EBL critical appraisal

1

• Effect of multiple daily insulins versus
  continues subcutaneous insulin infusion systemic
  review and meta-analysis
• Prepared By Shimelis Engida
• GSR/6186/14
• Adviser- zelalem Tilahun (BSc .MSc. asst prof)

2
Content

• Introduction
• Objective
• Method
• Result
• discussion
• Reference

3
Introduction

• Diabetes mellitus, often known as diabetes, is a
  collection of metabolic illnesses
• The diverse an aetiology includes abnormalities
  in insulin production, insulin action, or both.
• Characterized by the development of
  hyperglycaemia in the absence of therapy.
• Diabetes long-term consequences include
  retinopathy, nephropathy, and neuropathy.

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Conti

• Diabetes also increases the risk of various
  illnesses such as cardiac, peripheral arterial,
  and cerebrovascular disease, cataracts,, and non
  alcoholic fatty liver disease
• Diabetes mellitus (DM) has become more prevalent
  worldwide. Diabetes affected roughly 463million
  persons aged 20 to 79 worldwide in 2019,
  resulting in an estimated 1.5 million fatalities.

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Conti..

• By 2045, this figure is predicted to climb to 700
  million. Diabetes accounts for at least 727
  billion in health-care costs, accounting for 12
  of total adult spending.
• The frequency and number of diabetics have grown
  considerably, particularly in low- and middle
  income nations
• Symptoms include increased thirst, frequent
  urination, hunger, fatigue and blurred vision. In
  some cases, there may be no symptoms.

6
Conti

• It is now well established that the serious
  microvascular complications of diabetes are
  linked to the duration and severity of high blood
  sugar.
• The risk of developing complications of type 1
  diabetes (T1D) is related to glycaemic control
  and is reduced in patients by the use of
  intensive insulin treatment regimens
• multiple daily injections (MDI) ( 4) and
  continuous subcutaneous insulin infusion (CSII).

7
Conti..

• Despite a lack of evidence Despite a lack of
  evidence
• that the more expensive treatment with CSII is
  superior to MDI, both treatments are used widely
  within the NHS
• The term sliding scale' refers to increasing the
  premeal insulin dose dependent on blood sugar
  levels before the meal. For example, if a
  person's blood glucose level is between 140 mg/dL
  and 180 mg/dL, a short acting typical insulin
  dosage of 4 units insulin would be reasonable,

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Conti

• whereas a blood glucose level between 181 mg/dL
  and 220 mg/dL would require 6 units insulin.
• continuous subcutaneous insulin infusion
  (CSII)(insulin pump therapy) with an external
  pump are prominent ways of intensive insulin
  therapy (IIT)

9
Conti..

• MDI therapy included the bolus injection of short
  or rapid-acting
• insulin at each meal, along with long-acting
  insulin once or twice a to its established
  efficacy,
• improved pump technology and patient preference.
  Sometimes patients on CSII therapy
• discontinues it temporarily because of pump
  malfunction, skin problems or physical activity.
• During such periods, type 1 diabetic patients
  (T1DM) switching to MDI therapy could continue

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• Insulin pumps are wearable medical devices that
  inject rapid-acting insulin in the subcutaneous
  tissue of the abdomen at the almost continuous
  time, by a cannula connected to a disposable
  reservoir of insulin in the pump
• Insulin pump therapy (or continuous subcutaneous
  insulin infusion CSII) in people with type 1
  diabetes (T1D) presents advantages over multiple
  daily insulin injection (MDI) regimens.

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Conti

• These include improved glycaemic control and a
  reduced rate of hypoglycaemic episodes however,
  real-world data show that,
• despite using CSII with or without continuous
  monitoring devices, only 30 of adults with T1D
  achieve glycated haemoglobin (HbA1c) of lt53 mmol
  /mole (lt7.0)
• Despite this, many clinicians still use sliding
  scale insulin (SSI) regimens.

