The influence of insulin on anticipation and consummatory reward to food intake: A functional imaging study on healthy normal weight and overweight subjects employing intranasal insulin delivery.

Aberrant responses within homeostatic, hedonic and cognitive systems contribute to poor appetite control in those with an overweight phenotype. The hedonic system incorporates limbic and meso-limbic regions involved in learning and reward processing, as well as cortical regions involved in motivation, decision making and gustatory processing. Equally important within this complex, multifaceted framework are the cognitive systems involved in inhibitory control and valuation of food choices. Regions within these systems display insulin receptors and pharmacologically increasing central insulin concentrations using intranasal administration (IN-INS) has been shown to significantly reduce appealing food cue responsiveness and also food intake. In this work we describe a placebo-controlled crossover pharmacological functional magnetic resonance imaging (fMRI) study that looks at how IN-INS (160 IU) affects anticipatory and consummatory responses to sweet stimuli and importantly how these responses differ between healthy normal weight and overweight male individuals. This work shows that age matched normal weight and overweight (not obese) individuals respond similarly to both the anticipation and receipt of sweet stimuli under placebo conditions. However, increased central insulin concentrations produce marked differences between groups when anticipating sweet stimuli within the prefrontal cortex and midbrain as well as observed differences in the amygdala during consummatory responses.

Revealing the mechanisms behind novel auditory stimuli discrimination: An evaluation of silent functional MRI using looping star.

Looping Star is a near-silent, multi-echo, 3D functional magnetic resonance imaging (fMRI) technique. It reduces acoustic noise by at least 25dBA, with respect to gradient-recalled echo echo-planar imaging (GRE-EPI)-based fMRI. Looping Star has successfully demonstrated sensitivity to the cerebral blood-oxygen-level-dependent (BOLD) response during block design paradigms but has not been applied to event-related auditory perception tasks. Demonstrating Looping Star's sensitivity to such tasks could (a) provide new insights into auditory processing studies, (b) minimise the need for invasive ear protection, and (c) facilitate the translation of numerous fMRI studies to investigations in sound-averse patients. We aimed to demonstrate, for the first time, that multi-echo Looping Star has sufficient sensitivity to the BOLD response, compared to that of GRE-EPI, during a well-established event-related auditory discrimination paradigm: the "oddball" task. We also present the first quantitative evaluation of Looping Star's test-retest reliability using the intra-class correlation coefficient. Twelve participants were scanned using single-echo GRE-EPI and multi-echo Looping Star fMRI in two sessions. Random-effects analyses were performed, evaluating the overall response to tones and differential tone recognition, and intermodality analyses were computed. We found that multi-echo Looping Star exhibited consistent sensitivity to auditory stimulation relative to GRE-EPI. However, Looping Star demonstrated lower test-retest reliability in comparison with GRE-EPI. This could reflect differences in functional sensitivity between the techniques, though further study is necessary with additional cognitive paradigms as varying cognitive strategies between sessions may arise from elimination of acoustic scanner noise.

The effect of body mass index on retropubic midurethral slings.

BACKGROUND: Analyzing surgical databases uses "real-life" outcomes rather than highly selected cases from randomized controlled trials. Retropubic midurethral slings are a highly effective surgical treatment for stress urinary incontinence; however, if modifiable patient characteristics alter outcomes, thereby rendering treatments less effective, patients should be informed and given the opportunity to change that characteristic. OBJECTIVE: The aim of this study was to evaluate the effect of body mass index on patient-reported outcome measures by analyzing midurethral slings from the British Society of Urogynaecology database. MATERIALS AND METHODS: The British Society of Urogynaecology approved analysis of 11,859 anonymized midurethral slings from 2007 to 2016. The primary outcome of this retrospective cohort study was to assess how body mass index affects patient-reported outcome measures. Outcomes were assessed at 6 weeks, 3 months, 6 months, or 12 months after surgery, depending on local arrangements. Outcomes were compared by body mass index groups using χ2 tests. RESULTS: As BMI increased, Patient Global Impression of Improvement (PGI-I) scores declined. Women with a normal body mass index (18 to <25) reported feeling better in 91.6% of cases compared to lower rates in BMI groups >30 (87.7-72%) (P < .001). Patient-reported outcome measures for stress urinary incontinence inversely correlated with body mass index, with 97% of women with normal body mass index stating that they were cured/improved compared to women in higher body mass index groups (84-94%) reporting lower rates (P < .005). Patient-reported outcome measures for overactive bladder show that as body mass index increases, patients reported higher rates of worsening symptoms (P < .05). There were higher rates of perforation at the low and high extremes of body mass index. CONCLUSION: Our results suggest increased body mass index is associated with poorer outcomes after midurethral sling surgery, and that patients should be given the opportunity to change their body mass index. These data could help to develop a model to predict personalized success and complication rates, which may improve shared decision making and give an impetus to modify characteristics to improve outcomes.

