 young infants
to either group A (n=894), group B (n=884), group C (n=896), or group D (n=890). 
We excluded 200 randomly assigned infants, who did not fulfil the predefined
criteria of adherence to treatment and adequate follow-up. In the per-protocol
analysis, 828 infants were included in group A, 826 in group B, 862 in group C,
and 848 in group D. 67 (8%) infants failed treatment in group A compared with 51
(6%) infants in group B (risk difference -1·9%, 95% CI -4·4 to 0·1), 65 (8%) in
group C (-0·6%, -3·1 to 2·0), and 46 (5%) in group D (-2·7%, -5·1 to 0·3).
Treatment failure in groups B, C, and D was within the similarity margin compared
with group A. During the 15 days after random allocation, 12 (1%) infants died in
group A, compared with ten (1%) infants in group B, 20 (2%) infants in group C,
and 11 (1%) infants in group D. An infant in group A had a serious adverse event
other than death (injection abscess).
INTERPRETATION: The three simplified regimens were as effective as injectable
procaine benzylpenicillin-gentamicin for 7 days on an outpatient basis in young
infants with clinical signs of severe infection, without signs of critical
illness, and whose caregivers did not accept referral for hospital admission.
FUNDING: Bill & Melinda Gates Foundation grant to WHO.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID: 25842221  [PubMed - indexed for MEDLINE]


11. Lancet. 2015 Feb 28;385(9970):800-11. doi: 10.1016/S0140-6736(14)61005-9. Epub
2015 Feb 6.

Management of acute aortic dissection.

Nienaber CA(1), Clough RE(2).

Author information: 
(1)University Heart Centre Rostock, University of Rostock, Rostock, Germany.
Electronic address: christoph.nienaber@med.uni-rostock.de. (2)King's College
London, Cardiovascular Imaging Department, Lambeth Wing St Thomas, London, UK.

A new appraisal of the management of acute aortic dissection is timely because of
recent developments in diagnostic strategies (including biomarkers and imaging), 
endograft design, and surgical treatment, which have led to a better
understanding of the epidemiology, risk factors, and molecular nature of aortic
dissection. Although open surgery is the main treatment for proximal aortic
repair, use of endovascular management is now established for complicated distal
dissection and distal arch repair, and has recently been discussed as a
pre-emptive measure to avoid late complications by inducing aortic remodelling.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID: 25662791  [PubMed - indexed for MEDLINE]


12. Lancet. 2015 May 2;385(9979):1729-37. doi: 10.1016/S0140-6736(14)62449-1. Epub
2015 Jan 30.

Oseltamivir treatment for influenza in adults: a meta-analysis of randomised
controlled trials.

Dobson J(1), Whitley RJ(2), Pocock S(1), Monto AS(3).

Author information: 
(1)Department of Medical Statistics, London School of Hygiene & Tropical
Medicine, London, UK. (2)Department of Pediatrics, Microbiology, Medicine and
Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
(3)Department of Epidemiology, University of Michigan School of Public Health,
MI, USA. Electronic address: asmonto@umich.edu.

Erratum in
    Lancet. 2015 May 2;385(9979):1728.
    Lancet. 2015 May 2;385(9979):1728.

Comment in
    Lancet. 2015 Sep 19;386(9999):1134-5.
    Lancet. 2015 Sep 19;386(9999):1135.
    Lancet. 2015 May 2;385(9979):1700-2.
    Lancet. 2015 Sep 19;386(9999):1135-6.
    Lancet. 2015 Sep 19;386(9999):1134.
    Lancet. 2015 Sep 19;386(9999):1133-4.

