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The development of effective neuroprotective agents for sporadic Alzheimer's disease is a formidable challenge because this disease is multifactorial and heterogeneous. Tau-mediated neurotoxicity lias been implicated as a downstream effector of Abeta pathology and as an increasingly compelling target for Alzheimer's disease therapies. The tau hypothesis of pathogenesis of Alzheimer's disease proposes that dysregulation of tau phosphorylation, misfolding and subsequent aggregation of tau and tau fibrillization may play a significant role in causing synaptic loss and neuronal loss. Thus, reducing hyperphosphotylation of tau, reducing aggregation of tau and promoting clearance of hyperphosphorylated tau and tau aggregates may reduce neurotoxicity and may be important in the treatment of Alzheimer's disease. An expanding number of tau-based therapies (eg, kinase inhibitors, mictrotubule stabilizers) are being investigated by researchers in both the pharmaceutical industry and academia. Research in the next few years may soon bring the full potential of tau-based therapies for Alzheimer's disease in sight. [ABSTRACT FROM AUTHOR]

Infantile-onset Pompe disease (IOPD) is caused by a deficiency in the enzyme acid alpha-glucosidase (GAA). It is characterized by severe and progressive hypertrophic cardiomyopathy and muscle weakness with death in the first 2 years of life if left untreated. Enzyme replacement therapy (ERT) with alglucosidase-alfa is lifesaving, but its effectiveness is influenced by the patient's cross-reactive immunologic material (CRIM) status, dose of ERT, and the development of high antibody titers, which can reduce the therapy's efficacy. The inability of CRIM-negative IOPD patients to produce native GAA exposes them to a high risk of development of anti-rhGAA IgG antibody titers, leading to treatment failure. We present the case of CRIM-negative dizygotic twins treated with high-dose alglucosidase-alfa (40 mg/kg/week), initiated at 28 days (Twin A) and 44 days (Twin B). Both twins received immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG to mitigate antibody response. Initial evaluations revealed elevated left ventricular mass index (LVMI) and elevated biomarkers (urine glucose tetrasaccharide (Glc 4 ), creatine kinase (CK), and aspartate aminotransferase (AST)) in both twins. Following treatment, cardiac function and biomarkers normalized within several months, with a slight delay in Twin B compared to Twin A, likely attributed to the later initiation of ERT. Both twins safely tolerated ITI, achieving immune tolerance with low antibody titers. At 28 months, the twins transitioned to avalglucosidase-alfa (40 mg/kg every other week (EOW)), which was well tolerated without an increase in antibody titers. At 39 months, both twins exhibited normal cardiac function, LVMI, and biomarkers. Motor skills continued to improve, though some kinematic concerns persisted. These cases underscore the importance of early, high-dose ERT combined with ITI in managing CRIM-negative IOPD. While transitioning to avalglucosidase-alfa at 40 mg/kg/EOW was beneficial and well-tolerated in our patients, further studies are needed to confirm its long-term efficacy compared to the high-dose weekly 40 mg/kg alglucosidase-alfa., Competing Interests: Priya S. Kishnani reports a relationship with Sanofi Genzyme that includes: board membership, consulting or advisory, and funding grants. Priya S. Kishnani reports a relationship with Amicus Therapeutics Inc. Research & Gene Therapy Center of Excellence that includes: board membership, consulting or advisory, and funding grants. Priya S. Kishnani reports a relationship with Maze Therapeutics Inc. that includes: consulting or advisory and equity or stocks. Priya S. Kishnani reports a relationship with Asklepios BioPharmaceutical Inc. that includes: consulting or advisory and equity or stocks. Priya S. Kishnani reports a relationship with Babies that includes: board membership. Ankit K. Desai reports a relationship with Sanofi Genzyme that includes: funding grants. Ankit K. Desai reports a relationship with Lysosomal Storage Network that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Introduction: Pompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels., Method: In a single-center, open-label prospective study, we assessed ITI therapy's efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI., Results: This study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea., Conclusion: ITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Chen, Hsu, Fang, Desai, Lee, Hwu, Tsai, Kishnani and Chien.)

