Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Sleep disorders in parkinsonian and nonparkinsonian LRRK2 mutation carriers

OBJECTIVE: In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC). METHODS: A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD./nRESULTS: Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC. CONCLUSIONS: Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD.This manuscript received support through the grant number 061130/31 from "La Fundació la Marató de TV3" to Eduard Tolosa. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers

Objective: In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC). Methods: A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD. Results: Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC. Conclusions: Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD

LRRK2-Parkinson Disease patients with associated REM sleep behavior disorder.

<p><b>LEDD</b>: L-Dopa Equivalent daily dose; <b>M+AT</b>: polysomnographic montage quantifying "any" (tonic or phasic) type of EMG activity in the mentalis muscle plus bilateral anterior tibialis phasic EMG activity in REM sleep, using 3-sec mini-epochs (the cut-off for patients with RBD is 46.4%)[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132368#pone.0132368.ref038" target="_blank">38</a>]; <b>Mentalis</b>: EMG activity quantification of "any" (tonic and phasic) type of EMG activity in the mentalis muscle during REM sleep, using 3-sec mini-epochs (the cut-off for patients with RBD is 18.2%.)[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132368#pone.0132368.ref038" target="_blank">38</a>]; <b>MoCA</b>: Montreal Cognitive Assessment; <b>PIGD</b>: postural instability gait difficulty motor subtype; <b>SINBAR</b>: polysomnographyc montage quantifying "any" (tonic or phasic) type of EMG activity in the mentalis muscle and phasic EMG activity in the right and left flexor digitorumsuperficialis muscles during REM sleep, using 3-sec mini-epochs (the cut-off for patients with RBD is 32%)[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132368#pone.0132368.ref038" target="_blank">38</a>]; <b>RBD</b>: REM sleep behaviour disorder; <b>RBDSQ</b>: REM sleep behavior disorder screening questionnaire; <b>UPDRS-III</b>: Unified Parkinson Disease Rating Scale motor exam; <b>V-PSG:</b> video-polysomnography.</p><p>LRRK2-Parkinson Disease patients with associated REM sleep behavior disorder.</p

Subjects with restless legs syndrome.

<p><b>ESS</b>: Epworth Sleepiness Scale; <b>IRLSGRS</b>: International Restless-legs syndrome Study Group Scale; <b>LEDD</b>: L-Dopa Equivalent daily dose; <b>LRRK2-PD</b>: LRRK2 Parkinson disease subjects;<b>MSLT</b>: Multiple Sleep Latency Sleep Test; <b>NA</b>: Not applicable; <b>NMC</b>: Non-manifesting carriers; <b>NMNC</b>: Non-manifesting non-carriers; <b>PSQI</b>: Pittsburg Sleep Quality Index; <b>PDSS-2</b>: Parkinson Disease Sleep Scale 2; <b>PLMSI</b>: Periodic Leg Movements in Sleep Index; <b>RLS:</b> Restless Legs Syndrome.</p><p>Subjects with restless legs syndrome.</p

Electromyographic activity in REM sleep.

<p>Bars represent the percentage of electromyographic activity found during REM sleep in the different groups included in the study. Grey bars represent the percentage of electromyographic activity found in individuals who were diagnosed with RBD. White bars represent the percentage of electromyographic activity found in individuals who had no RBD. The dotted transversal line indicates that 32% of electromyographic activity is the cut-off value for the diagnosis of RBD according to the SINBAR method. Electromyographic activity ≥32% during REM sleep is indicative of RBD[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132368#pone.0132368.ref038" target="_blank">38</a>]. IPD: Idiopathic Parkinson disease; LRRK2-PD: LRRK2 Parkinson disease; NMC: non-manifesting carriers; NMNC: non-manifesting non-carriers; RBD: REM sleep behavior disorder; SINBAR: polysomnographic montage quantifying "any" (phasic or tonic) type of EMG activity in the mentalis muscle and phasic EMG activity in the right and left flexor digitorum superficialis muscles during REM sleep using 3-sec mini-epochs.</p

Sleep related clinical data and comparisons between groups.

<p>Data are presented as mean, standard deviation, number and percentage.</p><p><b>ESS:</b> Epworth Sleepiness Scale; <b>IPD</b>: Idiopathic Parkinson Disease; <b>IRLSGRS</b>: International Restless Legs Syndrome Study Group Scale; <b>LRRK2-PD</b>: LRRK2 Parkinson Disease; <b>NA</b>: Not applicable; <b>NMC</b>: Non-manifesting carriers; <b>NMNC:</b> Non-manifesting non-carriers; <b>PSQI</b>: Pittsburg Sleep Quality Index; <b>PD</b>: Parkinson disease; <b>PDSS-2</b>: Parkinson’s Disease Sleep Scale 2; <b>RBD</b>: REM sleep behavior disorder; <b>RBDSQ</b>: RBD screening questionnaire.</p><p>Sleep related clinical data and comparisons between groups.</p

Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy caused by mutations in MLC1 or GLIALCAM. The GLIALCAM gene product functions as an MLC1 beta-subunit. We aim to further clarify the molecular mechanisms of MLC caused by mutations in MLC1 or GLIALCAM. For this purpose, we analyzed a human post-mortem brain obtained from an MLC patient, who was homozygous for a missense mutation (S69L) in MLC1. We showed that this mutation affects the stability of MLC1 in vitro and reduces MLC1 protein levels in the brain to almost undetectable. However, the amount of GlialCAM and its localization were nearly unaffected, indicating that MLC1 is not necessary for GlialCAM expression or tar- geting. These findings were supported by experiments in primary astrocytes and in heterologous cells. In addition, we demonstrated that MLC1 and GlialCAM form homo- and hetero-complexes and that MLC-causing mutations in GLIALCAM mainly reduce the formation of GlialCAM homo-complexes, leading to a defect in the trafficking of GlialCAM alone to cell junctions. GLIALCAM mutations also affect the trafficking of its associ- ated molecule MLC1, explaining why GLIALCAM and MLC1 mutations lead to the same disease: MLC. © The Author 2011. Published by Oxford University Press

Demographic and parkinsonian clinical data and comparisons between groups.

<p>Data are presented as mean, standard deviation, number and percentage.</p><p><b>HADS</b>: Hospital Anxiety and Depression scale; <b>IPD</b>: Idiopathic Parkinson Disease; <b>LRRK2-PD</b>: LRRK2 Parkinson Disease; <b>MoCA</b>: Montreal Cognitive Assessment; <b>NA</b>: Not applicable; <b>NMC</b>: Non-manifesting carriers; <b>NMNC:</b> Non-manifesting non-carriers; <b>PDQ-39</b>: 39-item Parkinson Disease Questionnaire; <b>PIGD</b>: postural instability gait difficulty; <b>PD</b>: Parkinson disease; <b>UPDRS</b>: Unified Parkinson Disease Rating Scale.</p><p>Demographic and parkinsonian clinical data and comparisons between groups.</p