Human Toxicity Caused by Indole and Indazole Carboxylate Synthetic Cannabinoid Receptor Agonists: From Horizon Scanning to Notification.

BACKGROUND: The emergence of novel psychoactive substances (NPS), particularly synthetic cannabinoid receptor agonists (SCRA), has involved hundreds of potentially harmful chemicals in a highly dynamic international market challenging users', clinicians', and regulators' understanding of what circulating substances are causing harm. We describe a toxicovigilance system for NPS that predicted the UK emergence and identified the clinical toxicity caused by novel indole and indazole carboxylate SCRA. METHODS: To assist early accurate identification, we synthesized 5 examples of commercially unavailable indole and indazole carboxylate SCRA (FUB-NPB-22, 5F-NPB-22, 5F-SDB-005, FUB-PB-22, NM-2201). We analyzed plasma and urine samples from 160 patients presenting to emergency departments with severe toxicity after suspected NPS use during 2015 to 2016 for these and other NPS using data-independent LC-MS/MS. RESULTS: We successfully synthesized 5 carboxylate SCRAs using established synthetic and analytical chemistry methodologies. We identified at least 1 SCRA in samples from 49 patients, including an indole or indazole carboxylate SCRA in 17 (35%), specifically 5F-PB-22 (14%), FUB PB-22 (6%), BB-22 (2%), 5F NPB-22 (20%), FUB NPB-22 (2%), and 5F-SDB-005 (4%). In these 17 patients, there was analytical evidence of other substances in 16. Clinical features included agitation and aggression (82%), reduced consciousness (76%), acidosis (47%), hallucinations and paranoid features (41%), tachycardia (35%), hypertension (29%), raised creatine kinase (24%), and seizures (12%). CONCLUSIONS: This toxicovigilance system predicted the emergence of misuse of indole and indazole carboxylate SCRA, documented associated clinical harms, and notified relevant agencies. Toxicity appears consistent with other SCRA, including mental state disturbances and reduced consciousness.

Tolterodine ER reduced increased bladder wall thickness in women with overactive bladder. A randomized, placebo-controlled, double-blind, parallel group study.

AIMS: We evaluated the effect of Tolterodine extended release (TER) versus placebo on bladder wall thickness (BWT) using transvaginal ultrasound in women with overactive bladder (OAB). MATERIALS AND METHODS: We recruited 79 women with symptoms of OAB with a mean age of 47 years who had a BWT of at least 5 mm and a post-micturition volume of less than 50 mL at screening. Subjects received TER 4 mg or placebo once daily for the first 12 weeks of the study. For the subsequent 12 weeks, all subjects received TER 4 mg once daily. BWT was measured at screening, weeks 12 and 24. Subjects recorded number of micturitions, incontinence episodes and urgency episodes, and volume voided per micturition at regular intervals during the study. RESULTS: Treatment with TER for 12 weeks produced a statistically significant decrease from baseline in BWT (mean [SD] = 0.9 [1.4] mm; P < 0.05) that was not evident following treatment with placebo (0.2 [1.6] mm; P = 0.54). However, the treatment difference did not reach statistical significance (LS Mean = -0.4; 95%CI: -1.2, 0.3; P = 0.25). After 12 weeks of treatment, subjects who had taken TER showed an improvement in each bladder diary variable compared to placebo-treated subjects. CONCLUSIONS: TER may have a direct effect on BWT in women with OAB. Larger studies are warranted to further investigate the effect of behavioral interventions and antimuscarinics, such as TER, on BWT in women with OAB and increased BWT.

Patterns of Acute Toxicity Associated with New Psychoactive Substances.