BACKGROUND: Despite widespread use, questions remain about the efficacy of
oseltamivir in the treatment of influenza. We aimed to do an individual patient
data meta-analysis for all clinical trials comparing oseltamivir with placebo for
treatment of seasonal influenza in adults regarding symptom alleviation,
complications, and safety.
METHODS: We included all published and unpublished Roche-sponsored randomised
placebo-controlled, double-blind trials of 75 mg twice a day oseltamivir in
adults. Trials of oseltamivir for treatment of naturally occurring influenza-like
illness in adults reporting at least one of the study outcomes were eligible. We
also searched Medline, PubMed, Embase, the Cochrane Central Register of
Controlled Trials, and the ClinicalTrials.gov trials register for other relevant
trials published before Jan 1, 2014 (search last updated on Nov 27, 2014). We
analysed intention-to-treat infected, intention-to-treat, and safety populations.
The primary outcome was time to alleviation of all symptoms analysed with
accelerated failure time methods. We used risk ratios and Mantel-Haenszel methods
to work out complications, admittances to hospital, and safety outcomes.
FINDINGS: We included data from nine trials including 4328 patients. In the
intention-to-treat infected population, we noted a 21% shorter time to
alleviation of all symptoms for oseltamivir versus placebo recipients (time ratio
0·79, 95% CI 0·74-0·85; p<0·0001). The median times to alleviation were 97·5 h
for oseltamivir and 122·7 h for placebo groups (difference -25·2 h, 95% CI -36·2
to -16·0). For the intention-to-treat population, the estimated treatment effect
was attenuated (time ratio 0·85) but remained highly significant (median
difference -17·8 h). In the intention-to-treat infected population, we noted
fewer lower respiratory tract complications requiring antibiotics more than 48 h
after randomisation (risk ratio [RR] 0·56, 95% CI 0·42-0·75; p=0·0001; 4·9%
oseltamivir vs 8·7% placebo, risk difference -3·8%, 95% CI -5·0 to -2·2) and also
fewer admittances to hospital for any cause (RR 0·37, 95% CI 0·17-0·81; p=0·013; 
0·6% oseltamivir, 1·7% placebo, risk difference -1·1%, 95% CI -1·4 to -0·3).
Regarding safety, oseltamivir increased the risk of nausea (RR 1·60, 95% CI
1·29-1·99; p<0·0001; 9·9% oseltamivir vs 6·2% placebo, risk difference 3·7%, 95% 
CI 1·8-6·1) and vomiting (RR 2·43, 95% CI 1·83-3·23; p<0·0001; 8·0% oseltamivir
vs 3·3% placebo, risk difference 4·7%, 95% CI 2·7-7·3). We recorded no effect on
neurological or psychiatric disorders or serious adverse events.
INTERPRETATION: Our findings show that oseltamivir in adults with influenza
accelerates time to clinical symptom alleviation, reduces risk of lower
respiratory tract complications, and admittance to hospital, but increases the
occurrence of nausea and vomiting.
FUNDING: Multiparty Group for Advice on Science (MUGAS) foundation.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID: 25640810  [PubMed - indexed for MEDLINE]


13. Lancet. 2015 Apr 18;385(9977):1511-8. doi: 10.1016/S0140-6736(14)62447-8. Epub
2015 Jan 19.

Adjunct prednisone therapy for patients with community-acquired pneumonia: a
multicentre, double-blind, randomised, placebo-controlled trial.

Blum CA(1), Nigro N(2), Briel M(3), Schuetz P(4), Ullmer E(5), Suter-Widmer I(2),
Winzeler B(2), Bingisser R(6), Elsaesser H(5), Drozdov D(4), Arici B(1), Urwyler
SA(2), Refardt J(2), Tarr P(7), Wirz S(7), Thomann R(8), Baumgartner C(9),
Duplain H(10), Burki D(11), Zimmerli W(5), Rodondi N(9), Mueller B(4),
Christ-Crain M(12).

