Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with ...improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary Duchenne muscular dystrophy (DMD) is a severe, progressive disease that affects 1 in 3600–6000 live male births. Although guidelines are available for various aspects of DMD, comprehensive ...clinical care recommendations do not exist. The US Centers for Disease Control and Prevention selected 84 clinicians to develop care recommendations using the RAND Corporation–University of California Los Angeles Appropriateness Method. The DMD Care Considerations Working Group evaluated assessments and interventions used in the management of diagnostics, gastroenterology and nutrition, rehabilitation, and neuromuscular, psychosocial, cardiovascular, respiratory, orthopaedic, and surgical aspects of DMD. These recommendations, presented in two parts, are intended for the wide range of practitioners who care for individuals with DMD. They provide a framework for recognising the multisystem primary manifestations and secondary complications of DMD and for providing coordinated multidisciplinary care. In part 1 of this Review, we describe the methods used to generate the recommendations, and the overall perspective on care, pharmacological treatment, and psychosocial management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A coordinated, multidisciplinary approach to care is essential for optimum management of the primary manifestations and secondary complications of Duchenne muscular dystrophy (DMD). Contemporary care ...has been shaped by the availability of more sensitive diagnostic techniques and the earlier use of therapeutic interventions, which have the potential to improve patients' duration and quality of life. In part 2 of this update of the DMD care considerations, we present the latest recommendations for respiratory, cardiac, bone health and osteoporosis, and orthopaedic and surgical management for boys and men with DMD. Additionally, we provide guidance on cardiac management for female carriers of a disease-causing mutation. The new care considerations acknowledge the effects of long-term glucocorticoid use on the natural history of DMD, and the need for care guidance across the lifespan as patients live longer. The management of DMD looks set to change substantially as new genetic and molecular therapies become available.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal glycogen-hydrolyzing enzyme acid α-glucosidase (GAA). The adult-onset form, late-onset Pompe disease (LOPD), has ...been characterized by glycogen accumulation primarily in skeletal, cardiac, and smooth muscles, causing weakness of the proximal limb girdle and respiratory muscles. However, increased scientific study of LOPD continues to enhance understanding of an evolving phenotype.
To expand our understanding of the evolving phenotype of LOPD since the approval of enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme™/Lumizyme™) in 2006.
All articles were included in the review that provided data on the charactertistics of LOPD identified via the PubMed database published since the approval of ERT in 2006. All signs and symptoms of the disease that were reported in the literature were identified and included in the review.
We provide a comprehensive review of the evolving phenotype of LOPD. Our findings support and extend the knowledge of the multisystemic nature of the disease.
With the advent of ERT and the concurrent increase in the scientific study of LOPD, the condition once primarily conceptualized as a limb-girdle muscle disease with prominent respiratory involvement is increasingly recognized to be a condition that results in signs and symptoms across body systems and structures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary Optimum management of Duchenne muscular dystrophy (DMD) requires a multidisciplinary approach that focuses on anticipatory and preventive measures as well as active interventions to address ...the primary and secondary aspects of the disorder. Implementing comprehensive management strategies can favourably alter the natural history of the disease and improve function, quality of life, and longevity. Standardised care can also facilitate planning for multicentre trials and help with the identification of areas in which care can be improved. Here, we present a comprehensive set of DMD care recommendations for management of rehabilitation, orthopaedic, respiratory, cardiovascular, gastroenterology/nutrition, and pain issues, as well as general surgical and emergency-room precautions. Together with part 1 of this Review, which focuses on diagnosis, pharmacological treatment, and psychosocial care, these recommendations allow diagnosis and management to occur in a coordinated multidisciplinary fashion.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Increased glycolytic metabolism recently emerged as an essential process driving host defense against Mycobacterium tuberculosis (Mtb), but little is known about how this process is regulated during ...infection. Here, we observe repression of host glycolysis in Mtb-infected macrophages, which is dependent on sustained upregulation of anti-inflammatory microRNA-21 (miR-21) by proliferating mycobacteria. The dampening of glycolysis by miR-21 is mediated through targeting of phosphofructokinase muscle (PFK-M) isoform at the committed step of glycolysis, which facilitates bacterial growth by limiting pro-inflammatory mediators, chiefly interleukin-1β (IL-1β). Unlike other glycolytic genes, PFK-M expression and activity is repressed during Mtb infection through miR-21-mediated regulation, while other less-active isoenzymes dominate. Notably, interferon-γ (IFN-γ), which drives Mtb host defense, inhibits miR-21 expression, forcing an isoenzyme switch in the PFK complex, augmenting PFK-M expression and macrophage glycolysis. These findings place the targeting of PFK-M by miR-21 as a key node controlling macrophage immunometabolic function.
