Octopus follow-up: 20 year prognosis in patients randomized to on-pump CABG, off-pump CABG or PCI.

BACKGROUND: The very long-term outcomes of off-pump versus on-pump Coronary Artery Bypass Grafting (CABG) and Percutaneous Coronary Intervention (PCI) are largely unclear. We linked 20-years outcomes of two randomized trials to evaluate re-intervention and mortality outcomes for on-pump CABG, off-pump CABG and PCI. METHODS: A data linkage project was performed using data as registered within the Netherlands Heart Registration (NHR), Statistics Netherlands (CBS) and the Octopus trials. Between 1998 and 2000, these trials randomized patients with coronary artery disease to on-pump versus off-pump CABG (OctoPump trial), or to PCI versus off-pump CABG (OctoStent trial). With data linkage, the original 5 years follow-up time for clinical events was extended to 20 years, including mortality and coronary reinterventions. RESULTS: After 20 years, in the OctoPump trial all-cause mortality was 50.0% after on-pump, and 46.5% after off-pump CABG. There was no difference in the combined outcome of mortality and re-interventions (HR 0.82, 95% CI 0.59-1.12). In the OctoStent trial, all-cause mortality was 56.7% after PCI and 52.5% after off-pump CABG. There was no difference in the combined outcome of mortality and re-interventions (HR 0.76, 95% CI 0.57-1.04). Off-pump CABG patients underwent less re-interventions than PCI patients (HR 0.52, 95% CI 0.33-0.80). CONCLUSION: This study revealed no differences in 20-year survival between patients randomized to on-pump versus off-pump CABG, or to PCI versus off-pump-CABG. However, off-pump CABG patients underwent less re-interventions than PCI patients.

Impact of symptom duration and mechanical circulatory support on prognosis in cardiogenic shock complicating acute myocardial infarction.

BACKGROUND: Mortality rates in patients with cardiogenic shock complicating acute myocardial infarction (AMICS) remain high despite advancements in AMI care. Our study aimed to investigate the impact of prehospital symptom duration on the prognosis of AMICS patients and those receiving mechanical circulatory support (MCS). METHODS AND RESULTS: We conducted a retrospective cohort study with data registered in the Netherlands Heart Registration. A total of 1,363 patients with AMICS who underwent percutaneous coronary intervention between 2017 and 2021 were included. Patients presenting after out-of-hospital cardiac arrest were excluded. Most patients were male (68%), with a median age of 69 years (IQR 61-77), predominantly presenting with ST-elevation myocardial infarction (86%). The overall 30-day mortality was 32%. Longer prehospital symptom duration was associated with a higher 30-day mortality with the following rates: < 3 h, 26%; 3-6 h, 29%; 6-24 h, 36%; ≥ 24 h, 46%; p < 0.001. In a subpopulation of AMICS patients with MCS (n = 332, 24%), symptom duration of > 24 h was associated with significantly higher mortality compared to symptom duration of < 24 h (59% vs 45%, p = 0.029). Multivariate analysis identified > 24 h symptom duration, age and in-hospital cardiac arrest as predictors of 30-day mortality in MCS patients. CONCLUSION: Prolonged prehospital symptom duration was associated with significantly increased 30-day mortality in patients presenting with AMICS. In AMICS patients treated with MCS, a symptom duration of > 24 h was an independent predictor of poor survival. These results emphasise the critical role of early recognition and intervention in the prognosis of AMICS patients.

Characteristics and outcome in cardiogenic shock according to vascular access site for percutaneous coronary intervention.

AIMS: The optimal vascular access site for percutaneous coronary interventions (PCIs) in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) remains uncertain. While observational data favour transradial access (TRA) due to lower complication rates and mortality, transfemoral access (TFA) PCI offers advantages such as shorter access and procedure times, along with quicker escalation to mechanical circulatory support (MCS). In this study, we aimed to investigate factors associated with a transfemoral approach and compare mortality rates between TRA and TFA in AMI-CS patients undergoing PCI. METHODS AND RESULTS: Data from a nationwide registry of AMI-CS patients undergoing PCI (2017-2021) were analysed. We compared patient demographics, procedural details, and outcomes between TRA and TFA groups. Logistic regression identified access site factors and radial-to-femoral crossover predictors. Propensity score-matched (PSM) analysis examined the impact of access site on mortality. Of the 1562 patients, 45% underwent TRA PCI, with an increasing trend over time. Transfemoral access patients were more often female, had a history of coronary artery bypass grafting, lower blood pressure, higher resuscitation and intubation rates, and elevated lactate levels. After PSM, 30-day mortality was lower in TRA (33% vs. 46%, P < 0.001). Predictors for crossover included left coronary artery interventions, multivessel PCI, and MCS initiation. CONCLUSION: Significant differences exist between TRA and TFA PCI in AMI-CS. Transfemoral access was more common in patients with worse haemodynamics and was associated with higher 30-day mortality compared with TRA. This mortality difference persisted in the PSM analysis.

