Increasing the bioavailability of oral esketamine by a single dose of cobicistat: A case study.

BACKGROUND: Intranasal esketamine is an approved drug for treatment­resistant depression (TRD); however, it is costly and may result in specific adverse effects. In this single case study, we explored if oral esketamine can be a suitable alternative. METHODS: In collaboration with a 39­year­old female with TRD, we compared plasma concentration curves of intranasal (84 mg) and oral (1, 2 and 4 mg/kg) esketamine. Because oral esketamine has a relatively low bioavailability, it results in a different ratio between esketamine and its primary metabolite noresketamine. To increase the bioavailability of oral esketamine, we co­administered a single dose of the cytochrome P­450 (CYP) 3A4 inhibitor cobicistat (150 mg). RESULTS: For all doses administered, oral esketamine resulted in lower esketamine but higher noresketamine peak plasma concentrations compared with intranasal treatment. Using oral esketamine it was not possible to generate a similar esketamine plasma concentration curve as with the intranasal treatment, except when combined with cobicistat (esketamine 2 mg/kg plus cobicistat 150 mg). CONCLUSIONS: Our findings demonstrate that cobicistat effectively increases the bioavailability of oral esketamine. Further research is required in a larger population, especially to investigate the clinical benefit of cobicistat as a booster drug for oral esketamine.

Safety and Feasibility of the BYCROSS® Atherectomy Device for the Treatment of Femoropopliteal Arterial Obstructions: Single-Center Short-Term Outcomes.

Background: Endovascular techniques have gained preference over peripheral arterial bypass surgery due to their minimally invasive nature; however, endovascular treatments often show limited efficacy in arterial segments with a high atherosclerotic load. The use of atherectomy devices enables the removal of calcified plaque material and may promote arterial wall remodeling. This study assessed the technical success, safety, and feasibility of the BYCROSS® atherectomy device in femoropopliteal lesions. Methods: This single-center, retrospective cohort study analyzed elective patients undergoing BYCROSS® atherectomy for chronic peripheral arterial disease from March 2022 to May 2023. Patient data, procedural details, and outcomes were retrospectively collected from electronic patient records. The primary performance endpoints of this study were technical success, complications, and patency rates. Primary safety endpoints included 30-day and short-term major adverse limb events (MALEs), major adverse cardiovascular events (MACEs), and mortality rate. Results: The study included 19 patients (median age, 71 years; 63% male) with Fontaine class IIb (26%), III (21%), or IV (53%). The BYCROSS® atherectomy device was used to treat 22 limbs in the femoropopliteal tract, of which 11 lesions (50%) were occlusions and 11 were stenoses, with a median length of 24 cm (interquartile range: 17-38). Technical success was achieved in all cases: 4.5% required atherectomy only, 50% required additional balloon angioplasties, 41% required balloon angioplasties and stenting, and 4.5% required segments only stenting. Additional treatment of below-the-knee arteries was performed in 12 patients. Procedurally related complications (not limited to the use of the BYCROSS® device) occurred in 23% of limbs, including distal embolization and laceration. At 30 days, mortality was 5%, the MACE rate was 11%, and the MALE rate was 0%. The observed mortality rate was not directly related to the procedure. Patency (<50% restenosis at duplex ultrasound) was 83% at 30 days. Conclusions: The use of the BYCROSS® atherectomy device for the treatment of femoropopliteal lesions appears to be safe and feasible, with high technical success and low MALE and MACE rates in a challenging population with long-segment femoropopliteal lesions. Long-term follow-up in larger patient series is needed to confirm these findings and to determine the durability of this technique.

A genetic risk score to predict treatment nonresponse in psychotic depression.