This chapter begins by considering why it is important to understand the clinical patterns of acute toxicity associated with new psychoactive substances (NPS), the challenges associated with gathering these data, the sources of information available and the limitations of each. It describes the data triangulation approach that can be used to combine individual, each inherently limited, data sources to help build the picture of the pattern of acute non-fatal toxicity associated with NPS. The chapter illustrates the data triangulation approach by the use of clinical examples and aims to consider mechanism of action data in conjunction with clinical features to provide an overarching understanding of the clinical presentation. Examples of the most important individual and groups of NPS were identified using multimodal literature searching based on the most relevant terms. The chapter provides descriptive accounts that are a complete reference source on the patterns of acute toxicity.

Rapid and equivalent systemic bioavailability of the antidotes HI-6 and dicobalt edetate via the intraosseous and intravenous routes.

BACKGROUND: Rapid and effective administration of antidotes by emergency medical responders is needed to improve the survival of patients severely poisoned after deliberate release of chemical weapons, but intravenous access is difficult to obtain while wearing personal protective equipment and in casualties with circulatory collapse. To test the hypothesis that rapid and substantial bioavailability of the antidotes HI-6 oxime and dicobalt edetate can be achieved via the intraosseous (IO) route, plasma concentration-time profiles of these antidotes were compared after administration by the intravenous and IO routes in a minipig animal model. METHODS: 12 male Göttingen minipigs were randomly allocated to receive 7.14 mg/kg of HI-6 (by rapid bolus) then 4.28 mg/kg of dicobalt edetate (over 1 min) via the intravenous or IO route. Plasma concentrations of each antidote were measured over 360 min following administration and plasma concentration-time profiles plotted for each drug by each route. RESULTS: Peak HI-6 and cobalt concentrations occurred within 2 min of administration by both the intravenous and IO routes. Mean areas under the concentration-time curves (SD) to the end of the experiment (area under the concentration-time curve, AUC (0-t)) for cobalt were 430 (47, intravenous) and 445 (40, IO) µg-min/mL (mean difference 15, 95% CI -41 to 70, p=0.568) and for HI-6 were 2739 (1038, intravenous) and 2772 (1629, IO) µg-min/mL (mean difference 0.33, 95% CI -1724 to 1790, p=0.97). Increases in heart rate (by 50 beats/min intravenous and 27 beats/min IO) and BP, (by 67/58 mm Hg intravenous and 78/59 mm Hg IO), were observed after dicobalt edetate, consistent with the known adverse effects of this antidote. DISCUSSION: This study demonstrates rapid and similar systemic bioavailability of HI-6 and dicobalt edetate when given by the IO and intravenous routes. IO delivery of these antidotes is appropriate in the acute management of patients with organophosphate and cyanide intoxication when the intravenous route is impractical.

Increasing frequency of severe clinical toxicity after use of 2,4-dinitrophenol in the UK: a report from the National Poisons Information Service.

OBJECTIVE: 2,4-Dinitrophenol (DNP) increases energy consumption by uncoupling oxidative phosphorylation. Although not licensed as a medicine, it is sometimes used by 'body sculptors' and for weight loss as a 'fat burning' agent. This research was performed to characterise patterns of presentation, clinical features and outcomes of patients reported to the National Poisons Information Service (NPIS) in the UK after exposure to DNP. METHODS: NPIS telephone enquiry records and user sessions for TOXBASE, the NPIS online information database, related to DNP, were reviewed from 1 January 2007 to 31 December 2013. RESULTS: Of the 30 separate systemic exposures to DNP reported by telephone to NPIS during the study period (27 males, 3 females, with a median age of 23.5 years), there were 3 during 2007-2011 (inclusive), 5 during 2012 and 22 during 2013. TOXBASE user sessions also increased sharply from 6 in 2011 to 35 in 2012 and 331 in 2013. The modes of exposure reported in telephone enquiries were chronic (n=2), acute (n=12) and subacute (n=16). Commonly reported clinical features were fever (47%), tachycardia (43%), sweating (37%), nausea or vomiting (27%), skin discolouration or rash (23%), breathing difficulties (23%), abdominal pain (23%), agitation (13%) and headache (13%). There were five (17%, 95% CI 6.9% to 34%) fatalities, four involving acute overdose. CONCLUSIONS: The study indicates a substantial recent increase in clinical presentations with toxicity caused by exposure to DNP in the UK with an associated high mortality. Further steps are needed to warn potential users of the severe and sometimes fatal toxicity that may occur after exposure to this compound.

Methoxetamine toxicity reported to the National Poisons Information Service: clinical characteristics and patterns of enquiries (including the period of the introduction of the UK's first Temporary Class Drug Order).