Native coronary artery or bypass graft percutaneous coronary intervention in patients after previous coronary artery bypass surgery: A large nationwide analysis from the Netherlands Heart Registration.

BACKGROUND: Patients with previous coronary artery bypass surgery (CABG) who require repeat revascularization frequently undergo percutaneous coronary intervention (PCI). We sought to identify factors associated with the decision to intervene on the native vessel versus a bypass graft and investigate their outcomes in a large nationwide prospective registry. METHODS: We identified patients who underwent PCI with a history of prior CABG from the Netherlands Heart Registration between 2017 and 2021 and stratified them by isolated native vessel PCI versus PCI including at least one venous- or arterial graft. The primary endpoint of major adverse cardiac events (MACE) was a composite of all-cause death and target vessel revascularization (TVR) at one-year post PCI. The key secondary endpoint was a composite of all-cause death, myocardial infarction (MI), and TVR at 30 days. RESULTS: Out of 154,146 patients who underwent PCI, 12,822 (8.3%) had a prior CABG. Isolated native vessel PCI was most frequently performed (75.2%), while an acute coronary syndrome (ACS) presentation was most strongly associated with graft interventions. The primary outcome of MACE at one-year post PCI occurred more frequently in interventions including grafts compared with native vessels alone (19.7% vs. 14.3%; adjOR 1.267; 95% CI 1.101-1.457); p < 0.001) driven by TVR. There was however no difference in mortality or the key secondary endpoint between the two groups. CONCLUSION: In this nationwide prospective registry, ACS presentation was strongly associated with bypass graft PCI. At one year after PCI, interventions including bypass grafts had a higher composite of MACE compared with isolated native vessel interventions.

Hospital infections and health-related quality of life after cardiac surgery: a multicenter survey.

BACKGROUND: Recent research suggested that hospital infections are a predictive marker for physical non-recovery one year after cardiothoracic surgery. The purpose of this study was to explore whether this risk factor is etiologic. Additional, the influence of a potential effect modifying factor, diabetes mellitus, was investigated. METHODS: In this multicenter study, patients underwent elective or urgent cardiothoracic surgery between 01-01-2015 and 31-12-2019, and completed pre- and one year post-operative Short Form Health Survey 36/12 quality of life questionnaires. A binary logistic regression model, in which the inverse of the propensity score for infection risk was included as a weight variable, was used. Second, this analysis was stratified for diabetes mellitus status. RESULTS: 8577 patients were included. After weighing for the propensity score, the standardized mean differences of all variables decreased and indicated sufficient balance between the infection and non-infection groups. Hospital infections were found to be a risk factor for non-recovery after cardiothoracic surgery in the original and imputed dataset before weighting. However, after propensity score weighing, hospital infections did not remain significantly associated with recovery (OR for recovery = 0.79; 95% CI [0.60-1.03]; p = 0.077). No significant interaction between diabetes mellitus and hospital infections on recovery was found (p = 0.845). CONCLUSIONS: This study could not convincingly establish hospital infections as an etiologic risk factor for non-improvement of physical recovery in patients who underwent cardiothoracic surgery. In addition, there was no differential effect of hospital infections on non-improvement of physical recovery for patients with and without diabetes mellitus. Trial registration International Clinical Trials Registry Platform ID NL9818; date of registration, 22-10-2021 ( https://trialsearch.who.int/ ).

Characteristics, Treatment Strategies and Outcome in Cardiogenic Shock Complicating Acute Myocardial Infarction: A Contemporary Dutch Cohort.

Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) is associated with high morbidity and mortality. Our study aimed to gain insights into patient characteristics, outcomes and treatment strategies in CS patients. Patients with CS who underwent percutaneous coronary intervention (PCI) between 2017 and 2021 were identified in a nationwide registry. Data on medical history, laboratory values, angiographic features and outcomes were retrospectively assessed. A total of 2328 patients with a mean age of 66 years and of whom 73% were male, were included. Mortality at 30 days was 39% for the entire cohort. Non-survivors presented with a lower mean blood pressure and increased heart rate, blood lactate and blood glucose levels (p-value for all <0.001). Also, an increased prevalence of diabetes, multivessel coronary artery disease and a prior coronary event were found. Of all patients, 24% received mechanical circulatory support, of which the majority was via intra-aortic balloon pumps (IABPs). Furthermore, 79% of patients were treated with at least one vasoactive agent, and multivessel PCI was performed in 28%. In conclusion, a large set of hemodynamic, biochemical and patient-related characteristics was identified to be associated with mortality. Interestingly, multivessel PCI and IABPs were frequently applied despite a lack of evidence.

Multivessel versus Culprit-Only Percutaneous Coronary Intervention in Patients with Non-ST-Elevation Acute Coronary Syndrome.

Background: There is uncertainty whether multivessel (MV-PCI) or culprit-only percutaneous coronary intervention (CO-PCI) should be the treatment of choice in patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) and multivessel disease (MVD). Aims: To evaluate clinical characteristics and outcomes in these patients undergoing MV-PCI or CO-PCI at the index procedure. Methods: Data were retrieved from the nationwide Netherlands Heart Registration. All NSTE-ACS patients with MVD undergoing PCI between 1 January 2017 and 1 October 2019 were grouped into a MV-PCI or CO-PCI group. The primary endpoint was all-cause mortality at long-term follow-up (median 756 days (593−996)). Secondary endpoints were reinterventions, urgent CABG, myocardial infarction (MI) < 30 days, target vessel revascularisation (TVR) and mortality at 1 year. Propensity score matching analyses were performed. Results: In total, 10,507 NSTE-ACS patients with MVD were included into the MV-PCI (N = 4235) and CO-PCI group (N = 6272). Analysing crude data, mortality rates at long-term follow-up (10.7% vs. 10.2%; p = 0.383), mortality at 1 year (6.0% vs. 5.6%; p = 0.412) and MI <30 days (0.8% vs. 0.9%; p = 0.513) were similar between both groups. Reinterventions (11.1% vs. 20.0%; p < 0.001), urgent CABG (0.1% vs. 0.4%; p = 0.001) and TVR (5.2% vs. 6.7%; p = 0.003) occurred less often in the MV-PCI group. Survival analysis after multiple imputation and propensity score matching showed similar mortality rates at long-term follow-up (log-rank p = 0.289), but a significant reduction for reinterventions in the MV-PCI group (log-rank p < 0.001). Conclusion: NSTE-ACS patients with MVD undergoing MV-PCI have similar mortality rates at long-term follow-up compared to CO-PCI. However, improved event-free survival in terms of fewer coronary reinterventions was observed.

Using real-world data to monitor and improve quality of care in coronary artery disease: results from the Netherlands Heart Registration.

Worldwide, quality registries for cardiovascular diseases enable the use of real-world data to monitor and improve the quality of cardiac care. In the Netherlands Heart Registration (NHR), cardiologists and cardiothoracic surgeons register baseline, procedural and outcome data across all invasive cardiac interventional, electrophysiological and surgical procedures. This paper provides insight into the governance and processes as organised by the NHR in collaboration with the hospitals. To clarify the processes, examples are given from the percutaneous coronary intervention and coronary artery bypass grafting registries. Physicians who are mandated by their hospital to instruct the NHR to process their data are united in registration committees. The committees determine standard sets of variables and periodically discuss the completeness and quality of data and patient-relevant outcomes. In the case of significant variation in outcomes, processes of healthcare delivery are discussed and good practices are shared in a non-competitive and safe setting. To create new insights for further improvement in patient-relevant outcomes, quality projects are initiated on, for example, multivessel disease treatment, cardiogenic shock and diagnostic intracoronary procedures. Moreover, possibilities are explored to expand the quality registries through additional relevant indicators, such as resource use before and after the procedure, by enriching NHR data with other existing data resources.

