Non-cell-autonomous cancer progression from chromosomal instability.

Chromosomal instability (CIN) is a driver of cancer metastasis1-4, yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing-a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell-cell interactions from single-cell transcriptomic data-we show that CIN-induced chronic activation of the cGAS-STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumour microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signalling abrogates CIN-dependent effects on the tumour microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumour cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signalling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumours spurred by CIN-induced inflammation.

Neurotensin orchestrates valence assignment in the amygdala.

The ability to associate temporally segregated information and assign positive or negative valence to environmental cues is paramount for survival. Studies have shown that different projections from the basolateral amygdala (BLA) are potentiated following reward or punishment learning1-7. However, we do not yet understand how valence-specific information is routed to the BLA neurons with the appropriate downstream projections, nor do we understand how to reconcile the sub-second timescales of synaptic plasticity8-11 with the longer timescales separating the predictive cues from their outcomes. Here we demonstrate that neurotensin (NT)-expressing neurons in the paraventricular nucleus of the thalamus (PVT) projecting to the BLA (PVT-BLA:NT) mediate valence assignment by exerting NT concentration-dependent modulation in BLA during associative learning. We found that optogenetic activation of the PVT-BLA:NT projection promotes reward learning, whereas PVT-BLA projection-specific knockout of the NT gene (Nts) augments punishment learning. Using genetically encoded calcium and NT sensors, we further revealed that both calcium dynamics within the PVT-BLA:NT projection and NT concentrations in the BLA are enhanced after reward learning and reduced after punishment learning. Finally, we showed that CRISPR-mediated knockout of the Nts gene in the PVT-BLA pathway blunts BLA neural dynamics and attenuates the preference for active behavioural strategies to reward and punishment predictive cues. In sum, we have identified NT as a neuropeptide that signals valence in the BLA, and showed that NT is a critical neuromodulator that orchestrates positive and negative valence assignment in amygdala neurons by extending valence-specific plasticity to behaviourally relevant timescales.

Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2- breast tumor cells.

The CDK4/6 inhibitor palbociclib blocks cell cycle progression in Estrogen receptor-positive, human epidermal growth factor 2 receptor-negative (ER+/HER2-) breast tumor cells. Despite the drug's success in improving patient outcomes, a small percentage of tumor cells continues to divide in the presence of palbociclib-a phenomenon we refer to as fractional resistance. It is critical to understand the cellular mechanisms underlying fractional resistance because the precise percentage of resistant cells in patient tissue is a strong predictor of clinical outcomes. Here, we hypothesize that fractional resistance arises from cell-to-cell differences in core cell cycle regulators that allow a subset of cells to escape CDK4/6 inhibitor therapy. We used multiplex, single-cell imaging to identify fractionally resistant cells in both cultured and primary breast tumor samples resected from patients. Resistant cells showed premature accumulation of multiple G1 regulators including E2F1, retinoblastoma protein, and CDK2, as well as enhanced sensitivity to pharmacological inhibition of CDK2 activity. Using trajectory inference approaches, we show how plasticity among cell cycle regulators gives rise to alternate cell cycle "paths" that allow individual tumor cells to escape palbociclib treatment. Understanding drivers of cell cycle plasticity, and how to eliminate resistant cell cycle paths, could lead to improved cancer therapies targeting fractionally resistant cells to improve patient outcomes.

A yeast-based system to study SARS-CoV-2 Mpro structure and to identify nirmatrelvir resistant mutations.

The SARS-CoV-2 main protease (Mpro) is a major therapeutic target. The Mpro inhibitor, nirmatrelvir, is the antiviral component of Paxlovid, an orally available treatment for COVID-19. As Mpro inhibitor use increases, drug resistant mutations will likely emerge. We have established a non-pathogenic system, in which yeast growth serves as an approximation for Mpro activity, enabling rapid identification of mutants with altered enzymatic activity and drug sensitivity. The E166 residue is known to be a potential hot spot for drug resistance and yeast assays identified substitutions which conferred strong nirmatrelvir resistance and others that compromised activity. On the other hand, N142A and the P132H mutation, carried by the Omicron variant, caused little to no change in drug response and activity. Standard enzymatic assays confirmed the yeast results. In turn, we solved the structures of Mpro E166R, and Mpro E166N, providing insights into how arginine may drive drug resistance while asparagine leads to reduced activity. The work presented here will help characterize novel resistant variants of Mpro that may arise as Mpro antivirals become more widely used.

Transient gas-induced differential refractive index effects in as-drawn hollow core optical fibers.