12
Conti

• The medical literature supports the fact that
  sliding scale dosing of insulin is an ineffective
  means to control blood glucose concentrations.
• A better tool for controlling hyperglycaemia is
  clearly needed.
• Conventional sliding scales for insulin infusion
  have been shown to be associated with delay in
  reaching target and increased risk of
  hypoglycaemia and glycaemic variability

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Objective

• The aim of these systemic review and
  meta-analysis
• To compare glycaemic control during treatment
  with continues subcutaneous insulin infusion
  (CSII) versus multiple daily infusion MDI)
  (sliding scale )

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Methods

• This systematic review and meta-analysis were
  reported by Preferred Reporting Items for
  Systematic reviews and Meta-analysis (PRISMA)
  statement guideline for systematic reviews and
  meta-analysis
• guided by PRISMA checklists this review did not
  have a protocol and hence not registered.
• Data sources and searching strategies
• We searched candidate articles using PubMed, Web
  of Science, Cochrane library, Embase, and Google
  Scholar

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Conti..

• Electronic databases were searched using the
  combinations of the following
• key terms and Mesh terms along with the Boolean
  operators (OR, AND)
• The searching was conducted from inception to
  October 28, 2022 sliding scale, multiple daily
  insulin infusion, continuous subcutaneous insulin
  infusion and insulin pump

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Inclusion and exclusion criteria

• We included all articles conducted with people of
  any age or sex suffering from type 1 or type 2
  diabetes mellitus and who were on insulin
  treatment (excluding pregnant women).
• comparing CSII with traditional injections in
  type 1 diabetes and type 2 diabetes with English
  language
• we include adult and paediatric exclude animal
  study and duplicated and study related with other
  than insulin comparison of MDI and CSII

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Data extraction

• A protocol for data extraction was designed by
  the authors and data were extracted independently
  by two authors (SE and ZT).
• Any disagreements were resolved by consensus
  through discussion Data were extracted on the
  name of the first author and types of diabetics
  mallets, year of publication, author, study
  group, CSII regimen, MDI place of study, study
  design, participants, sample size, outcome of
  each article

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Outcome definition

• The mean out came of this systematic review and
  meta analysis efficacy of MDI slide scale and
  continuous subcutaneous insulin infusion by
  evaluated glycaemic control
• if expressed as a percentage of glycated
  haemoglobin (HbA1 or HbA1c), insulin
  requirements, occurrence of severe and mild
  hypoglycaemic episodes

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Assessment of quality of the studies

• Data from each study included were extracted by
  the two independent reviewers.
• the quality of the included studies using van
  Tulder scale. if there were different outcomes,
  we adjusted the discrepancy in the results
  through discussion

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Data analysis and synthesis

• We conducted a meta-analysis using revman. Forest
  plots were used to estimate pooled prevalence
  with a 95 confidence interval (CI) to provide a
  visual summary of the data.
• To evaluate heterogeneity among studies, the
  Cochrans Q test and I square (I2) indices were
  used.
• A significance threshold of p lt 0.05 was applied
  to the heterogeneity (I2).

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Conti..

• At present heterogeneity, a random-effects model
  was used to compute the overall effect.
• regions on the dm patient glycaemic control.
  Meta-regression was also performed to assess the
  sources of the heterogeneity between the studies.

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Results

• Study selection
• The details of our search strategy were depicted
  in Figure 1. From all database searches, 582
  records were identified. Forty records removed
  that is ineligible, and three records removed
  with other reason and Seventeen duplicates, were
  removed keeping 522 records
• Moreover, 488 records were removed because the
  titles and abstracts are unrelated to the
  outcomes of the review. The remaining 34 are
  selected for retrieval with in these 25 articles
  were removed and 9 full articles were critically
  assessed for eligibility.

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Conti..

• Then, 3 articles were removed, 2 article are not
  full text and the remaining one was clinical
  trial protocol, then we add 3 articles from other
  source, in the end 9 full articles were selected
  and included in qualitative and quantitative
  analysis
• Characteristics of the included studies
• We included 9 RCTs in the systematic review and
  meta-analysis, with 1530 patients, and mean age
  of 38 years. Table 1 shows the summary of all
  included studies, and the detailed summary of
  each study can be found.

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Conti..

• All patients were diagnosed with T1DM, and T2DM
  clinically, and an open-label study design. Seven
  of the included studies were parallel studies and
  two had a crossover design. were considered for
  this review. Except one study Most study studies
  not specified (NS) their short-acting insulin
• types of insulin pump for CSII and MDI
  treatment. For further detailed information on
  the type of insulin and the type of pumps used,
  see Table 1. MDI treatment was compared with
  different CSII regimens,

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Conti..