Introduction: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT., Methods: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment., Results: In total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week., Discussion: These case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted., Competing Interests: AD has received grant support from Sanofi Genzyme and the Lysosomal Disease Network. AD has received honoraria from Sanofi Genzyme. CG has received Honoraria from Sanofi, Amicus Therapeutics, and RegenX Bio. RW serves on the Scientific Advisory Board for and owns equity in M6P Therapeutics. PK has received research/grant support from Sanofi Genzyme and Amicus Therapeutics. PK has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, Bayer, and Asklepios Biopharmaceutical, Inc. (AskBio). PK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Pompe Disease Advisory Board for Amicus Therapeutics, and Advisory Board for Babies. PK has equity with Maze Therapeutics and has held equity in Asklepios Biopharmaceuticals and may receive milestone payments related to that equity in the future. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Desai, Shrivastava, Grant, Wang, Burt and Kishnani.)

Introduction: The efficacy of enzyme replacement therapy (ERT) with alglucosidase alfa for infantile-onset Pompe disease (IOPD) is limited in some patients due to the development of high and sustained antibody titers (HSAT; ≥12,800)., Methods: We carried out detailed immunophenotyping of IOPD patients (n=40), including analysis of circulating cell populations by flow cytometry and plasma cytokines by multiplex array, to determine whether patients with HSAT have unique immunological characteristics compared to those with low titers (LT; <12,800)., Results: Compared to patients with LT, patients who develop HSAT were skewed toward a type 2 immune profile, with an increased frequency of Th2 cells that was positively correlated with levels of Th2 (IL-4, IL-5, IL-13) and pro-inflammatory (IL-6, TNF-α, MIP-1α, MIP-1β) cytokines. B cells were increased in HSAT patients with a decreased fraction of unswitched memory B cells. Plasma GM-CSF concentrations were lower on average in HSAT patients, while CXCL11 was elevated. Finally, using principal components analysis, we derived an HSAT Signature Score that successfully stratified patients according to their antibody titers., Discussion: The immune profiles revealed in this study not only identify potential biomarkers of patients that developed HSAT but also provide insights into the pathophysiology of HSAT that will ultimately lead to improved immunotherapy strategies., Competing Interests: AD has received grant support from Sanofi Genzyme and the Lysosomal Disease Network. AD has received honoraria from Sanofi Genzyme. PK has received research/grant support from Sanofi Genzyme and Amicus Therapeutics. PK has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, Bayer, and Asklepios Biopharmaceutical, Inc. AskBio. PK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Pompe Disease Advisory Board for Amicus Therapeutics, and Advisory Board for Baebies. PK has equity with Maze Therapeutics and has held equity in Asklepios Biopharmaceuticals, and may receive milestone payments related to that equity in the future. AR is on the Medical Advisory Board of Sonoma Biotherapeutics, and the Scientific Advisory Boards of 4DMT and the Alice and YT Chen Genetics and Genomics Center and is a Consultant for EpiVax, Inc. AR is employed by Epivax, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Desai, Smith, Yi, Rosenberg, Burt and Kishnani.)