Psychotic depression is a severe and difficult-to-treat subtype of major depressive disorder for which higher rates of treatment-resistant depression were found. Studies have been performed aiming to predict treatment-resistant depression or treatment nonresponse. However, most of these studies excluded patients with psychotic depression. We created a genetic risk score (GRS) based on a large treatment-resistant depression genome-wide association study. We tested whether this GRS was associated with nonresponse, nonremission and the number of prior adequate antidepressant trials in patients with a psychotic depression. Using data from a randomized clinical trial with patients with a psychotic depression (n = 122), we created GRS deciles and calculated positive prediction values (PPV), negative predictive values (NPV) and odds ratios (OR). Nonresponse and nonremission were assessed after 7 weeks of treatment with venlafaxine, imipramine or venlafaxine plus quetiapine. The GRS was negatively correlated with treatment response (r = -0.32, p = 0.0023, n = 88) and remission (r = -0.31, p = 0.0037, n = 88), but was not correlated with the number of prior adequate antidepressant trials. For patients with a GRS in the top 10%, we observed a PPV of 100%, a NPV of 73.7% and an OR of 52.4 (p = 0.00072, n = 88) for nonresponse. For nonremission, a PPV of 100%, a NPV of 51.9% and an OR of 21.3 (p = 0.036, n = 88) was observed for patients with a GRS in the top 10%. Overall, an increased risk for nonresponse and nonremission was seen in patients with GRSs in the top 40%. Our results suggest that a treatment-resistant depression GRS is predictive of treatment nonresponse and nonremission in psychotic depression.

Importance of sac regression after EVAR and the role of EndoAnchors.

The initial success and widespread adoption of endovascular aneurysm repair (EVAR) for the treatment of abdominal aortic aneurysms have been tempered by numerous reports of secondary interventions and increased long-term mortality compared with open repair. Over the past decade, several studies on postoperative sac dynamics after EVAR have suggested that the presence of sac regression is a benign feature with a favorable prognosis. Conversely, increasing sacs and even stable sacs can be indicators of more unstable sac behavior with worse outcomes in the long-term. Endoleaks were initially perceived as the main drivers of sac behavior. However, the observation that sac regression can occur in the presence of endoleaks, and vice versa - increasing sacs without evidence of endoleak - on imaging studies, suggests the involvement of other contributing factors. These factors can be divided into anatomical factors, patient characteristics, sac thrombus composition, and device-related factors. The shift of interest away from especially type 2 endoleaks is further supported by promising results with the use of EndoAnchors regarding postoperative sac behavior. This review provides an overview of the existing literature on the implications and known risk factors of post-EVAR sac behavior, describes the accurate measurement of sac behavior, and discusses the use of EndoAnchors to promote sac regression.

The Relationship of Early Sleep Improvement With Response to Pharmacotherapy in Unipolar Psychotic Depression.

BACKGROUND: Since insomnia and depression are interrelated, improved sleep early in antidepressant pharmacotherapy may predict a positive treatment outcome. We investigated whether early insomnia improvement (EII) predicted treatment outcome in psychotic depression (PD) and examined if there was an interaction effect between EII and treatment type to assess if findings were treatment-specific. METHODS: This study is a secondary analysis of a randomized trial comparing 7 weeks treatment with the antidepressants venlafaxine, imipramine and venlafaxine plus the antipsychotic quetiapine in PD ( n = 114). Early insomnia improvement, defined as ≥20% reduced insomnia after 2 weeks, was assessed by the Hamilton Rating Scale for Depression (HAM-D-17). Associations between EII and treatment outcome were examined using logistic regressions. Subsequently, we added interaction terms between EII and treatment type to assess interaction effects. The predictive value of EII was compared with early response on overall depression (≥20% reduced HAM-D-17 score after 2 weeks). RESULTS: EII was associated with response (odds ratio [OR], 7.9; 95% confidence interval [CI], 2.7-23.4; P = <0.001), remission of depression (OR, 6.1; 95% CI, 1.6-22.3; P = 0.009), and remission of psychosis (OR, 4.1; 95% CI, 1.6-10.9; P = 0.004). We found no interaction effects between EII and treatment type on depression outcome. Early insomnia improvement and early response on overall depression had a comparable predictive ability for treatment outcome. CONCLUSIONS: Early insomnia improvement was associated with a positive outcome in pharmacotherapy of PD, regardless of the medication type. Future studies are needed to confirm our findings and to examine the generalizability of EII as predictor in treatment of depression.

[Prevention of delirium in the Intensive Care Unit]. / Preventie van delier op de intensive care.