When a hollow core fiber is drawn, the core and cladding holes within the internal cane geometry are pressurized with an inert gas to enable precise control over the internal microstructure of the fiber and counteract surface tension forces. Primarily by considering the temperature drop as the fiber passes through the furnace and the geometrical transformation of the internal microstructure from preform-to-fiber, we recently established that the gas pressure within the final 'as-drawn' fiber is substantially below atmospheric pressure. We have also established that slight changes in the gas refractive index within the core and surrounding cladding holes induced by changes in gas pressure are sufficient to significantly affect both the modality and loss of the fiber. Here we demonstrate, through both simulations and experimental measurements, that the combination of these effects leads to transient changes in the fiber's attenuation when the fibers are opened to atmosphere post-fabrication. It is important to account for this phenomenon for accurate fiber characterization, particularly when long lengths of fiber are drawn where it could take many weeks for every part of the internal microstructure to reach atmospheric pressure.

Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.

INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. HIGHLIGHTS: Mutation position influences Aß burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aß burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.

Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease.

OBJECTIVE: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). METHODS: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, ß-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. RESULTS: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. INTERPRETATION: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744.

Ag(III)···Ag(III) Argentophilic Interaction in a Cofacial Corrole Dyad.

Metallophilic interactions between closed-shell metal centers are exemplified by d10 ions, with Au(I) aurophilic interactions as the archetype. Such an interaction extends to d8 species, and examples involving Au(III) are prevalent. Conversely, Ag(III) argentophilic interactions are uncommon. Here, we identify argentophilic interactions in silver corroles, which are authentic Ag(III) species. The crystal structure of a monomeric silver corrole is a dimer in the solid state, and the macrocycle exhibits an atypical domed conformation. In order to evaluate whether this represents an authentic metallophilic interaction or a crystal-packing artifact, the analogous cofacial or "pacman" corrole was prepared. The conformation of the monomer was recapitulated in the silver pacman corrole, exhibiting a short 3.67 Å distance between metal centers and a significant compression of the xanthene backbone. Theoretical calculations support the presence of a rare Ag(III)···Ag(III) argentophilic interaction in the pacman complex.

Depletion of Endothelial-Derived 2-AG Reduces Blood-Endothelial Barrier Integrity via Alteration of VE-Cadherin and the Phospho-Proteome.

Mounting evidence supports the role of the endocannabinoid system in neurophysiology, including blood-brain barrier (BBB) function. Recent work has demonstrated that activation of endocannabinoid receptors can mitigate insults to the BBB during neurological disorders like traumatic brain injury, cortical spreading depression, and stroke. As alterations to the BBB are associated with worsening clinical outcomes in these conditions, studies herein sought to examine the impact of endocannabinoid depletion on BBB integrity. Barrier integrity was investigated in vitro via bEnd.3 cell monolayers to assess endocannabinoid synthesis, barrier function, calcium influx, junctional protein expression, and proteome-wide changes. Inhibition of 2-AG synthesis using DAGLα inhibition and siRNA inhibition of DAGLα led to loss of barrier integrity via altered expression of VE-cadherin, which could be partially rescued by exogenous application of 2-AG. Moreover, the deleterious effects of DAGLα inhibition on BBB integrity showed both calcium and PKC (protein kinase C)-dependency. These data indicate that disruption of 2-AG homeostasis in brain endothelial cells, in the absence of insult, is sufficient to disrupt BBB integrity thus supporting the role of the endocannabinoid system in neurovascular disorders.

Serious Mental Illness and Sexual Offending in Forensic Psychiatric Patients.

The role of serious mental illness among those who sexually offend is not well understood. We investigated clinical and risk-related areas of difference between male forensic psychiatric patients with (n = 86) and without (n = 245) a sexual offense history, including the age at which indications of mental disorder and criminal offending first emerged, from a registry of Ontario patients adjudicated Not Criminally Responsible on account of Mental Disorder (NCRMD) from 1999-2012. We further explored motivations for offending among a subset of patients deemed NCRMD for a sexual offense specifically (n = 41). While no differences were found in the age onset of illness or offending across those with and without a sexual offending history, the former group was rated as having higher levels of historical/static risk for violence. Forensic patients with a sexual offense history were also more likely to offend against a stranger, and less likely to offend against a family member. Sexual index offenses were psychotically-motivated in the majority of cases, but with a meaningful proportion appearing to reflect criminogenic motivations, especially substance use and paraphilic interests. Results suggest greater similarity than difference among forensic patients with and without a sexual offense history, but also highlight an important divergence from the literature showing that victims of sexual offenses are frequently known to the individual committing them.