• All 9 studies included in this analysis reported
  glucose control as the main outcome.
• However, the significant difference disappeared
  in the overall studies are (p0.05).
• Moreover, significant difference was found in
  mean change of HbA1c () (mean difference from
  baseline to end of study) between the patient
  treated with CSII and MDI in the overall analysis
  (WMD-0.02, 97 CI1.02 to 47.01, p0.05,

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Discussion

• Based on the general result of this systematic
  review and meta-analysis, the following
• conclusions can be drawn on CSII therapy in
  patients with type 1 and type 2 diabetes
  mellitus.
• In adult, elderly and young patients with type 1
  diabetes mellitus, CSII treatment in comparison
  to MDI therapy leads to better glycaemic control
  without a rise in hypoglycaemic events and with
  lower insulin requirements.
• CSII can thus be considered a valuable therapy
  option in adult patients with type 1 diabetes
  mellitus. In patients with type 2 diabetes
  mellitus treatment with CSII is better glycaemic
  control

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• CSII can thus be considered a valuable therapy
  option in adult patients with type 1 diabetes
  mellitus. In patients with type 2 diabetes
  mellitus treatment with CSII is better glycaemic
  control
• when compared with MDI therapy. Also, there was
  no difference in hypoglycaemic events and insulin
  requirements between the two treatments. It can
• therefore be generalized that in patients with
  type 2 diabetes mellitus CSII application is more
  effective than MDI treatment.

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Conti..

• Results from studies investigating patients with
  type 1 diabetes mellitus suggested a beneficial
  effect of CSII therapy compared with MDI therapy
  in terms of glycated haemoglobin,
• but because of the small number of patients under
  investigation and the short duration of the
  included trials, conclusions on adolescent
  patients are less firm than for adult patients
  with type 1 diabetes mellitus.

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Conti..

• There is also no clear information about
  hypoglycaemia in adolescents because of the
  insufficient reporting of such events.
• Due to the very limited data available, no
  meaningful inferences could be drawn on the
  possible effects of CSII treatment in younger
  children.
• Even though this review, bringing together
  evidence for three important patient groups, is,
  to our knowledge, one of the most comprehensive
  on the topic to date,
• there are some limitations warranting caution in
  interpreting the validity of the results.

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• Furthermore, in the meta-analysis of differences
  in HbA1c in patients with type 1 diabetes
  mellitus, a high degree of heterogeneity was
  detected.
• To investigate this heterogeneity several
  sensitivity analyses were performed.
• The positive effect of CSII treatment was
  likewise seen in trials that lasted for less than
  or more than 6 months. Comparing the studies
  according to their design, the result remained
  statistically significant in favour of CSII
  treatment in both parallel and
• crossover trials. While in studies using HbA1c
  measurements CSII treatment resulted in a
  statistically significant lower HbA1c value, in
  (the older) studies using HbA1 to measure
  glycaemic control the difference between the
  treatment groups was not statistically
  significant..

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• The three studies published in the year 2000 and
  later, where newer devices were in use (which we
  also offer in our outpatient clinic at the
  Medical University Graz), further supported the
  superiority of CSII treatment.
• In addition, even in these studies, where
  short-acting insulin analogues, today probably
  the most commonly used bolus insulin type, were
  used, clear clinically relevant superiority was
  unproven.
• However, none of these sensitivity analyses could
  explain the observed heterogeneity,
• which is most probably caused by a combination of
  several confounding factors (studies dating back
  to 1982, low study quality, different study
  designs, small treatment groups,
• different CSII pumps, etc.). It should also be
  noted that the heterogeneity is not so much
  caused
• by qualitatively different results, but by
  quantitative differences. From these limitations
  it is
• clear that the results obtained from this
  meta-analysis have to be interpreted cautiously
  even
• though they are consistent with previously
  published meta-analyses
• In terms of insulin requirements, there is no any
  meta-analysis was done because it is not
• relevant, insulin requirement is only a relevant
  outcome for the healthcare system but not
• relevant for the individual patient. In any case,
  a meta-analysis would not have helped interpret
• the data more effectively, due to differences in
  reporting

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• In addition, even in these studies, where
  short-acting insulin analogues, today probably
  the most commonly used bolus insulin type, were
  used, clear clinically relevant superiority was
  unproven.
• However, none of these sensitivity analyses could
  explain the observed heterogeneity, which is most
  probably caused by a combination of several
  confounding factors
• (studies dating back to 1982, low study quality,
  different study designs, small treatment groups,
• different CSII pumps, etc.). It should also be
  noted that the heterogeneity is not so much
  caused by qualitatively different results, but by
  quantitative differences.