OBJECTIVE: To report the demographic and clinical characteristics of cases of methoxetamine toxicity reported to The National Poisons Information Service (NPIS) by healthcare professionals. To assess the pattern of enquiries from health professionals to the UK NPIS related to methoxetamine, including the period of the making of the UK first Temporary Class Drug Order (TCDO). METHODS: All telephone enquiries to and user sessions for TOXBASE, the NPIS on-line information resource, related to methoxetamine (and synonyms 'MXE', 'mket' and '2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone') were reviewed from 1 April 2010 to 1 August 2012. Data were compared for the 3 months before and after the TCDO. RESULTS: There were 47 telephone enquiries and 298 TOXBASE sessions regarding methoxetamine during the period of study. Comparing the 3 months before and after the TCDO, TOXBASE sessions for methoxetamine fell by 79% (from 151 to 32) and telephone enquiries by 80% (from 15 to 3). Clinical features reported by enquirers were consistent with case reports of analytically confirmed methoxetamine toxicity and typical toxidromes were of stimulant (36%), reduced consciousness (17%), dissociative (11%) and cerebellar (6.4%) types, but also particularly featured acute disturbances in mental heath (43%). CONCLUSIONS: Structured NPIS data may reveal trends in drugs of abuse use and toxicity when interpreted within their limitations. Since April 2012, there have been fewer enquiries to NPIS from clinicians, indicating reduced presentations with suspected methoxetamine toxicity to healthcare services. It is unclear if this is related to the TCDO made on 5 April 2012.

Support and practical advice for the use of nutrition support teams.

There are many guidelines recommending that provision of parenteral nutrition (PN) should be supervised by nutrition support teams (NSTs). There is some evidence that these teams make economic sense, decrease complications and result in greater delivery of target nutritional requirements. Moreover, a recent report on the quality of PN care in the UK found only 19% was considered to be consistent with current good practice. Recommendations exist on how to set up teams, but advice on the practical aspects of doing the job is lacking. In this article, the authors outline the NST method of practice at North Shore Hospital in Auckland, New Zealand, including its assessment sheet and a description of its working acronym LIFEWRAP, which is used to ensure consistent assessment and care.

Omnivore, vegan and vegetarian diet quality associations with depressive symptoms: A comparative cross-sectional analysis of the Australian Longitudinal Study on Women's Health.

BACKGROUND: Depressive symptoms are experienced by >350 million people globally. Research suggests that a diet rich in plant foods could be protective against depressive symptoms, but vegans and vegetarians who eat a predominant plant-based diet are known to have higher depressive symptoms than omnivores. METHODS: This study aims to explore a secondary analysis of the association between diet quality and depressive symptoms in women born between 1973 and 1978 who follow vegan, vegetarian, and omnivore diets from the Australian Longitudinal Study of Women's Health at baseline (1996) and at three time points (2000, 2003 and 2009). RESULTS: After controlling for covarying factors, there was a significant association between diet quality and depressive symptoms in both the plant-based and omnivore groups at both time points F(9, 4851) = 106.90, p < .001. There was no significant difference between diet quality and depressive symptoms between diet type. CONCLUSIONS: Despite diet type (plant-based or omnivore), adhering to a high-quality diet may decrease depressive symptoms and a low-quality diet may increase depressive symptoms in Australian women. LIMITATIONS: Caution should be exercised when interpreting these results due to the small sample sizes and small resulting coefficients, there is uncertainty that coefficients this small can be associated with any meaningful change in an individual being treated for depressive symptoms in a clinical setting.

Investigating acoustic startle habituation and prepulse inhibition with silent functional MRI and electromyography in young, healthy adults.