Author information: 
(1)Endocrinology, Diabetology and Metabolism, Department of Internal Medicine and
Department of Clinical Research, University Hospital Basel, Basel, Switzerland;
Medical University Clinic, Departments of Internal and Emergency Medicine and
Department of Endocrinology, Diabetology and Clinical Nutrition, Kantonsspital
Aarau, Aarau, Switzerland. (2)Endocrinology, Diabetology and Metabolism,
Department of Internal Medicine and Department of Clinical Research, University
Hospital Basel, Basel, Switzerland. (3)Basel Institute for Clinical Epidemiology
and Biostatistics, Department of Clinical Research, University Hospital Basel,
Basel, Switzerland; Department of Clinical Epidemiology and Biostatistics,
McMaster University, Hamilton, ON, Canada. (4)Medical University Clinic,
Departments of Internal and Emergency Medicine and Department of Endocrinology,
Diabetology and Clinical Nutrition, Kantonsspital Aarau, Aarau, Switzerland.
(5)Medical University Clinic, Kantonsspital Baselland/Liestal, Liestal,
Switzerland. (6)Emergency Department, University Hospital Basel, Basel,
Switzerland. (7)Medical University Clinic, Kantonsspital Baselland/Bruderholz,
Bruderholz, Switzerland. (8)Department of Internal Medicine, Bürgerspital,
Solothurn, Switzerland. (9)Department of General Internal Medicine, Inselspital, 
Bern University Hospital, Bern, Switzerland. (10)Clinic of Internal Medicine,
Hôpital du Jura, Site de Delémont, Delémont, Switzerland. (11)Viollier AG,
Postfach, Basel, Switzerland. (12)Endocrinology, Diabetology and Metabolism,
Department of Internal Medicine and Department of Clinical Research, University
Hospital Basel, Basel, Switzerland. Electronic address: mirjam.christ@usb.ch.

Comment in
    Lancet. 2015 Sep 5;386(9997):954.
    Lancet. 2015 Sep 5;386(9997):953.
    Lancet. 2015 Sep 5;386(9997):955.
    Rev Med Suisse. 2015 Mar 11;11(465):625.
    Lancet. 2015 Sep 5;386(9997):954-5.
    Lancet. 2015 Aug 1;386(9992):431.
    Lancet. 2015 Sep 5;386(9997):956.
    Lancet. 2015 Apr 18;385(9977):1484-5.
    Lancet. 2015 Sep 5;386(9997):954.

BACKGROUND: Clinical trials yielded conflicting data about the benefit of adding
systemic corticosteroids for treatment of community-acquired pneumonia. We
assessed whether short-term corticosteroid treatment reduces time to clinical
stability in patients admitted to hospital for community-acquired pneumonia.
METHODS: In this double-blind, multicentre, randomised, placebo-controlled trial,
we recruited patients aged 18 years or older with community-acquired pneumonia
from seven tertiary care hospitals in Switzerland within 24 h of presentation.
Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg
daily for 7 days or placebo. The computer-generated randomisation was done with
variable block sizes of four to six and stratified by study centre. The primary
endpoint was time to clinical stability defined as time (days) until stable vital
signs for at least 24 h, and analysed by intention to treat. This trial is
registered with ClinicalTrials.gov, number NCT00973154.
FINDINGS: From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for
eligibility, 785 patients were randomly assigned to either the prednisone group
(n=392) or the placebo group (n=393). Median time to clinical stability was
shorter in the prednisone group (3·0 days, IQR 2·5-3·4) than in the placebo group
(4·4 days, 4·0-5·0; hazard ratio [HR] 1·33, 95% CI 1·15-1·50, p<0·0001).
Pneumonia-associated complications until day 30 did not differ between groups (11
[3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR]
0·49 [95% CI 0·23-1·02]; p=0·056). The prednisone group had a higher incidence of
in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR
1·96, 95% CI 1·31-2·93, p=0·0010). Other adverse events compatible with
corticosteroid use were rare and similar in both groups.
INTERPRETATION: Prednisone treatment for 7 days in patients with
community-acquired pneumonia admitted to hospital shortens time to clinical
stability without an increase in complications. This finding is relevant from a
patient perspective and an important determinant of hospital costs and
efficiency.
FUNDING: Swiss National Science Foundation, Viollier AG, Nora van Meeuwen
Haefliger Stiftung, Julia und Gottfried Bangerter-Rhyner Stiftung.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID: 25608756  [PubMed - indexed for MEDLINE]


14. Lancet. 2015 Mar 14;385(9972):947-55. doi: 10.1016/S0140-6736(14)61886-9. Epub
2014 Nov 16.

Mechanical versus manual chest compression for out-of-hospital cardiac arrest
(PARAMEDIC): a pragmatic, cluster randomised controlled trial.

Perkins GD(1), Lall R(2), Quinn T(3), Deakin CD(4), Cooke MW(2), Horton J(2),
Lamb SE(5), Slowther AM(2), Woollard M(3), Carson A(6), Smyth M(7), Whitfield
R(8), Williams A(8), Pocock H(9), Black JJ(9), Wright J(10), Han K(11), Gates
S(2); PARAMEDIC trial collaborators.