The effects of substitution of hospital ward care from medical doctors to physician assistants on non-adherence to guidelines on medication prescribing.

AIM: This study determined the effect of substitution of inpatient care from medical doctors (MDs) to physician assistants (PAs) on non-adherence to guidelines on medication prescribing. METHODS: A multicenter matched-controlled study was performed comparing wards on which PAs provide medical care in collaboration with MDs (PA/MD model), with wards on which only MDs provide medical care (MD model). A set of 17 quality indicators to measure non-adherence to guidelines on medication prescribing by PAs and MDs was composed by 14 experts in a modified Delphi procedure. The indicators covered different pharmacotherapeutic subjects, such as gastric protection in case of use of NSAID or prevention of obstipation in case of use of opioids. These indicators were expressed in proportions by dividing the number of patients in which the prescriber did not adhere to a guideline, by all patients that were applicable. Multivariable regression analysis was performed in order to adjust for potential confounders. RESULTS: 1021 patients from 17 hospital wards in the 'PA/MD model' group and 1286 patients from 17 hospital wards in the 'MD model' group were included. Two of the 17 quality indicators showed significantly less non-adherence to guidelines for the PA/MD model; the indicators concerning prescribing gastric protection in case of use of NSAID in combination with corticosteroids (OR 0.42, 95% CI 0.19-0.90) and in case of use of NSAID in patients older than 70 years (OR 0.47, 95% 0.23-0.95). For none of the other quality indicators for prescribing of medication a difference between the MD model and the PA/MD model was found. CONCLUSION: This study suggests that the non-adherence to guidelines on medication prescribing on wards with the PA/MD model does not differ from wards with traditional house staffing by MDs only. Further research is needed to determine quality, efficiency and safety of prescribing behavior of PAs.

Defining and Measuring a Standard Set of Patient-Relevant Outcomes in Coronary Artery Disease.

Systematic outcome measurement enables to continuously improve treatment results and stimulates dissemination of best practices. For patients with coronary artery disease, no examples yet exist of standard sets of patient-relevant outcome measures that have already been fully implemented at a large scale in clinical care. The aim of this paper is twofold: (1) to share the standard set of outcome measures as developed by Meetbaar Beter, and (2) to show how the standard set is presented and published to support improvement of cardiac care. A step-wise approach was followed by an expert panel to construct a standard set of outcome measures. This resulted in a comprehensive set of relevant outcome measures, comprising 4 generic and 11 treatment-specific outcomes. Both short-term and long-term outcomes measures up to 5 years of follow-up were included. Relevant initial conditions were selected to enable case-mix adjustment. The standard set has been implemented in 21 hospitals across the Netherlands. The results and experiences have been used to fine-tune the set in 4 reporting cycles in 2012 to 2016, using an annual maintenance cycle. Currently about 83,000 percutaneous coronary interventions and 30,000 coronary artery bypass graftings are included in the dataset, covering the majority of all percutaneous coronary interventions and coronary artery bypass graftings in the Netherlands. In conclusion, Meetbaar Beter has defined and implemented a comprehensive set of patient-relevant outcome measures for coronary artery disease, and the variation of the results among the centers indicates that there are sufficient opportunities to further improve cardiac care in the Netherlands.

The impact of the implementation of physician assistants in inpatient care: A multicenter matched-controlled study.

BACKGROUND: Medical care for admitted patients in hospitals is increasingly reallocated to physician assistants (PAs). There is limited evidence about the consequences for the quality and safety of care. This study aimed to determine the effects of substitution of inpatient care from medical doctors (MDs) to PAs on patients' length of stay (LOS), quality and safety of care, and patient experiences with the provided care. METHODS: In a multicenter matched-controlled study, the traditional model in which only MDs are employed for inpatient care (MD model) was compared with a mixed model in which besides MDs also PAs are employed (PA/MD model). Thirty-four wards were recruited across the Netherlands. Patients were followed from admission till one month after discharge. Primary outcome measure was patients' LOS. Secondary outcomes concerned eleven indicators for quality and safety of inpatient care and patients' experiences with the provided care. RESULTS: Data on 2,307 patients from 34 hospital wards was available. The involvement of PAs was not significantly associated with LOS (ß 1.20, 95%CI 0.99-1.40, p = .062). None of the indicators for quality and safety of care were different between study arms. However, the involvement of PAs was associated with better experiences of patients (ß 0.49, 95% CI 0.22-0.76, p = .001). CONCLUSIONS: This study did not find differences regarding LOS and quality of care between wards on which PAs, in collaboration with MDs, provided medical care for the admitted patients, and wards on which only MDs provided medical care. Employing PAs seems to be safe and seems to lead to better patient experiences. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01835444.