Optical time domain backscattering of antiresonant hollow core fibers.

Today's lowest-loss hollow core fibers are based on antiresonance guidance. They have been shown both theoretically and experimentally to have very low levels of backscattering arising from the fiber structure - 45 dB below that of traditional optical fibers with a solid silica glass core. This makes their longitudinal characterization using conventional reflectometric techniques very challenging. However, it was recently estimated that when filled with air, their backscattering coefficient increases to about 30 dB below that of standard solid core fibers. This level should be measurable with commercially available high performance optical time domain reflectometers (OTDR). Here we demonstrate - for the first time to the best of our knowledge - the measurement of backscattering from the air inside a hollow core fiber. We show that the characterization of multi-km long hollow core fibers with 15 m spatial resolution is possible using a commercial OTDR instrument. To benefit from its full dynamic range, we strongly suppress the 4% back-reflections that ordinarily occur at the OTDR's standard fiber output when directly-connected to a hollow core fiber. Furthermore, low coupling loss into the hollow core fiber (0.3 dB in our experiment) also helps to maximize the achievable OTDR signal-to-noise ratio. This approach enables distributed characterization and fault-finding in low-loss hollow core fibers, a topic of increasing importance as these fibers are now starting to be installed in commercial optical communication networks.

Methionine synthase deficiency: Variable clinical presentation and benefit of early diagnosis and treatment.

Methionine synthase deficiency (cblG complementation group) is a rare inborn error of metabolism affecting the homocysteine re-methylation pathway. It leads to a biochemical phenotype of hyperhomocysteinemia and hypomethioninemia. The clinical presentation of cblG is variable, ranging from seizures, encephalopathy, macrocytic anemia, hypotonia, and feeding difficulties in the neonatal period to onset of psychiatric symptoms or acute neurologic changes in adolescence or adulthood. Given the variable and nonspecific symptoms seen in cblG, the diagnosis of affected patients is often delayed. Medical management of cblG includes the use of hydroxocobalamin, betaine, folinic acid, and in some cases methionine supplementation. Treatment has been shown to lead to improvement in the biochemical profile of affected patients, with lowering of total homocysteine levels and increasing methionine levels. However, the published literature contains differing conclusions on whether treatment is effective in changing the natural history of the disease. Herein, we present five patients with cblG who have shown substantial clinical benefit from treatment with objective improvement in their neurologic outcomes. We demonstrate more favorable outcomes in our patients who were treated early in life, especially those who were treated before neurologic symptoms manifested. Given improved outcomes from treatment of presymptomatic patients, cblG warrants inclusion in newborn screening.

An Unusual Finding in a Patient Presenting for Pulmonary Thromboendarterectomy: Pulmonary Venous Thrombosis.

Pulmonary venous thrombosis (PVT) is a rare but potentially devastating disease state with a largely unknown incidence. The most common etiologies of PVT are secondary to complications of lung surgery, malignancy, catheter ablation for atrial fibrillation, and idiopathic causes. Diagnosis can be challenging because presenting symptoms often are vague and nonspecific, or even asymptomatic, and traditional diagnostic modalities, such as chest radiography and arterial phase computed tomography scans, are poor techniques for diagnosis. The authors present a case of a patient presenting for pulmonary thromboendarterectomy for a presumed diagnosis of chronic thromboembolic pulmonary hypertension who was found incidentally to have a PVT, on intraoperative transesophageal echocardiography. Due to significant thrombus burden, the new finding of PVT, and known association of PVT and malignancy, a biopsy of mediastinal lymph nodes was obtained, which revealed metastatic cervical carcinoma. The pulmonary endarterectomy procedure was aborted.

Predictive Factors for Velopharyngeal Insufficiency Following Primary Cleft Palate Repair.