Collaborators: Gordon V, Kaye C, Brace-McDonnell S, Johnson H, Ruders I, Davis S,
Rumble S, Packard K, Hoddell B, Morrow N, Daffern C, Hennings S, Duggan S, Willis
A, Muthiah C, Price G, Jones I, Hallam P, Harris E, Rosser A, Parcell G, Wilson
K, England E, Teague I, Rooke H, Brock N, Jones R, Byers S, Blair L, Shaw G,
McClelland G, Norris J, Williams K, McCabe C, Hulme C, Kelly C.

Author information: 
(1)Warwick Clinical Trials Unit, University of Warwick, Coventry, UK; Heart of
England NHS Foundation Trust, Birmingham, UK. Electronic address:
g.d.perkins@warwick.ac.uk. (2)Warwick Clinical Trials Unit, University of
Warwick, Coventry, UK. (3)Surrey Peri-operative Anaesthesia Critical care
collaborative Research Group, Faculty of Health and Medical Sciences, University
of Surrey, Guildford, UK. (4)Surrey Peri-operative Anaesthesia Critical care
collaborative Research Group, Faculty of Health and Medical Sciences, University
of Surrey, Guildford, UK; South Central Ambulance Service NHS Foundation Trust,
Otterbourne, UK; NIHR Southampton Respiratory Biomedical Research Unit,
University Hospital Southampton NHS Foundation Trust, Southampton Hampshire.
(5)Warwick Clinical Trials Unit, University of Warwick, Coventry, UK; University
of Oxford, Oxford, UK. (6)West Midlands Ambulance Service NHS Foundation Trust,
Brierley Hill, UK. (7)Warwick Clinical Trials Unit, University of Warwick,
Coventry, UK; West Midlands Ambulance Service NHS Foundation Trust, Brierley
Hill, UK. (8)Welsh Ambulance Services NHS Trust, Denbighshire, Wales, UK.
(9)South Central Ambulance Service NHS Foundation Trust, Otterbourne, UK.
(10)North East Ambulance Service NHS Foundation Trust, Newcastle upon Tyne, UK;
Royal Victoria Infirmary, Newcastle upon Tyne, UK. (11)North East Ambulance
Service NHS Foundation Trust, Newcastle upon Tyne, UK.

Comment in
    Lancet. 2015 Jul 4;386(9988):26-7.
    Lancet. 2015 Jul 4;386(9988):26.
    Lancet. 2015 Mar 14;385(9972):920-2.

BACKGROUND: Mechanical chest compression devices have the potential to help
maintain high-quality cardiopulmonary resuscitation (CPR), but despite their
increasing use, little evidence exists for their effectiveness. We aimed to study
whether the introduction of LUCAS-2 mechanical CPR into front-line emergency
response vehicles would improve survival from out-of-hospital cardiac arrest.
METHODS: The pre-hospital randomised assessment of a mechanical compression
device in cardiac arrest (PARAMEDIC) trial was a pragmatic, cluster-randomised
open-label trial including adults with non-traumatic, out-of-hospital cardiac
arrest from four UK Ambulance Services (West Midlands, North East England, Wales,
South Central). 91 urban and semi-urban ambulance stations were selected for
participation. Clusters were ambulance service vehicles, which were randomly
assigned (1:2) to LUCAS-2 or manual CPR. Patients received LUCAS-2 mechanical
chest compression or manual chest compressions according to the first trial
vehicle to arrive on scene. The primary outcome was survival at 30 days following
cardiac arrest and was analysed by intention to treat. Ambulance dispatch staff
and those collecting the primary outcome were masked to treatment allocation.
Masking of the ambulance staff who delivered the interventions and reported
initial response to treatment was not possible. The study is registered with
Current Controlled Trials, number ISRCTN08233942.
FINDINGS: We enrolled 4471 eligible patients (1652 assigned to the LUCAS-2 group,
2819 assigned to the control group) between April 15, 2010 and June 10, 2013. 985
(60%) patients in the LUCAS-2 group received mechanical chest compression, and 11
(<1%) patients in the control group received LUCAS-2. In the intention-to-treat
analysis, 30 day survival was similar in the LUCAS-2 group (104 [6%] of 1652
patients) and in the manual CPR group (193 [7%] of 2819 patients; adjusted odds
ratio [OR] 0·86, 95% CI 0·64-1·15). No serious adverse events were noted. Seven
clinical adverse events were reported in the LUCAS-2 group (three patients with
chest bruising, two with chest lacerations, and two with blood in mouth). 15
device incidents occurred during operational use. No adverse or serious adverse
events were reported in the manual group.
INTERPRETATION: We noted no evidence of improvement in 30 day survival with
LUCAS-2 compared with manual compressions. On the basis of ours and other recent
randomised trials, widespread adoption of mechanical CPR devices for routine use
does not improve survival.
FUNDING: National Institute for Health Research HTA - 07/37/69.