Background: The COVID-19 pandemic has created an unprecedented situation which the treatment of maxillofacial trauma, especially mandibular fractures that were previously managed using general anaesthesia had to be performed under local anaesthesia. In these cases, there was a requirement for an anaesthetic agent that would have a rapid onset but also provide a prolonged effect. The aim of the study was to evaluate the onset, duration, depth, required volume of anaesthesia of lidocaine with epinephrine versus combination of lidocaine and bupivacaine with epinephrine anaesthetic agents in surgical management of isolated mandibular fracture patients., Methods: A total of 30 patients with isolated mandibular fractures reported to our hospital included the study group. Patients were randomly distributed to two groups, Group A and Group B. Group A received local anaesthesia using 2% Lidocaine with 1:80,000 adrenaline and Group B received 0.5% Bupivacaine with 1:2,00,000 adrenaline combined with 2% Lidocaine with 1:80,000 adrenaline at a ratio of 1:1. The outcome variables were recorded and the data was tabulated and analysed using un-paired students t test., Results: The combination of anaesthetic agents had longer duration of action (mean: 182.47 min, P-value: 0.001) and required lesser volume of anaesthetic solutions (mean: 5.38 mL, P-value: 0.001) as compared to usage of lidocaine alone. Although combination group showed quicker onset (mean: 4 min 8 s), the result was insignificant (p-value: 0.345)., Conclusion: The study found that the combination of lidocaine and bupivacaine could serve as a potential anaesthetic cocktail in effective surgical management of isolated mandibular fractures., Clinical Relevance: Maxillofacial injuries can be managed efficiently under local anaesthesia using combination of lidocaine and bupivacaine., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: A major challenge to adeno-associated virus (AAV)-mediated gene therapy is the presence of anti-AAV capsid neutralizing antibodies (NAbs), which can block viral vector transduction even at very low titers. In the present study, we examined the ability of a combination immunosuppression (IS) treatment with bortezomib and a mouse-specific CD20 monoclonal antibody to suppress anti-AAV NAbs and enable readministration of AAV vectors of the same capsid in mice., Methods: An AAV8 vector (AAV8-CB-hGAA) that ubiquitously expresses human α-glucosidase was used for initial gene therapy and a second AAV8 vector (AAV8-LSP-hSEAP) that contains a liver-specific promoter to express human secreted embryonic alkaline phosphatase (hSEAP) was used for AAV readministration. Plasma samples were used for determination of anti-AAV8 NAb titers. Cells isolated from whole blood, spleen, and bone marrow were analyzed for B-cell depletion by flow cytometry. The efficiency of AAV readministration was determined by the secretion of hSEAP in blood., Results: In näive mice, an 8-week IS treatment along with AAV8-CB-hGAA injection effectively depleted CD19 + B220 + B cells from blood, spleen, and bone marrow and prevented the formation of anti-AAV8 NAbs. Following administration of AAV8-LSP-hSEAP, increasing levels of hSEAP were detected in blood for up to 6 weeks, indicating successful AAV readministration. In mice pre-immunized with AAV8-CB-hGAA, comparison of IS treatment for 8, 12, 16, and 20 weeks revealed that the 16-week IS treatment demonstrated the highest plasma hSEAP level following AAV8-LSP-hSEAP readministration., Conclusions: Our data suggest that this combination treatment is an effective IS approach that will allow retreatment of patients with AAV-mediated gene therapy. A combination IS treatment with bortezomib and a mouse-specific CD20 monoclonal antibody effectively suppressed anti-AAV NAbs in naïve mice and in mice with pre-existing antibodies, allowing successful readministration of the same AAV capsid vector., (© 2023 John Wiley & Sons Ltd.)

Background: Ablative procedures of the oral cavity require composite removal of tissues, which results in compromise of both functional activities and esthetic mutilation and proves to be a reconstructive challenge. This paper focuses on the reliability and versatility of a single perforator-based anterolateral thigh (ALT) flap in oral cancer reconstruction., Materials and Methods: All patients who underwent reconstruction with a single perforator-based ALT for oral cancer defects at our center were included in the study., Results: Forty-seven patients who underwent reconstruction with a single perforator-based ALT flap were included in our study. The average flap size in our series was 111 cm 2 , with the largest measuring 375 cm 2 . They was a complete loss of flap in two patients; both of them underwent salvage procedure and were reconstructed with pectoralis major myocutaneous flap. One had a partial loss that underwent re-exploration., Conclusion: We conclude that a single perforator-based ALT is a very safe, reliable, and versatile flap for head and neck reconstruction. The microvascular anastomosis may be expensive and technically a limitation; however, it has found a permanent place in our head and neck reconstructive toolkit and is the workhorse flap for head and neck reconstruction.