OBJECTIVE: Velopharyngeal insufficiency (VPI) remains a known complication of primary palatoplasty. We sought to identify factors associated with the incidence of VPI and create a predictive model for VPI development in our population. DESIGN: A single-institution, retrospective review. SETTING: Multidisciplinary clinic in a tertiary academic institution. PATIENTS: A total of 453 consecutive patients undergoing primary palatoplasty from 1999 to 2016 were reviewed. Inclusion required follow-up past age 5. Patients who were non-verbal, and thus unable to undergo speech evaluation, were excluded. MAIN OUTCOME MEASURES: Primary outcome was VPI, defined as revision palatoplasty or recommendation by speech-language pathology. RESULTS: Of 318 patients included, 179 (56%) were male. Median age at primary repair was 1.0 years (0.9-1.1) with a median age of 8.8 years at last follow-up. One hundred nineteen (37%) patients developed VPI at a median age of 5.0 years (3.8-6.5). Higher rates were seen with posterior fistula (65% vs 14%, P <.01) and straight-line repair (41% vs 9%, P <.01), with lower rates in patients with Veau I clefts (22% vs 39%, P <.05). Patients with VPI were older at last follow-up. Following multivariate regression, factors remaining significant were posterior fistula (odds ratio [OR]: 11.3, 95% CI: 6.1-22.0), primary Furlow repair (OR: 0.18, 95% CI: 0.03-0.68), genetic diagnoses (OR: 2.92, 95% CI: 1.1-7.9), and age at last follow-up (OR: 1.11, 95% CI: 1.01-1.2). CONCLUSIONS: Length of follow-up, posterior fistulae, and genetic diagnoses are associated with VPI formation. Furlow repair may protect against formation of VPI. Use of allograft, Veau class, birth type, birth weight, and race are not independently associated with VPI formation.

REVIEW: Practical strategies to maintain anabolism by intravenous nutritional management in children with inborn metabolic diseases.

One of the most vital elements of management for patients with inborn errors of intermediary metabolism is the promotion of anabolism, the state in which the body builds new components, and avoidance of catabolism, the state in which the body breaks down its own stores for energy. Anabolism is maintained through the provision of a sufficient supply of substrates for energy, as well as critical building blocks of essential amino acids, essential fatty acids, and vitamins for synthetic function and growth. Patients with metabolic diseases are at risk for decompensation during prolonged fasting, which often occurs during illnesses in which enteral intake is compromised. During these times, intravenous nutrition must be supplied to fully meet the specific nutritional needs of the patient. We detail our approach to intravenous management for metabolic patients and its underlying rationale. This generally entails a combination of intravenous glucose and lipid as well as early introduction of protein and essential vitamins. We exemplify the utility of our approach in case studies, as well as scenarios and specific disorders which require a more careful administration of nutritional substrates or a modification of macronutrient ratios.

Hollow-core resonator fiber optic gyroscope using nodeless anti-resonant fiber.

Resonator fiber optic gyroscope (RFOG) performance has hitherto been limited by nonlinearity, modal impurity, and backscattering in the sensing fibers. The use of hollow-core fiber (HCF) effectively reduces nonlinearity, but the complex interplay among glass and air-guided modes in conventional HCF technologies can severely exacerbate RFOG instability. By employing high-performance nested anti-resonant nodeless fiber, we demonstrate long-term stability in a hollow-fiber RFOG of 0.05 deg/h, nearing the levels required for civil aircraft navigation. This represents a ${{3}} \times$ improvement over any prior hollow-core RFOG and a factor of ${{500}} \times$ over any prior result at integration times longer than 1 h.

Diagnostic Accuracy of Spiral Whole-Heart Quantitative Adenosine Stress Cardiovascular Magnetic Resonance With Motion Compensated L1-SPIRIT.

BACKGROUND: Variable density spiral (VDS) pulse sequences with motion compensated compressed sensing (MCCS) reconstruction allow for whole-heart quantitative assessment of myocardial perfusion but are not clinically validated. PURPOSE: Assess performance of whole-heart VDS quantitative stress perfusion with MCCS to detect obstructive coronary artery disease (CAD). STUDY TYPE: Prospective cross sectional. POPULATION: Twenty-five patients with chest pain and known or suspected CAD and nine normal subjects. FIELD STRENGTH/SEQUENCE: Segmented steady-state free precession (SSFP) sequence, segmented phase sensitive inversion recovery sequence for late gadolinium enhancement (LGE) imaging and VDS sequence at 1.5 T for rest and stress quantitative perfusion at eight short-axis locations. ASSESSMENT: Stenosis was defined as ≥50% by quantitative coronary angiography (QCA). Visual and quantitative analysis of MRI data was compared to QCA. Quantitative analysis assessed average myocardial perfusion reserve (MPR), average stress myocardial blood flow (MBF), and lowest stress MBF of two contiguous myocardial segments. Ischemic burden was measured visually and quantitatively. STATISTICAL TESTS: Student's t-test, McNemar's test, chi-square statistic, linear mixed-effects model, and area under receiver-operating characteristic curve (ROC). RESULTS: Per-patient visual analysis demonstrated a sensitivity of 84% (95% confidence interval [CI], 60%-97%) and specificity of 83% [95% CI, 36%-100%]. There was no significant difference between per-vessel visual and quantitative analysis for sensitivity (69% [95% CI, 51%-84%] vs. 77% [95% CI, 60%-90%], P = 0.39) and specificity (88% [95% CI, 73%-96%] vs. 80% [95% CI, 64%-91%], P = 0.75). Per-vessel quantitative analysis ROC showed no significant difference (P = 0.06) between average MPR (0.68 [95% CI, 0.56-0.81]), average stress MBF (0.74 [95% CI, 0.63-0.86]), and lowest stress MBF (0.79 [95% CI, 0.69-0.90]). Visual and quantitative ischemic burden measurements were comparable (P = 0.85). DATA CONCLUSION: Whole-heart VDS stress perfusion demonstrated good diagnostic accuracy and ischemic burden evaluation. No significant difference was seen between visual and quantitative diagnostic performance and ischemic burden measurements. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Diagnosis and Treatment of Intracardiac Thrombus.