Copyright © 2015 Perkins et al. Open Access article distributed under the terms
of CC BY. Published by Elsevier Ltd. All rights reserved.

PMID: 25467566  [PubMed - indexed for MEDLINE]


15. Lancet. 2014 Dec 13;384(9960):2132-40. doi: 10.1016/S0140-6736(14)60841-2. Epub
2014 Aug 26.

Short-course oral co-trimoxazole versus intramuscular benzathine benzylpenicillin
for impetigo in a highly endemic region: an open-label, randomised, controlled,
non-inferiority trial.

Bowen AC(1), Tong SY(2), Andrews RM(2), O'Meara IM(2), McDonald MI(3), Chatfield
MD(2), Currie BJ(2), Carapetis JR(4).

Author information: 
(1)Menzies School of Health Research, Charles Darwin University, Darwin, NT,
Australia. Electronic address: asha.bowen@menzies.edu.au. (2)Menzies School of
Health Research, Charles Darwin University, Darwin, NT, Australia. (3)James Cook
University, Townsville, QLD, Australia. (4)Telethon Kids Institute, University of
Western Australia, Perth, WA, Australia.

Comment in
    Lancet. 2014 Dec 13;384(9960):2090-1.

BACKGROUND: Impetigo affects more than 110 million children worldwide at any one
time. The major burden of disease is in developing and tropical settings where
topical antibiotics are impractical and lead to rapid emergence of antimicrobial
resistance. Few trials of systemic antibiotics are available to guide management
of extensive impetigo. As such, we aimed to compare short-course oral
co-trimoxazole with standard treatment with intramuscular benzathine
benzylpenicillin in children with impetigo in a highly endemic setting.
METHODS: In this randomised, controlled, non-inferiority trial, Indigenous
Australian children aged 3 months to 13 years with purulent or crusted
non-bullous impetigo were randomly assigned (1:1:1) to receive benzathine
benzylpenicillin (weight-banded injection), twice-daily co-trimoxazole for 3 days
(4 mg/kg plus 20 mg/kg per dose), or once-daily co-trimoxazole for 5 days (8
mg/kg plus 40 mg/kg per dose). At every visit, participants were randomised in
blocks of six and 12, stratified by disease severity. Randomisation was done by
research nurses and codes were in sealed, sequentially numbered, opaque
envelopes. Independent reviewers masked to treatment allocation compared digital
images of sores from days 0 and 7. The primary outcome was treatment success at
day 7 in a modified intention-to-treat analysis. This trial is registered with
the Australian New Zealand Clinical Trials Registry, number ACTRN12609000858291.
FINDINGS: Between Nov 26, 2009, and Nov 20, 2012, 508 patients were randomly
assigned to receive benzathine benzylpenicillin (n=165 [156 analysed]),
twice-daily co-trimoxazole for 3 days (n=175 [173 analysed]), or once-daily
co-trimoxazole for 5 days (n=168 [161 analysed]). Treatment was successful in 133
(85%) children who received benzathine benzylpenicillin and 283 (85%) who
received pooled co-trimoxazole (absolute difference 0·5%; 95% CI -6·2 to 7·3),
showing non-inferiority of co-trimoxazole (10% margin). Results for twice-daily
co-trimoxazole for 3 days and once-daily co-trimoxazole for 5 days were similar. 
Adverse events occurred in 54 participants, 49 (90%) of whom received benzathine
benzylpenicillin.
INTERPRETATION: Short-course co-trimoxazole is a non-inferior, alternative
treatment to benzathine benzylpenicillin for impetigo; it is palatable,
pain-free, practical, and easily administered.
FUNDING: Australian National Health and Medical Research Council.