The survival of infantile-onset Pompe disease (IOPD) patients has improved dramatically since the introduction of enzyme replacement therapy (ERT) with a1glucosidase alfa. However, long-term IOPD survivors on ERT demonstrate motor deficits indicating that current therapy cannot completely prevent disease progression in skeletal muscle. We hypothesized that in IOPD, skeletal muscle endomysial stroma and capillaries would show consistent changes that could impede the movement of infused ERT from blood to muscle fibers. We retrospectively examined 9 skeletal muscle biopsies from 6 treated IOPD patients using light and electron microscopy. We found consistent ultrastructural endomysial stromal and capillary changes. The endomysial interstitium was expanded by lysosomal material, glycosomes/glycogen, cellular debris, and organelles, some exocytosed by viable muscle fibers and some released on fiber lysis. Endomysial scavenger cells phagocytosed this material. Mature fibrillary collagen was seen in the endomysium, and both muscle fibers and endomysial capillaries showed basal laminar reduplication and/or expansion. Capillary endothelial cells showed hypertrophy and degeneration, with narrowing of the vascular lumen. Ultrastructurally defined stromal and vascular changes likely constitute obstacles to movement of infused ERT from capillary lumen to muscle fiber sarcolemma, contributing to the incomplete efficacy of infused ERT in skeletal muscle. Our observations can inform approaches to overcoming these barriers to therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The therapeutic landscape for cardiac amyloidosis is rapidly evolving. In the last decade, our focus has shifted from dealing with the inevitable complications of continued extracellular infiltration of amyloid fibrils to earlier identification of these patients with prompt initiation of targeted therapy to prevent further deposition. Although much of the focus on novel targeted therapies is within the realm of transthyretin amyloidosis, light chain amyloidosis has benefited due to an overlap particularly in the final common pathway of fibrillogenesis and extraction of amyloid fibrils from the heart. Here, we review the targeted therapeutics for transthyretin and light chain amyloidosis. For transthyretin amyloidosis, the list of current and future therapeutics continues to evolve; and therefore, it is crucial to become familiar with the underlying mechanistic pathways of the disease. Although targeted therapeutic choices in AL amyloidosis are largely driven by the hematology team, the cardiac adverse effect profiles of these therapies, particularly in those with advanced amyloidosis, provide an opportunity for early recognition to prevent decompensation and can help inform recommendations regarding therapy changes when required., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Infantile onset Pompe disease (IOPD) is a rare devastating disease that presents in early infancy with rapidly progressive hypertrophic cardiomyopathy, severe generalized myopathy and death within the first year of life. The emergence of enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has improved the natural course of IOPD with a significant impact on cardiomyopathy but has a more limited effect on the progression of myopathy and consequently the later deterioration of the disease. Possible reasons for reduced ERT efficacy include insufficient enzyme, partial targeting of skeletal muscle and the development of IgG rhGAA antibodies especially in patients who are cross-reactive immunological material (CRIM) negative. We report a CRIM-negative IOPD female patient who started treatment upon diagnosis at 4.5 months with ERT at 20 mg/kg every other week and a course of combined immunomodulation with rituximab, methotrexate and IVIG according to the published Duke protocol and increased ERT within a month to 40 mg/kg/week. Despite initial good clinical response to ERT and immunomodulation, monthly monitoring identified a gradual increase of serum antibody titers to rhGAA necessitating a second course of immunomodulation with bortezomib and maintenance rituximab and methotrexate. A gradual reduction in frequency of immunotherapy was instituted and over a period of 14 months was discontinued. Serum anti-rhGAA antibody titers remained negative for 5 months since cessation of immunomodulation and the patient is now immune tolerant with recovery of CD19. At the age of 30 months the patient is walking independently and has normal cardiac function and anatomy. We recommend initiating ERT at 40 mg/kg/week in CRIM-negative IOPD patients, concomitant with immunomodulation and monthly monitoring of serum anti-rhGAA IgG titers upon confirmation of the diagnosis., Competing Interests: AKD has received grant support from Sanofi Genzyme and the Lysosomal Disease Network. PSK has received research/grant support from Sanofi Genzyme and Amicus Therapeutics. PSK has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, JCR Pharmaceutical and Asklepios Biopharmaceutical, Inc. (AskBio). PSK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Amicus Therapeutics, and Baebies. PSK has equity in Asklepios Biopharmaceutical, Inc. (AskBio), which is developing gene therapy for Pompe disease and Maze Therapeutics, which is developing small molecule in Pompe disease. YZ has received travel reimbursement from Sanofi Genzyme, RS has received travel reimbursement and speaker payments from Sanofi Genzyme., (© 2022 The Authors.)