Delirium is highly prevalent in the Intensive Care Unit (ICU) and is strongly associated with negative patient outcomes. We aimed to present an overview of the effectiveness of non-pharmacological and pharmacological interventions to prevent delirium in ICU patients. Multicomponent non-pharmacological interventions are proven effective in the prevention of delirium. These interventions are aimed at multiple domains, including re-orientation, providing a safe and healing environment, cognitive stimulation, mobilization and family engagement. A special type of multicomponent intervention is the ''A-F bundle'', comprising both non-pharmacological and pharmacological interventions. Multicomponent non-pharmacological interventions and the ''A-F bundle'' are recommended. There is insufficient evidence for the effectiveness of pharmacological prophylaxis using antipsychotics, dexmedetomidine, melatonin or thiamin, except for delirium due to substance withdrawal. Therefore, pharmacological interventions should be aimed at minimizing delirogenousmedication (especially benzodiazepines and opiates), adequate pain management and the prevention of deep and continuous sedation.

[Consider (es)ketamine for treatment-resistant depression]. / Overweeg (es)ketamine bij therapieresistente depressie.

Major depressive disorder has a high prevalence globally. Although pharmacotherapy and psychotherapy are effective for most patients, about one third is treatment resistant. Ketamine, known as an anesthetic, is a new treatment option that can be effective in patients with treatment-resistant depression. (es)ketamine works relatively fast. However, the long-term effects are still relatively unknown. In the Netherlands, S-Ketamine is currently administered in various forms, of which only the nasal spray is registered for treatment-resistant depression. Currently, many studies have been conducted on the use of (es)ketamine. In this article we describe the latest state of affairs regarding its effectiveness and safety.

Effectiveness of Genotype-Specific Tricyclic Antidepressant Dosing in Patients With Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Evidence of the clinical benefit of pharmacogenetics-informed treatment (PIT) with antidepressants is still limited. Especially for tricyclic antidepressants (TCAs), pharmacogenetics may be of interest because therapeutic plasma concentrations are well defined, identification of optimal dosing can be time consuming, and treatment is frequently accompanied by adverse effects. Objective: To determine whether PIT results in faster attainment of therapeutic TCA plasma concentrations compared with usual treatment in patients with unipolar major depressive disorder (MDD). Design, Setting, and Participants: This randomized clinical trial compared PIT with usual treatment among 111 patients at 4 centers in the Netherlands. Patients were treated with the TCAs nortriptyline, clomipramine, or imipramine, with clinical follow-up of 7 weeks. Patients were enrolled from June 1, 2018, to January 1, 2022. At inclusion, patients had unipolar nonpsychotic MDD (with a score of ≥19 on the 17-item Hamilton Rating Scale for Depression [HAMD-17]), were aged 18 to 65 years, and were eligible for TCA treatment. Main exclusion criteria were a bipolar or psychotic disorder, substance use disorder, pregnancy, interacting comedications, and concurrent use of psychotropic medications. Intervention: In the PIT group, the initial TCA dosage was based on CYP2D6 and CYP2C19 genotypes. The control group received usual treatment, which comprised the standard initial TCA dosage. Main Outcomes and Measures: The primary outcome was days until attainment of a therapeutic TCA plasma concentration. Secondary outcomes were severity of depressive symptoms (measured by HAMD-17 scores) and frequency and severity of adverse effects (measured by Frequency, Intensity, and Burden of Side Effects Rating scores). Results: Of 125 patients randomized, 111 (mean [SD] age, 41.7 [13.3] years; 69 [62.2%] female) were included in the analysis; of those, 56 were in the PIT group and 55 were in the control group. The PIT group reached therapeutic concentrations faster than the control group (mean [SD], 17.3 [11.2] vs 22.0 [10.2] days; Kaplan-Meier χ21 = 4.30; P = .04). No significant difference in reduction of depressive symptoms was observed. Linear mixed-model analyses showed that the interaction between group and time differed for the frequency (F6,125 = 4.03; P = .001), severity (F6,114 = 3.10; P = .008), and burden (F6,112 = 2.56; P = .02) of adverse effects, suggesting that adverse effects decreased relatively more for those receiving PIT. Conclusions and Relevance: In this randomized clinical trial, PIT resulted in faster attainment of therapeutic TCA concentrations, with potentially fewer and less severe adverse effects. No effect on depressive symptoms was observed. These findings indicate that pharmacogenetics-informed dosing of TCAs can be safely applied and may be useful in personalizing treatment for patients with MDD. Trial Registration: ClinicalTrials.gov Identifier: NCT03548675.

[A DNA medication pass for everyone?] / Iedereen een DNA-medicatiepas?