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•Mtb infection of macrophages limits metabolic reprogramming over time•Glycolysis is limited through sustained induction of anti-inflammatory miR-21•PFK-M is a miR-21 target gene•IFN-γ promotes glycolysis by targeting miR-21
Hackett et al. identify a role for the anti-inflammatory miR-21 in limiting host glycolysis during tuberculosis (TB) infection to favor bacterial replication. This occurs by targeting a pro-glycolytic isoform at the rate-limiting step in glycolysis, PFK-M, a process antagonized by the host Th1-cytokine IFN-γ, to promote full macrophage activation and antimicrobial function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pompe disease is an inherited, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase and accumulation of glycogen in tissues, resulting in cellular dysfunction, ...muscle damage, and functional disabilities. Enzyme replacement therapy with alglucosidase alfa (Myozyme/Lumizyme) has led to better outcomes, but many patients have plateaued or declined despite treatment. The second-generation ERT avalglucosidase alfa (Nexviazyme) was designed to have enhanced cellular uptake via the conjugation of additional bis-mannose-6-phosphate residues. There have been trials comparing the efficacy of alglucosidase and avalglucosidase, but there remains a need for more real-world data on patients who switched from alglucosidase to avalglucosidase.
A chart review was conducted on
= 15 patients with late-onset Pompe disease followed at a single center who switched from alglucosidase to avalglucosidase and continued for at least 6 months.
A total of
= 8/15 patients received alglucosidase for more than 3 years prior to switching, and
= 7/15 received it for more than 5 years prior to switching. There were statistically significant improvements in CK, Hex4, and AST with mean differences of -104.8 U/L, -3.0 mmol/molCr, and -14.7 U/L, respectively, post-switch. 6-Minute Walk Test; comfortable gait speed; Gait, Stairs, Gower, Chair; and Quick Motor Function Test scores improved or stabilized in most patients post-switch (
= 8/12,
= 11/12,
= 9/12,
=7/11, respectively). Of
= 7 patients with pulmonary function testing,
= 4/7 had improved upright FVC. Patient-reported outcomes revealed improvements in dyspnea (
= 4/4), physical function (
= 3/4), fatigue (
= 2/3), and lower back pain (
= 3/3). Avalglucosidase was well tolerated without infusion-associated reactions, and all
= 7 patients on home infusions continued receiving ERT at home. Anti-drug antibodies were seen in
= 9/10 of patients on alglucosidase and
= 8/13 of those on avalglucosidase, with titers below 12,800 in a majority of patients. We also present the first outcome data for a patient with LOPD who is non-ambulatory and a full-time wheelchair user; she demonstrated meaningful improvements in quality of life and motor function with the switch.
In summary, improved outcomes were seen in most patients, with a subset whose decline persisted. This study presents evidence that switching from alglucosidase to avalglucosidase may be associated with improved outcomes in certain patients with LOPD.
Steadily improving management of Duchenne muscular dystrophy (DMD) continues to lead to improved physical and functional status, allowing increasingly successful transitions to independence and ...self-actualization in adulthood. Rehabilitation principles remain key to overall management for individuals with DMD with increasing options for ever more successful management, reflecting a changing natural history based on the use of glucocorticoids, more consistent comprehensive care, and the emergence of disease-modifying treatments. Advances and expansion in assessment, cardiorespiratory management, preventive management of contracture and deformity, assistive technology, "smart" technology, and robotics with increased emphasis on function, participation, self-advocacy, and independence in decision-making should allow individuals with DMD to experience childhood and transition to adulthood with support that allows for increasing success in the achievement of individual goals and fulfillment across the life span.
Aim
To evaluate safety and motor function after treatment with allogeneic umbilical cord blood (AlloCB) or umbilical cord tissue‐derived mesenchymal stromal cells (hCT‐MSC) in children with cerebral ...palsy (CP).