Introduction: Startle habituation and prepulse inhibition (PPI) are distinct measures of different sensory information processes, yet both result in the attenuation of the startle reflex. Identifying startle habituation and PPI neural mechanisms in humans has mostly evolved from acoustic-focused rodent models. Human functional magnetic resonance imaging (fMRI) studies have used tactile startle paradigms to avoid the confounding effects of gradient-related acoustic noise on auditory paradigms and blood-oxygen-level-dependent (BOLD) measures. This study aimed to examine the neurofunctional basis of acoustic startle habituation and PPI in humans with silent fMRI. Methods: Using silent fMRI and simultaneous electromyography (EMG) to measure startle, the neural correlates of acoustic short-term startle habituation and PPI [stimulus onset asynchronies (SOA) of 60 ms and 120 ms] were investigated in 42 healthy adults (28 females). To derive stronger inferences about brain-behaviour correlations at the group-level, models included EMG-assessed measures of startle habituation (regression slope) or PPI (percentage) as a covariate. A linear temporal modulator was modelled at the individual-level to characterise functional changes in neural activity during startle habituation. Results: Over time, participants showed a decrease in startle response (habituation), accompanied by decreasing thalamic, striatal, insula, and brainstem activity. Startle habituation was associated with the linear temporal modulation of BOLD response amplitude in several regions, with thalamus, insula, and parietal lobe activity decreasing over time, and frontal lobe, dorsal striatum, and posterior cingulate activity increasing over time. The paradigm yielded a small amount of PPI (9-13%). No significant neural activity for PPI was detected. Discussion: Startle habituation was associated with the thalamus, putamen, insula, and brainstem, and with linear BOLD response modulation in thalamic, striatal, insula, parietal, frontal, and posterior cingulate regions. These findings provide insight into the mediation and functional basis of the acoustic primary startle circuit. Instead, whilst reduced compared to conventional MRI, scanner noise may have disrupted prepulse detection and processing, resulting in low PPI and impacting our ability to map its neural signatures. Our findings encourage optimisation of the MRI environment for acoustic PPI-based investigations in humans. Combining EMG and functional neuroimaging methods shows promise for mapping short-term startle habituation in healthy and clinical populations.

Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene.

Hermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding and pulmonary fibrosis result from defects of melanosomes, platelet dense granules and lysosomes. HPS is common in Puerto Rico, where it is caused by mutations in the genes HPS1 and, less often, HPS3 (ref. 8). In contrast, only half of non-Puerto Rican individuals with HPS have mutations in HPS1 (ref. 9), and very few in HPS3 (ref. 10). In the mouse, more than 15 loci manifest mutant phenotypes similar to human HPS, including pale ear (ep), the mouse homolog of HPS1 (refs 13,14). Mouse ep has a phenotype identical to another mutant, light ear (le), which suggests that the human homolog of le is a possible human HPS locus. We have identified and found mutations of the human le homolog, HPS4, in a number of non-Puerto Rican individuals with HPS, establishing HPS4 as an important HPS locus in humans. In addition to their identical phenotypes, le and ep mutant mice have identical abnormalities of melanosomes, and in transfected melanoma cells the HPS4 and HPS1 proteins partially co-localize in vesicles of the cell body. In addition, the HPS1 protein is absent in tissues of le mutant mice. These results suggest that the HPS4 and HPS1 proteins may function in the same pathway of organelle biogenesis.

Accuracy of substance exposure history in patients attending emergency departments after substance misuse; a comparison with biological sample analysis.

CONTEXT: Acute toxicity caused by illicit substance use is a common reason for emergency department (ED) presentation. Knowledge of the substances involved is helpful for predicting and managing potential toxicity, but limited information is available about the accuracy of patient-reported substance exposure. This study assessed the accuracy of the history of exposure in those reporting use of a single substance by comparison with those identified by detailed toxicological analysis, focusing on synthetic cannabinoid receptor agonists (SCRA). METHODS: Adults (≥16 years) presenting between March 2015 and July 2021 to participating UK hospitals with toxicity after reporting use of a single illicit substance were included. Exposure details were documented from medical records and blood and/or urine samples analysed using high-resolution accurate mass liquid chromatography-mass spectrometry (HRAM LCMS). Sensitivity, specificity, and positive and negative predictive values of the exposure history were calculated by comparison with biological sample analysis ("gold standard"). RESULTS: Single substance exposure was reported for 474 (median age 33 years, IQR: 18 range 16-75, 80% males) patients. Analysis commonly identified multiple substances (Median 3, IQR 2-5). A history of exposure was documented for 121 of 151 patients where a SCRA or metabolite was detected on analysis (sensitivity 80.1%, 95% CI 72.9, 86.2%). Corresponding proportions were lower for 3,4-methylenedioxymethamphetamine (MDMA, 44/70, 62.9%., 95% CI 50.5%, 74.1%), heroin 41/108 (38.0% 95% CI 28.8-47.8%) and cocaine (22/56, 31.3%, 95% CI 20.9, 43.6%). CONCLUSIONS: Multiple undeclared substances were detected analytically in most patients reporting single substance use. Clinicians should be alert to the potential presence and toxicity of unreported substances when managing patients presenting after substance misuse.