Pharmacogenetics holds the promise of personalized medicine, resulting in higher effectiveness and fewer adverse effects. Yet, the clinical benefit of a pre-emptive pharmacogenetic test has not been demonstrated rigorously. Recently an open-label real-world implementation study has been published, in which patients were randomized to either genotype-informed treatment (based on a 12-gene pharmacogenetic panel) or standard treatment. The study shows that genotype-informed prescription of different types of medication, i.e., opioids, anticoagulants and antidepressants, leads to a 30% reduction of clinically relevant adverse effects. This result is promising and indicates that genotype-informed treatment improves medication safety. Unfortunately, the influence of genotype-informed treatment on the balance between effectiveness and adverse effects could not be assessed and cost-effectiveness data are pending. Hence, a pharmacogenetic panel and a DNA medication pass for everyone are on the horizon, but not yet there.

Outcomes and Patency of Endovascular Infrapopliteal Reinterventions in Patients With Chronic Limb-Threatening Ischemia.

PURPOSE: Endovascular revascularization is the preferred treatment to improve perfusion of the lower extremity in patients with chronic limb-threatening ischemia (CLTI). Patients with CLTI often present with stenotic-occlusive lesions involving the infrapopliteal arteries. Although the frequency of treating infrapopliteal lesions is increasing, the reintervention rates remain high. This study aimed to determine the outcomes and patency of infrapopliteal endovascular reinterventions. METHODS: This retrospective, multicenter cohort study of 3 Dutch hospitals included patients who underwent an endovascular infrapopliteal reintervention in 2015 up to 2021 after a primary infrapopliteal intervention for CLTI. The outcome measures after the reintervention procedures included technical success rate, the mortality rate and complication rate (any deviation from the normal postinterventional course) at 30 days, overall survival, amputation-free survival (AFS), freedom from major amputation, major adverse limb event (MALE), and recurrent reinterventions (a reintervention following the infrapopliteal reintervention). Cox proportional hazard models were used to determine risk factors for AFS and freedom from major amputation or recurrent reintervention. RESULTS: Eighty-one patients with CLTI were included. A total of 87 limbs underwent an infrapopliteal reintervention in which 122 lesions were treated. Technical success was achieved in 99 lesions (81%). The 30-day mortality rate was 1%, and the complication rate was 13%. Overall survival and AFS at 1 year were 69% (95% confidence interval [CI], 55%-79%) and 54% (95% CI, 37%-67%), respectively, and those at 2.5 years were 45% (95% CI, 33%-56%) and 21% (95% CI, 11%-33%), respectively. Freedom from major amputation, MALE, and recurrent reinterventions at 1 year and 2.5 years were 59% (95% CI, 46%-70%) and 41% (95% CI, 25%-56%); 54% (95% CI, 41%-65%) and 36% (95% CI, 21%-51%); and 68% (95% CI, 55%-78%) and 51% (95% CI, 33%-66%), respectively. A Global Limb Anatomic Staging System score of III showed an increased hazard ratio of 2.559 (95% CI, 1.078-6.072; p=0.033) for freedom of major amputation or recurrent reintervention. CONCLUSIONS: The results of this study indicate that endovascular infrapopliteal reinterventions can be performed with acceptable 30-day mortality and complication rates. However, outcomes and patency were moderate to poor, with low AFS, high rates of major amputations, and recurrent reinterventions. CLINICAL IMPACT: This multicenter retrospective study evaluating outcome and patency of endovascular infrapopliteal reinterventions for CLTI, shows that endovascular infrapopliteal reinterventions can be performed with acceptable 30-day mortality and complication rates. However, the short- and mid-term outcomes of the infrapopliteal reinterventions were moderate to poor, with low rates of AFS and a high need for recurrent reinterventions. While the frequency of performing infrapopliteal reinterventions is increasing with additional growing complexity of the disease, alternative treatment options such as venous bypass grafting or deep venous arterialization may be considered and should be studied in randomized controlled trials.

Three cases of spontaneous major bleeding in patients with a COVID-19 infection.