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• From these limitations it is clear that the
  results obtained from this meta-analysis have to
  be interpreted cautiously even
• though they are consistent with previously
  published meta-analyses In terms of insulin
  requirements, there is no any meta-analysis was
  done because it is not relevant, insulin
  requirement is only a relevant outcome for the
  healthcare system but not
• relevant for the individual patient. In any case,
  a meta-analysis would not have helped interpret
  the data more effectively, due to differences in
  reporting

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Conclusion
36

• Appraisal section

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• Critical Appraisal on an article entitled
• Continuous subcutaneous insulin infusion versus
  multiple daily injections in children and young
  people at diagnosis of type 1 diabetes the SCIPI
  RCT
• By shimelis Engida
• Adviser Mr zelalem Tilahun (B.Pharm ,MSc, asst
  prof)

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Out line

• Background and Overview
• Methods
• Results
• The Students Discussion and Conclusions
• EBL Critical Appraisal Checklist

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Background and overview

• Article Title/Citation
• Continuous subcutaneous insulin infusion versus
  multiple daily injections in children and young
  people at diagnosis of type 1 diabetes the SCIPI
  
• Blair J, McKay A, Rid yard C, Thorn borough K,
  Bedson E, Peak M, Didi M, Annan F, Gregory JW,
  Hughes D, Gamble C RCT. Health technology
  assessment. 2018 Aug 31 22.

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• Study objectives
• To compare glycaemic control during treatment
  with CSII and MDI
• to determine safety and effect on blood sugar
  control

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• Background
• The risk of developing long-term complications of
  type 1 diabetes (T1D) is related to glycaemic
  control and is reduced by the use of intensive
  insulin treatment regimens multiple daily
  injections (MDI) ( 4) and
• continuous subcutaneous insulin infusion (CSII).
  Despite a lack of evidence that the more
  expensive
• treatment with CSII is superior to MDI, both
  treatments are used widely within the NHS.
• Funding Sources
• Funding for this study was provided by the Health
  Technology Assessment programme of the National
  Institute for Health Research.

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Methods

• Study design and methodology
• open-label two-arm multicentre RCT comparing use
  of CSII with use of MDI in children and young
  people aged 7 months to 15 years who were newly
  diagnosed withT1DM
• Open-label randomised controlled trial with an
  internal pilot and 12-month follow-up with 1 1
  web-based
• block randomisation stratified by age and centre.

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• Patient selection and enrolment
• Patients were eligible to participate in the
  study if they met the following inclusion
  criteria-
• The patient has newly diagnosed T1D
• The patient is aged 7 months to 15 years.
• The parent/legal representative of the patient
  is willing to give consent for the study.
• The parent/legal representative of the patient
  is able to comply with the treatment regimen and
• study visits

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• Participants with the following characteristics
  were excluded from the trial-
• previous treatment for T1D
• Haemoglobinopathy
• co-existing pathology conditions likely to affect
  glycaemic control
• psychological or psychiatric disorders
• receipt of medication likely to affect glycaemic
  control
• allergy to a component of insulin aspart or
  insulin glargine
• sibling with existing T1D
• known thyroid condition in a non-euthyroid state
• known coeliac disease and inability to maintain a
  gluten-free diet

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• Outcome measures/endpoints
• The primary outcome was glycosylated haemoglobin
  (HbA1c) concentration at 12 months.
• The secondary outcomes were (1) HbA1c
  concentrations of lt 48 mmol/mol, (2) severe
  hypoglycaemia,(3) diabetic ketoacidosis (DKA),
  (4) T1D- or treatment-related adverse events
  (AEs), (5) change in body mass index and height
  standard deviation score, (6) insulin
  requirements, (7) QoL and (8) partial remission
  rate.
• The economic outcome was the incremental cost per
  quality-adjusted life-year (QALY) gained

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• Statistical analysis
• Primary analysis used the intention-to-treat
  (ITT) principle. A 0.05 level of statistical
  significance and 95 confidence intervals (CIs)
  are used throughout. The statistical analysis
  plan was developed prior to analysis
• and All analyses were conducted using SAS
  software (version 9.2 SAS Institute Inc., Cary,
  NC, USA). SAS and all other SAS Institute Inc.
  product or service names are registered
  trademarks or trademarks of SAS Institute Inc. in
  the USA and other countries. indicates USA
  registration.