The involvement of physician assistants in inpatient care in hospitals in the Netherlands: a cost-effectiveness analysis.

OBJECTIVE: To investigate the cost-effectiveness of substitution of inpatient care from medical doctors (MDs) to physician assistants (PAs). DESIGN: Cost-effectiveness analysis embedded within a multicentre, matched-controlled study. The traditional model in which only MDs are employed for inpatient care (MD model) was compared with a mixed model in which, besides MDs, PAs are also employed (PA/MD model). SETTING: 34 hospital wards across the Netherlands. PARTICIPANTS: 2292 patients were followed from admission until 1 month after discharge. Patients receiving daycare, terminally ill patients and children were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: All direct healthcare costs from day of admission until 1 month after discharge. Health outcome concerned quality-adjusted life years (QALYs), which was measured with the EuroQol five dimensions questionnaire (EQ-5D). RESULTS: We found no significant difference for QALY gain (+0.02, 95% CI -0.01 to 0.05) when comparing the PA/MD model with the MD model. Total costs per patient did not significantly differ between the groups (+€568, 95% CI -€254 to €1391, p=0.175). Regarding the costs per item, a difference of €309 per patient (95% CI €29 to €588, p=0.030) was found in favour of the MD model regarding length of stay. Personnel costs per patient for the provider who is primarily responsible for medical care on the ward were lower on the wards in the PA/MD model (-€11, 95% CI -€16 to -€6, p<0.01). CONCLUSIONS: This study suggests that the cost-effectiveness on wards managed by PAs, in collaboration with MDs, is similar to the care on wards with traditional house staffing. The involvement of PAs may reduce personnel costs, but not overall healthcare costs. TRIAL REGISTRATION NUMBER: NCT01835444.

Determinants of the sustained employment of physician assistants in hospitals: a qualitative study.

OBJECTIVES: To identify determinants of the initial employment of physician assistants (PAs) for inpatient care as well as of the sustainability of their employment. DESIGN: We conducted a qualitative study with semistructured interviews with care providers. Interviews continued until data saturation was achieved. All interviews were transcribed verbatim. A framework approach was used for data analysis. Codes were sorted by the themes, bringing similar concepts together. SETTING: This study was conducted between June 2014 and May 2015 within 11 different hospital wards in the Netherlands. The wards varied in medical speciality, as well as in hospital type and the organisational model for inpatient care. PARTICIPANTS: Participant included staff physicians, residents, PAs and nurses. RESULTS: The following themes emerged to be important for the initial employment of PAs and the sustainability of their employment: the innovation, individual factors, professional interactions, incentives and resources, capacity for organisational change and social, political and legal factors. CONCLUSIONS: 10 years after the introduction of PAs, there was little discussion among the adopters about the added value of PAs, but organisational and financial uncertainties played an important role in the decision to employ and continue employment of PAs. Barriers to employ and continue PA employment were mostly a consequence of locally arranged restrictions by hospital management and staff physicians, as barriers regarding national laws, PA education and competencies seemed absent.

Physician assistants in medical ward care: a descriptive study of the situation in the Netherlands.