In addition to the respiratory compromise typical for COVID-19 many papers reported on the thromboembolic complications in these often critically ill patients. In this report, three cases of patients that developed spontaneous major bleeding following treatment with therapeutic anticoagulation for thromboembolic complications of COVID-19 were described. Two cases were treated with coil-embolization and one patient could be treated conservatively. These cases illustrate the presence of a relevant bleeding risk against the background of the well-known thromboembolic complications associated with COVID-19. The increased risks of thromboembolic complications in COVID-19 warrant adequate prophylactic anticoagulation. The optimal dose to obtain a significant risk reduction without a significant increase in the incidence of major bleeding requires further research.

A Systematic Review and Meta-Analysis on Perioperative Cerebral and Hemodynamic Monitoring Methods during Carotid Endarterectomy.

BACKGROUND: To compare outcomes between different strategies of perioperative cerebral and hemodynamic monitoring during carotid endarterectomy. DATA SOURCES: MEDLINE, EMBASE, CINAHL, and Cochrane CENTRAL databases were searched. METHODS: This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and prospectively registered in the international prospective register of systematic reviews (CRD42021241891). The Grading of Recommendations, Assessment, Development and Evaluation approach was used to describe the methodological quality of the studies and certainty of the evidence. The primary outcome was 30-day stroke rate. Secondary outcomes measures are 30-day ipsilateral stroke, 30-day mortality, shunt rate, and complication rates. RESULTS: The search identified 3,460 articles. Seventeen randomized controlled trials (RCTs), three prospective observational studies and seven registries were included, reporting on 236,983 patients. The overall pooled 30-day stroke rate is 1.8% (95% CI 1.4-2.2%), ranging from 0 to 12.6%. In RCT's the pooled 30-day stroke rate is 2.7% (95% CI 1.6-3.7%) compared to 1.3% (95% CI 0.8-1.8%) in the registries. The overall stroke risk decreased from 3.7% before the year 2000 to 1.6% after 2000. No significant differences could be identified between different monitoring and shunting strategies, although a trend to higher stroke rates in routine no shunting arms of RCTs was observed. Overall, 30-day mortality, myocardial infarction and nerve injury rates are 0.6% (95% CI 0.4-0.8), 0.8% (95% CI 0.6-1.0) and 1.3% (95% CI 0.4-2.2), respectively. CONCLUSIONS: No significant differences between the compared shunting and monitoring strategies are found. However, routine no shunting is not recommended. The available data are too limited to prefer 1 method of neuromonitoring over another method when selective shunting is applied.

Biomarkers as predictors of treatment response to tricyclic antidepressants in major depressive disorder: A systematic review.

Tricyclic antidepressants (TCAs) are frequently prescribed in case of non-response to first-line antidepressants in Major Depressive Disorder (MDD). Treatment of MDD often entails a trial-and-error process of finding a suitable antidepressant and its appropriate dose. Nowadays, a shift is seen towards a more personalized treatment strategy in MDD to increase treatment efficacy. One of these strategies involves the use of biomarkers for the prediction of antidepressant treatment response. We aimed to summarize biomarkers for prediction of TCA specific (i.e. per agent, not for the TCA as a drug class) treatment response in unipolar nonpsychotic MDD. We performed a systematic search in PubMed and MEDLINE. After full-text screening, 36 papers were included. Seven genetic biomarkers were identified for nortriptyline treatment response. For desipramine, we identified two biomarkers; one genetic and one nongenetic. Three nongenetic biomarkers were identified for imipramine. None of these biomarkers were replicated. Quality assessment demonstrated that biomarker studies vary in endpoint definitions and frequently lack power calculations. None of the biomarkers can be confirmed as a predictor for TCA treatment response. Despite the necessity for TCA treatment optimization, biomarker studies reporting drug-specific results for TCAs are limited and adequate replication studies are lacking. Moreover, biomarker studies generally use small sample sizes. To move forward, larger cohorts, pooled data or biomarkers combined with other clinical characteristics should be used to improve predictive power.

Tricyclic antidepressants for major depressive disorder: a comprehensive evaluation of current practice in the Netherlands.