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Result

• Enrolment baseline characteristics
• A total of 293 participants, with a median age of
  9.8 years (minimum 0.7 years, maximum 16 years),
  were
• randomised (CSII, n 149 MDI, n 144) between
  May 2011 and January 2015. Primary outcome data
• were available for 97 of participants (CSII, n
  143 MDI, n 142)

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• Summary of primary secondary outcomes
• The primary outcome measure was glycaemic control
  (HbA1c) concentrations 12 months after diagnosis.
  Capillary blood samples were collected from
  finger-pricks into small capillary tubes
• Secondary outcome
• Percentage of participants in each group with a
  glycosylated haemoglobin level of lt 48 mmol/mol
  at 12
• months after diagnosis at the time the SCIPI
  study protocol was written, the target HbA1c
  concentration was
• lt 58 mmol/mol. However, in the most recent NICE
  guideline, the target has been reduced to 48
• mmol/mol.19 This lower figure was used in our
  analysis to ensure that the findings are relevant
  to current
• clinical practice however, as sites would have
  previously worked to the 58-mmol/mol threshold,
  the results
• for this are also presented

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Authors Discussion

• successful therapies that should be embraced and
  encouraged.
• However, the authors also recognised that parents
  may feel pressurised to allow use of CSII in
  their children, given the strong advocacy for
  CSII
• therapy from support groups and some health-care
  providers. Perhaps most importantly, physicians
  reported
• social benefits of the use of CSII allowing
  adolescent patients to become more independent
  and reducing
• parental stress around the unpredictable eating
  habits of young children and the need for
  frequent insulin
• injections. The physicians also felt that CSII
  therapy facilitated the physicianpatient
  relationship. In order
• to fully understand the drivers behind the
  widespread adoption of CSII, tools will need to
  be developed that
• accurately harness this information.

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Conclusions

• In this study, we did not record whether or not
  patients used CSII to its full potential. It is
  possible that
• enhanced CSII use would have resulted in improved
  glycaemic control and that this may be achievable
  
• through further education, training and support
  in the community. There may be a place for
  researching
• these elements of CSII use. However, such a
  package of care is likely to require increased
  investment, and
• this additional cost needs to be considered in
  the light of the health economic data reported in
  the SCIPI
• study. Very significant improvements in glycaemic
  control would be necessary for CSII to be seen as
  costeffective. Should such a project be
  undertaken, it would be essential to also examine
  the effect of enhanced
• education and support in the community on
  glycaemic control in children treated with MDI

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The Students Discussion and Conclusions

• Study strengths
• Title
• The title was self-descriptive, precise to the
  subject matter and quite clear
• Abstract
• It is well stated and precise and also attractive
  and it includes all information that is
  background, objective
• method results and key word lists

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• Introduction
• The authors explained and addressed the basic
  scientific background in this section.
• They highlighted previously published articles
  and they raised their concerns, gaps, insights
  and rationality for their work
• Method
• The methodology section was well organized.
• They had a clear inclusion and exclusion
  criterias, the measurement of outcome was
  legitimate for the objectives settled and the end
  points were clearly mentioned.
• The trial was approved by Ethical committee and
  statistical procedure used for analysis of data
  was specific

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• Results
• The data was presented by percentage and several
  tables.
• Follow up information was well presented and they
  used several tables to present their findings.
• Discussion/ Conclusion
• It was well elaborated section of the manuscript.
  
• The authors compare their findings with several
  other similar studies and they try to indicate
  interesting future study areas.
• They also had indicated their insights and
  reasonings in this section

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• Reference
• The manuscript had one hundreds fifty-eight
  citations
• All of them were well referenced
• Study weakness
• The weakness of the study me be prone for ethical
  valuation and may not get all data in the
  research
• because the research does not state the device
  and insulin type which use during the study

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Applicability and impact on healthcare providers
56

• Additional thoughts/Comments

57
Conclusions and Recommendations
58

• Acknowledgment

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