Copyright © 2014 Elsevier Ltd. All rights reserved.

PMID: 25172376  [PubMed - indexed for MEDLINE]


16. Lancet. 2014 Nov 29;384(9958):1929-35. doi: 10.1016/S0140-6736(14)60584-5. Epub
2014 Aug 5.

Effect of treatment delay, age, and stroke severity on the effects of intravenous
thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of
individual patient data from randomised trials.

Emberson J(1), Lees KR(2), Lyden P(3), Blackwell L(1), Albers G(4), Bluhmki E(5),
Brott T(6), Cohen G(7), Davis S(8), Donnan G(9), Grotta J(10), Howard G(11),
Kaste M(12), Koga M(13), von Kummer R(14), Lansberg M(4), Lindley RI(15), Murray
G(7), Olivot JM(4), Parsons M(16), Tilley B(10), Toni D(17), Toyoda K(13),
Wahlgren N(18), Wardlaw J(7), Whiteley W(7), del Zoppo GJ(19), Baigent C(20),
Sandercock P(7), Hacke W(21); Stroke Thrombolysis Trialists' Collaborative Group.

Collaborators: Baigent C, Blackwell L, Bluhmki E, Davies K, Emberson J, Halls H, 
Holland L, Howard G, Mathews C, Smith S, Wilson K.

Author information: 
(1)Clinical Trial Service Unit & Epidemiological Studies Unit, University of
Oxford, Oxford, UK. (2)University of Glasgow, Glasgow, UK. (3)Department of
Neurology, Cedars-Sinai, Los Angeles, CA, USA. (4)Stanford University, Stanford, 
CA, USA. (5)Boehringer Ingelheim, Ingelheim, Germany. (6)Mayo Clinic,
Jacksonville, FL, USA. (7)University of Edinburgh, Edinburgh, UK. (8)University
of Melbourne, Melbourne, VIC, Australia. (9)The Florey Institute of Neuroscience
and Mental Health, Melbourne, VIC, Australia. (10)University of Texas Health
Science Center, Houston, TX, USA. (11)University of Alabama, Birmingham, AL, USA.
(12)Helsinki University Central Hospital, Helsinki, Finland. (13)National
Cerebral and Cardiovascular Centre, Suita, Japan. (14)Technische University,
Dresden, Germany. (15)The George Institute for Global Health, University of
Sydney, Sydney, NSW, Australia. (16)University of Newcastle, Newcastle, NSW,
Australia. (17)Sapienza University, Rome, Italy. (18)Karolinska Institutet,
Clinical Neuroscience, Stockholm, Sweden. (19)University of Washington, Seattle, 
WA, USA. (20)Clinical Trial Service Unit & Epidemiological Studies Unit,
University of Oxford, Oxford, UK. Electronic address:
colin.baigent@ctsu.ox.ac.uk. (21)University of Heidelberg, Heidelberg, Germany.

Comment in
    Lancet. 2014 Nov 29;384(9958):1904-6.
    Lancet. 2015 Apr 11;385(9976):1366.
    Lancet. 2015 Apr 11;385(9976):1395-6.
    Lancet. 2015 Apr 11;385(9976):1395.
    Lancet. 2015 Apr 11;385(9976):1394-5.
    Lancet. 2015 Apr 11;385(9976):1396.
    Ann Intern Med. 2015 Jan 20;162(2):JC3.
    Lancet. 2015 Apr 11;385(9976):1394.
    Evid Based Med. 2015 Jun;20(3):108.