BACKGROUND: Traditionally tricyclic antidepressants (TCAs) have an important place in treatment of major depressive disorder (MDD). Today, often other antidepressant medications are considered as first step in the pharmacological treatment of MDD, mainly because they are associated with less adverse effects, whereby the position of TCAs appears unclear. In this study we aimed to examine the current practice of TCAs in treatment of unipolar MDD. METHODS: A mixed methods approach was applied. First, a selection of leading international and national guidelines was reviewed. Second, actual TCA prescription was examined by analyzing health records of 75 MDD patients treated with the TCAs nortriptyline, clomipramine or imipramine in different centers in the Netherlands. Third, promotors and barriers influencing the choice for TCAs and dosing strategies were explored using semi-structured interviews with 24 Dutch psychiatrists. RESULTS: Clinical practice guidelines were sometimes indirective and inconsistent with each other. Health records revealed that most patients (71%) attained therapeutic plasma concentrations within two months of TCA use. Patients who achieved therapeutic plasma concentrations reached them on average after 19.6 days (SD 10.9). Both health records and interviews indicated that therapeutic nortriptyline concentrations were attained faster compared to other TCAs. Various factors were identified influencing the choice for TCAs and dosing by psychiatrists. CONCLUSIONS: Guideline recommendations and clinical practice regarding TCA prescription for MDD vary. To increase consistency in clinical practice we recommend development of an up-to-date guideline integrating selection and dosing of TCAs, including the roles of therapeutic drug monitoring and pharmacogenetics. Such a guideline is currently lacking and would contribute to optimal TCA treatment, whereby efficacy and tolerability may be increased.

Association of the neutrophil to lymphocyte ratio and white blood cell count with response to pharmacotherapy in unipolar psychotic depression: An exploratory analysis.

Background: Low-grade inflammation occurs in a subgroup of patients with Major Depressive Disorder (MDD) and may be associated with response to antidepressant medications. The Neutrophil to Lymphocyte Ratio (NLR) and total White Blood cell Count (WBC) are markers of systemic inflammation which have not been investigated as predictors for outcome to pharmacotherapy in unipolar depression yet. Moreover, the association between inflammation and treatment response has not been studied in unipolar Psychotic Depression (PD). We conducted an exploratory analysis to examine the prognostic significance of NLR and WBC in pharmacotherapy of PD. Methods: Baseline NLR and WBC were examined in their association with response to seven weeks of treatment with antidepressants (venlafaxine or imipramine) and the combination of an antidepressant with an antipsychotic (venlafaxine plus quetiapine) in 87 patients with PD. Logistic regression models were adjusted for age, gender, Body Mass Index (BMI), depression severity, duration of the current episode and number of previous depressive episodes. Secondary outcomes were remission of depression and disappearance of psychotic symptoms. Results: Higher NLR was associated with increased response to pharmacotherapy (Exp(B) 1.66, 95 % CI 1.03-2.66, p = 0.036), but not with remission of depression or disappearance of psychotic symptoms. WBC was not associated with any of the outcome measures. Conclusion: NLR may be a novel, inexpensive and widely available biomarker associated with response to pharmacotherapy in PD. The association between white blood cell measures and treatment outcome should be further investigated for different types of antidepressants in PD and in non-psychotic MDD.

Nutritional implications of feeding free-living birds in public urban areas.

Supplementary feeding can affect populations of birds. It reduces energy spent on foraging and reduces the risk of starvation, but it also increases the risk of disease transmission and predation. Supplementary feeding may reduce species richness if some species are better able to exploit supplementary food resources than others. Feeding may also artificially inflate the carrying capacity of the ecosystem, leading to bird nuisance in the form of droppings and noise. The aim of this study was to characterise and quantify the risk factors and consequences of feeding free-living birds in public areas in the western part of the city of Amsterdam. In seven study areas, the following data were collected: bird population size and species composition, feeding events, and the type and amount of supplementary food offered. Estimations were made of the nutritional energy provided and the number of birds that could be supported by the food offered. Members of the public who fed the birds were invited to complete a questionnaire on various aspects of feeding. Results showed that supplementary feeding attracts juvenile gulls and feral pigeons, which could in the long-term affect biodiversity. Bread was the main category of supplementary food being offered (estimated to be 67% of the total amount of food). The majority of respondents fed birds so as not to waste bread and meal leftovers. In six of the seven areas studied, an overabundance of nutritional energy was calculated. We conclude that the current type and extent of supplementary feeding in the city of Amsterdam is nutritionally unbalanced and affects species diversity at a local level. The overabundance is undesirable for reasons of both animal health, because it can lead to malnutrition, and public health, because surplus food attracts rats and may also have a negative effect on water quality.