"Like a rabbit from a hat!"--a case of a sacrocolpopexy mesh being taken out by a patient.

Sacrocolpopexy, be it laparoscopic or abdominal, is associated with a risk of mesh extrusion. We report an interesting case of mesh extrusion with subsequent removal of the mesh from the vagina by the patient. We take this opportunity to review the literature regarding incidence, predisposing factors and complications of sacrocolpopexy mesh extrusion with specific reference to this case.

Operative technique of two parallel compression screws and autologous bone graft for ankle arthrodesis after failed total ankle replacement.

BACKGROUND: The management of failed total ankle replacement (TAR) depends on the primary indication, presence of infection, condition of adjacent joints, and available bone stock. In addition, the patient's expectations, age, and general health should also be taken into account. METHODS: This article describes a technique of arthrodesis in failed TAR with two parallel screws inserted in opposite directions and autologous cancellous bone graft. Four patients were managed using this technique. The subtalar joint and both malleoli were preserved. RESULTS: The average time for radiological union was 14.8 weeks. There were no hardware-related complications or infections. One patient developed subsequent subtalar arthritis and is waiting for subtalar joint fusion. CONCLUSION: The results from this small series of patients suggest that arthrodesis following failed total ankle replacement with two parallel screws and bone graft may be an effective technique.

The first three years of an inpatient adolescent forensic service.

Bluebird House opened in February 2008. It was built to fill the gap of inpatient adolescent forensic services covering the South and South-West of England. This article describes the development of this highly specialized unit in its first three years.

Incidents in an adolescent forensic secure inpatient service.

There has been increased research in recent years on incidents within adolescent inpatient psychiatric units, although findings to date have been somewhat inconsistent. We analysed all reported incidents by 37 consecutively discharged patients from a mixed sex adolescent forensic hospital. Findings include a very high overall rate of incidents. A small number of female patients with emerging emotionally unstable personality disorder accounted for the majority of violent incidents and other incidents. Almost all the patients assaulted someone during their admission. Patients on civil sections of the Mental Health Act had just as many incidents as patients on forensic sections. The vast majority of assaults were on staff. Peak times for incidents were the end of each day when education sessions were timetabled and the beginning of the night shift.

Anatomic description of the distal tibia: implications for internal fixation.

Fracture fixation using minimally invasive plating techniques around the distal tibia are well described, although there are a number of potential hazards and complications. Our study provides an anatomical description of the distal tibia and its relations to surrounding structures. Twenty magnetic resonance imaging scans of the distal tibia were analyzed in the coronal, sagittal, and axial planes. Measurements were taken by 2 observers on 2 occasions of the distance of anterior structures from the tibial cortex as well as dimensional parameters. The mean dimensions of the distal tibia at the level of the plafond were 39 mm medial-lateral and 36 mm anteroposterior. The anterior neurovascular bundle was found to be a mean of 3 mm from the anterior tibial cortex with the anterior tendinous structures located <6 mm. The intraclass correlation coefficient for the first observer was 0.8 and for the second observer was 0.78 with an interclass correlation coefficient of 0.8. This demonstrated excellent interobserver and intraobserver reliability. This study presents the first magnetic resonance imaging-based anatomical description of the distal tibia. It showed that key anatomical structures are in very close proximity to the distal tibia, and this is important to consider when treating fractures in this region with internal fixation.

The grouping of chemicals with effects on reproduction and development for the purpose of cumulative risk assessment in Europe.

The European Food Safety Authority (EFSA) is developing approaches for cumulative risk assessment by assigning chemicals (pesticides) to cumulative assessment groups (CAGs) based on common toxic effects on the target system. This document a reviews and refines the approach for reproduction and developmental toxicity published in 2016, to identify relevant substances for grouping with guidance for discriminating between direct effects on the reproductive system or on development of the offspring and those effects which are secondary to other toxicities. The refined approach is then considered in relation to the Classification, Labelling & Packaging (CLP) criteria based on which pesticides are classified for adverse effects on sexual function and fertility, for adverse effects on development of the offspring or for adverse effects on or via lactation. The proposed grouping of effects and accompanying guidance are intended to facilitate knowledge-based interpretation of data from test guideline reproduction and developmental toxicity studies for the purpose of cumulative risk assessment.