BACKGROUND: Alteplase is effective for treatment of acute ischaemic stroke but
debate continues about its use after longer times since stroke onset, in older
patients, and among patients who have had the least or most severe strokes. We
assessed the role of these factors in affecting good stroke outcome in patients
given alteplase.
METHODS: We did a pre-specified meta-analysis of individual patient data from
6756 patients in nine randomised trials comparing alteplase with placebo or open
control. We included all completed randomised phase 3 trials of intravenous
alteplase for treatment of acute ischaemic stroke for which data were available. 
Retrospective checks confirmed that no eligible trials had been omitted. We
defined a good stroke outcome as no significant disability at 3-6 months, defined
by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic
intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days
and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage
within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality.
FINDINGS: Alteplase increased the odds of a good stroke outcome, with earlier
treatment associated with bigger proportional benefit. Treatment within 3·0 h
resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase
versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35-2·27); delay
of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of
1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05-1·51); and delay of more
than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of
1166 (OR 1·15, 95% CI 0·95-1·40). Proportional treatment benefits were similar
irrespective of age or stroke severity. Alteplase significantly increased the
odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage
definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01-7·70,
p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI
4·11-10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91
[2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98-12·79, p<0·0001). The relative increase
in fatal intracranial haemorrhage from alteplase was similar irrespective of
treatment delay, age, or stroke severity, but the absolute excess risk
attributable to alteplase was bigger among patients who had more severe strokes. 
There was no excess in other early causes of death and no significant effect on
later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the
alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95%
CI 0·99-1·25, p=0·07). Taken together, therefore, despite an average absolute
increased risk of early death from intracranial haemorrhage of about 2%, by 3-6
months this risk was offset by an average absolute increase in disability-free
survival of about 10% for patients treated within 3·0 h and about 5% for patients
treated after 3·0 h, up to 4·5 h.
INTERPRETATION: Irrespective of age or stroke severity, and despite an increased
risk of fatal intracranial haemorrhage during the first few days after treatment,
alteplase significantly improves the overall odds of a good stroke outcome when
delivered within 4·5 h of stroke onset, with earlier treatment associated with
bigger proportional benefits.
FUNDING: UK Medical Research Council, British Heart Foundation, University of
Glasgow, University of Edinburgh.

Copyright © 2014 Emberson et al. Open Access article distributed under the terms
of CC BY. Published by Elsevier Ltd. All rights reserved.

PMCID: PMC4441266
PMID: 25106063  [PubMed - indexed for MEDLINE]


17. Lancet. 2014 Nov 1;384(9954):1586-96. doi: 10.1016/S0140-6736(14)60805-9. Epub
2014 Jul 23.

Efficacy of paracetamol for acute low-back pain: a double-blind, randomised
controlled trial.

Williams CM(1), Maher CG(2), Latimer J(2), McLachlan AJ(3), Hancock MJ(4), Day
RO(5), Lin CW(2).

Author information: 
(1)The George Institute for Global Health, Sydney Medical School, University of
Sydney, Camperdown, NSW, Australia; Hunter Medical Research Institute and School
of Medicine and Public Health, University of Newcastle, Callaghan, NSW,
Australia. Electronic address: cwilliams@georgeinstitute.org.au. (2)The George
Institute for Global Health, Sydney Medical School, University of Sydney,
Camperdown, NSW, Australia. (3)Faculty of Pharmacy and Centre for Education and
Research in Ageing, University of Sydney, Sydney, NSW, Australia. (4)Faculty of
Human Sciences, Macquarie University, Sydney, NSW, Australia. (5)Clinical
Pharmacology, University of New South Wales and St Vincent's Hospital,
Darlinghurst, NSW, Australia.

Comment in
    Lancet. 2014 Nov 1;384(9954):1556-7.
    Evid Based Med. 2015 Jun;20(3):100.
    Med Monatsschr Pharm. 2014 Oct;37(10):386-7.