Method
Ninety‐one children (52 males, 39 females; median age 3 years 7 months range 2–5 years) with CP due to hypoxic–ischemic encephalopathy, stroke, or periventricular leukomalacia were randomized to three arms: (1) the AlloCB group received 10 × 107 AlloCB total nucleated cells (TNC) per kilogram at baseline (n = 31); (2) the hCT‐MSC group received 2 × 106 hCT‐MSC at baseline, 3 months, and 6 months (n = 28); (3) the natural history control group received 10 × 107 AlloCB TNC per kilogram at 12 months (n = 31). Motor function was assessed with the Gross Motor Function Measure‐66 (GMFM‐66) and Peabody Developmental Motor Scale, Second Edition.
Results
Infusions (n = 143) were well tolerated, with eight infusion reactions (three in the AlloCB group, five in hCT‐MSC) and no other safety concerns. At 12 months, the mean differences (95% confidence intervals CI) between actual and expected changes in GMFM‐66 score were AlloCB 5.8 points (3.4–8.2), hCT‐MSC 4.3 (2.2–6.4), and natural history 3.1 (1.4–5.0). In exploratory, post hoc analysis, the mean GMFM‐66 score (95% CI) of the hCT‐MSC group was 1.4 points higher than natural history (−1.1 to 4.0; p = 0.27), and the AlloCB group was 3.3 points higher than natural history (0.59–5.93; p = 0.02) after adjustment for baseline Gross Motor Function Classification System level, GMFM‐66 score, and etiology.
Interpretation
High‐dose AlloCB is a potential cell therapy for CP and should be further tested in a randomized, blinded, placebo‐controlled trial.
What this paper adds
Unrelated donor allogeneic umbilical cord blood (AlloCB) and human umbilical cord tissue‐derived mesenchymal stromal cell infusion is safe in young children with cerebral palsy.
Significant changes in motor function were not observed 6 months after treatment.
One year later, treatment with AlloCB was associated with greater increases in Gross Motor Function Measure‐66 scores.
What this paper adds
Unrelated donor allogeneic umbilical cord blood (AlloCB) and human umbilical cord tissue‐derived mesenchymal stromal cell infusion is safe in young children with cerebral palsy.
Significant changes in motor function were not observed 6 months after treatment.
One year later, treatment with AlloCB was associated with greater increases in Gross Motor Function Measure‐66 scores.
This original article is commented on by Clowry on pages 1434–1435 of this issue.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The large number of spike substitutions in Omicron lineage variants (BA.1, BA.1.1., and BA.2) could jeopardize the efficacy of SARS-CoV-2 vaccines. We evaluated in mice the protective efficacy of the ...Moderna mRNA-1273 vaccine against BA.1 before or after boosting. Whereas two doses of mRNA-1273 vaccine induced high levels of neutralizing antibodies against historical WA1/2020 strains, lower levels against BA.1 were associated with breakthrough infection and inflammation in the lungs. A primary vaccination series with mRNA-1273.529, an Omicron-matched vaccine, potently neutralized BA.1 but inhibited historical or other SARS-CoV-2 variants less effectively. However, boosting with either mRNA-1273 or mRNA-1273.529 vaccines increased neutralizing titers and protection against BA.1 and BA.2 infection. Nonetheless, the neutralizing antibody titers were higher, and lung viral burden and cytokines were slightly lower in mice boosted with mRNA-1273.529 and challenged with BA.1. Thus, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against Omicron infection with limited differences in efficacy measured.
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•Primary immunization series with mRNA-1273 results in BA.1 breakthrough infection•Primary immunization with BA.1-matched vaccine neutralizes BA.1 but not Wuhan-1•Both mRNA-1273 and BA.1-matched boosters protect against BA.1 challenge•A BA.1-matched booster induces greater neutralizing antibody responses against BA.1
A comparison of the immunogenicity and efficacy of Omicron BA.1-matched and historical mRNA vaccines as boosters shows that although boosting with either vaccine increased neutralizing titers against Omicron BA.1 and BA.2, slightly greater protection against BA.1 challenge was observed in mice boosted with the BA.1-matched vaccine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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