ABSTRACT: Intracardiac thrombi can occur in a variety of locations and are frequently encountered in clinical practice. Yet evidence-based guidance for clinicians managing patients with intracardiac thrombi is often limited. This review summarizes what is known regarding the prevalence of intracardiac thrombus, diagnostic strategies, clinical relevance, and treatment options, focusing on four specific types of thrombus for which recent research has shifted clinical understanding and treatment decisions: (1) left atrial appendage thrombus, (2) cardiac implantable electronic device lead thrombus, (3) bioprosthetic aortic valve thrombus, and (4) left ventricular thrombus. Additional studies, ideally prospective, randomized, and head-to-head in design, are needed to better inform best practices in patients with intracardiac thrombi.

Biallelic B3GALT6 mutations cause spondylodysplastic Ehlers-Danlos syndrome.

Proteoglycans are among the most abundant and structurally complex biomacromolecules and play critical roles in connective tissues. They are composed of a core protein onto which glycosaminoglycan (GAG) side chains are attached via a linker region. Biallelic mutations in B3GALT6, encoding one of the linker region glycosyltransferases, are known to cause either spondyloepimetaphyseal dysplasia (SEMD) or a severe pleiotropic form of Ehlers-Danlos syndromes (EDS). This study provides clinical, molecular and biochemical data on 12 patients with biallelic B3GALT6 mutations. Notably, all patients have features of both EDS and SEMD. In addition, some patients have severe and potential life-threatening complications such as aortic dilatation and aneurysm, cervical spine instability and respiratory insufficiency. Whole-exome sequencing, next generation panel sequencing and direct sequencing identified biallelic B3GALT6 mutations in all patients. We show that these mutations reduce the amount of ß3GalT6 protein and lead to a complete loss of galactosyltransferase activity. In turn, this leads to deficient GAG synthesis, and ultrastructural abnormalities in collagen fibril organization. In conclusion, this study redefines the phenotype associated with B3GALT6 mutations on the basis of clinical, molecular and biochemical data in 12 patients, and provides an in-depth assessment of ß3GalT6 activity and GAG synthesis to better understand this rare condition.

Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency.

PURPOSE: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a life-threatening, ultrarare inborn error of metabolism. Case reports described successful D,L-3-hydroxybutyrate (D,L-3-HB) treatment in severely affected MADD patients, but systematic data on efficacy and safety is lacking. METHODS: A systematic literature review and an international, retrospective cohort study on clinical presentation, D,L-3-HB treatment method, and outcome in MADD(-like) patients. RESULTS: Our study summarizes 23 MADD(-like) patients, including 14 new cases. Median age at clinical onset was two months (interquartile range [IQR]: 8 months). Median age at starting D,L-3-HB was seven months (IQR: 4.5 years). D,L-3-HB doses ranged between 100 and 2600 mg/kg/day. Clinical improvement was reported in 16 patients (70%) for cardiomyopathy, leukodystrophy, liver symptoms, muscle symptoms, and/or respiratory failure. D,L-3-HB appeared not effective for neuropathy. Survival appeared longer upon D,L-3-HB compared with historical controls. Median time until first clinical improvement was one month, and ranged up to six months. Reported side effects included abdominal pain, constipation, dehydration, diarrhea, and vomiting/nausea. Median D,L-3-HB treatment duration was two years (IQR: 6 years). D,L-3-HB treatment was discontinued in 12 patients (52%). CONCLUSION: The strength of the current study is the international pooling of data demonstrating that D,L-3-HB treatment can be effective and safe in MADD(-like) patients.