BACKGROUND: Regular paracetamol is the recommended first-line analgesic for acute
low-back pain; however, no high-quality evidence supports this recommendation. We
aimed to assess the efficacy of paracetamol taken regularly or as-needed to
improve time to recovery from pain, compared with placebo, in patients with
low-back pain.
METHODS: We did a multicentre, double-dummy, randomised, placebo controlled trial
across 235 primary care centres in Sydney, Australia, from Nov 11, 2009, to March
5, 2013. We randomly allocated patients with acute low-back pain in a 1:1:1 ratio
to receive up to 4 weeks of regular doses of paracetamol (three times per day;
equivalent to 3990 mg paracetamol per day), as-needed doses of paracetamol (taken
when needed for pain relief; maximum 4000 mg paracetamol per day), or placebo.
Randomisation was done according to a centralised randomisation schedule prepared
by a researcher who was not involved in patient recruitment or data collection.
Patients and staff at all sites were masked to treatment allocation. All
participants received best-evidence advice and were followed up for 3 months. The
primary outcome was time until recovery from low-back pain, with recovery defined
as a pain score of 0 or 1 (on a 0-10 pain scale) sustained for 7 consecutive
days. All data were analysed by intention to treat. This study is registered with
the Australian and New Zealand Clinical Trial Registry, number ACTN
12609000966291.
FINDINGS: 550 participants were assigned to the regular group (550 analysed), 549
were assigned to the as-needed group (546 analysed), and 553 were assigned to the
placebo group (547 analysed). Median time to recovery was 17 days (95% CI 14-19) 
in the regular group, 17 days (15-20) in the as-needed group, and 16 days (14-20)
in the placebo group (regular vs placebo hazard ratio 0·99, 95% CI 0·87-1·14;
as-needed vs placebo 1·05, 0·92-1·19; regular vs as-needed 1·05, 0·92-1·20). We
recorded no difference between treatment groups for time to recovery (adjusted
p=0·79). Adherence to regular tablets (median tablets consumed per participant
per day of maximum 6; 4·0 [IQR 1·6-5·7] in the regular group, 3·9 [1·5-5·6] in
the as-needed group, and 4·0 [1·5-5·7] in the placebo group), and number of
participants reporting adverse events (99 [18·5%] in the regular group, 99
[18·7%] in the as-needed group, and 98 [18·5%] in the placebo group) were similar
between groups.
INTERPRETATION: Our findings suggest that regular or as-needed dosing with
paracetamol does not affect recovery time compared with placebo in low-back pain,
and question the universal endorsement of paracetamol in this patient group.
FUNDING: National Health and Medical Research Council of Australia and
GlaxoSmithKline Australia.

Copyright © 2014 Elsevier Ltd. All rights reserved.

PMID: 25064594  [PubMed - indexed for MEDLINE]


18. Lancet. 2014 Dec 6;384(9959):2064-76. doi: 10.1016/S0140-6736(13)62184-4. Epub
2014 Apr 21.

Diagnosis of reversible causes of coma.

Edlow JA(1), Rabinstein A(2), Traub SJ(3), Wijdicks EF(2).

Author information: 
(1)Department of Emergency Medicine, Beth Israel Deaconess Medical Center,
Harvard Medical School, Rochester, MN, USA. Electronic address:
jedlow@bidmc.harvard.edu. (2)Department of Neurology, Mayo Clinic, Rochester, MN,
USA. (3)Department of Emergency Medicine, Mayo Clinic, Scottsdale, AZ, USA.

Comment in
    Lancet. 2015 Mar 28;385(9974):1179-80.
    Lancet. 2015 Mar 28;385(9974):1179.
    Lancet. 2015 Mar 28;385(9974):1178.
    Lancet. 2015 Mar 28;385(9974):1178-9.

Because coma has many causes, physicians must develop a structured, algorithmic
approach to diagnose and treat reversible causes rapidly. The three main
mechanisms of coma are structural brain lesions, diffuse neuronal dysfunction,
and, rarely, psychiatric causes. The first priority is to stabilise the patient
by treatment of life-threatening conditions, then to use the history, physical
examination, and laboratory findings to identify structural causes and diagnose
treatable disorders. Some patients have a clear diagnosis. In those who do not,
the first decision is whether brain imaging is needed. Imaging should be done in
post-traumatic coma or when structural brain lesions are probable or possible
causes. Patients who do not undergo imaging should be reassessed regularly. If CT
is non-diagnostic, a checklist should be used use to indicate whether advanced
imaging is needed or evidence is present of a treatable poisoning or infection,
seizures including non-convulsive status epilepticus, endocrinopathy, or thiamine
deficiency.

Copyright © 2014 Elsevier Ltd. All rights reserved.

PMID: 24767707  [PubMed - indexed for MEDLINE]

Diagnostic

None

Review

None

Clinical Prediction Rules

None