RATIONALE, AIMS AND OBJECTIVES: Medical ward care has been increasingly reallocated from medical doctors (MDs) to physician assistants (PAs). Insight into their roles and tasks is limited. This study aims to provide insight into different organizational models of medical ward care, focusing on the position, tasks and responsibilities of the involved PAs and MDs. METHODS: In this cross-sectional descriptive study 34 hospital wards were included. Characteristics of the organizational models were collected from the heads of departments. We documented provider continuity by examination of work schedules. MDs and PAs in charge for medical ward care (n = 179) were asked to complete a questionnaire to measure workload, supervision and tasks performed. RESULTS: We distinguished four different organizational models for ward care: medical specialists in charge of admitted patients (100% MS), medical residents in charge (100% MR), PAs in charge (100% PA), both MRs and PAs in charge (mixed PA/MR). The wards with PAs had the highest provider continuity. PAs spend relatively more time on direct patient care; MDs spend relatively more time on indirect patient care. PAs spend more hours on quality projects (P = 0.000), while MDs spend more time on scientific research (P = 0.030). CONCLUSION: Across different organizational models for medical ward care, we found variations in time per task, time per bed and provider continuity. Further research should focus on the impact of these differences on outcomes and efficiency of medical ward care.

Dietary nucleotide and nucleoside exposure in infancy and atopic dermatitis, recurrent wheeze, and allergic sensitization.

We hypothesized that early life exposure to nucleotides and nucleosides lowers the risk of recurrent wheeze, atopic dermatitis, and allergic sensitization among n = 429 children. Concentrations in breast milk were established by high-performance liquid chromatography; concentrations in formula milks were obtained from manufacturers. Questionnaires and home visits were used to assess outcomes. Adjusted odds ratios in the highest tertile compared with those in the lowest tertile of exposure ranged from 1.11 to 1.99 in predominantly formula-fed children, and from 0.40 to 0.53 in predominantly breast-fed children, but were not significant. Thus, we found no evidence for association between nucleotide and nucleoside exposure and the development of atopic outcomes in children up to 2 years.

The effectiveness of substitution of hospital ward care from medical doctors to physician assistants: a study protocol.

BACKGROUND: Because of an expected shrinking supply of medical doctors for hospitalist posts, an increased emphasis on efficiency and continuity of care, and the standardization of many medical procedures, the role of hospitalist is increasingly allocated to physician assistants (PAs). PAs are nonphysician clinicians with medical tasks. This study aims to evaluate the effects of substitution of hospital ward care to PAs. METHODS/DESIGN: In a multicenter matched controlled study, the traditional model in which the role of hospitalist is taken solely by medical doctors (MD model) is compared with a mixed model in which a PA functions as a hospitalist, contingent with MDs (PA/MD model). Twenty intervention and twenty control wards are included across The Netherlands, from a range of medical specialisms. Primary outcome measure is patients' length of hospital stay. Secondary outcomes include indicators for quality of hospital ward care, patients experiences with medical ward care, patients health-related quality of life, and healthcare providers' experiences. An economic evaluation is conducted to assess the cost implications and potential efficiency of the PA/MD model. For most measures, data is collected from medical records or questionnaires in samples of 115 patients per hospital ward. Semi-structured interviews with healthcare professionals are conducted to identify determinants of efficiency, quality and continuity of care and barriers and facilitators for the implementation of PAs in the role of hospitalist. DISCUSSION: Findings from this study will help to further define the role of nonphysician clinicians and provides possible key components for the implementation of PAs in hospital ward care. Like in many studies of organizational change, random allocation to study arms is not feasible, which implies an increased risk for confounding. A major challenge is to deal with the heterogeneity of patients and hospital departments.

Pre-operative dietary restriction is feasible in live-kidney donors.

Dietary restriction (DR), defined as reduced energy intake without malnutrition, confers protection against renal ischemia and reperfusion injury in animal models. This pilot study investigates for the first time the feasibility of pre-operative DR in the clinical setting. Live-kidney donors were randomized between pre-operative DR or ad libitum intake. Seventeen participants were instructed to follow a 30% calorie-restricted diet, followed by one day of water-only fasting prior to surgery. Thirteen participants were allowed to eat ad libitum pre-operatively. Ninety-four percent of the donors adhered to the diet, 31.4% reduction in caloric intake was achieved. Post-operative well-being, appetite and ability to perform daily tasks were not different between both groups. There was no difference in post-transplant graft function of kidneys obtained from DR donors or control donors as determined by serum creatinine levels during the first post-operative month and renograms at post-operative day one. This study shows that mild dietary restriction is feasible in the setting of live-kidney donation. No effect was observed regarding post-operative graft function. Additional studies are warranted to investigate the appropriate regimen of dietary restriction to protecting against ischemia and reperfusion injury, such as increasing the magnitude and/or duration of the reduction in daily caloric intake.