Invasive fungal co-infections with COVID-19 are currently being reported at an alarming rate. Our study explores the importance of early identification of the disease, probable etiopathogenesis, clinical and radiological features and a treatment protocol for COVID-19 Associated Fungal Osteomyelitis of Jaws and Sinuses (CAFOJS). A one-year prospective study from June 2020 to May 2021 was conducted among CAFOJS diagnosed patients at a tertiary care center in South India. Demographic details, COVID-19 infection and treatment history, time taken for initiation of symptoms after COVID-19 diagnosis, medical history and clinical features were recorded. All patients were managed with a standard diagnostic and intervention protocol which included pre-operative and post-operative administration of Inj. Amphotericin B 50 mg (liposomal), early aggressive surgical debridement and tab. Posaconazole GR 300 mg OD for 90 days after discharge. Thirty-nine (78%) patients were diagnosed with CAFOJS out of 50 osteomyelitis patients. 35 patients (90%) were diabetic and 21 patients (54%) were known to receive steroids during the COVID-19 treatment. Sole existence of Mucorales spp. was seen in 30 patients (77%), Aspergillus fumigatus in 2 patients (5%), Curvularia spp. in 2 patients (5%). Concomitant existence of Mucorales and Aspergillus fumigatus was reported in two patients (5%) and Candida albicans in three patients (8%). Patients underwent treatment with standard protocol and no recurrence noted. CAFOJS is a clinical entity with aggressive presentation and warrants early diagnosis and treatment., Lay Summary: Invasive fungal infections of head and neck region cause necrosis of bones affected by it, especially maxilla. Early diagnosis and treatment are advocated in such infections due to its aggressive clinical presentation compared to similar infections before COVID-19 pandemic., (© The Author(s) 2022. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Purpose: Alveolar bone grafting is undertaken to provide stability to the dental arch and facilitate the eruption of permanent canine as teeth in the line of cleft usually have an altered pattern of eruption. The purpose of this study was to assess the eruption status and the change in the position and pattern of canine eruption after secondary alveolar bone grafting., Methods: An ambispective cohort study was conducted in patients operated for alveolar bone grafting with unilateral/bilateral alveolar cleft between the age of 9 to 13 years using autogenous iliac crest bone graft. The predictor variables of interest include the preoperative eruption status of canine (completely erupted/partially erupted/unerupted), stage of root development (one-third/two-third/more than two-third/complete) and position (vertical/lateral/buccopalatal) of the canine. The primary outcome variable is the eruption status of the canine (completely erupted/partially erupted/unerupted) at 6 months postoperatively. Secondary outcome variables include the stage of root development, change in the vertical, lateral and buccopalatal position of the canine observed in the first 6 months postoperatively with follow-up at 1 and 3 months. Another secondary outcome variable was the status of bone graft at 6 months postoperatively. Statistical analysis was done using Spearman's rank correlation and ANOVA chi-square test., Result: The study sample consisted of 30 non-syndromic alveolar cleft patients with a mean age of 11.9 years, out of which partial and complete eruption of canine was seen in 43.33 and 36.67%, respectively. The canine was unerupted in 20% of the cases (P = .001). There was evidence of continued root development through the grafted bone. No significant change in the angulation of canine was observed in the postoperative period., Conclusion: Significant change in the eruption status and root development of canine with no statistically significant change in the vertical and lateral angulation during eruption was observed. Identifying these risk factors by continuous postoperative monitoring will help in identifying the malposition at an early stage., (Copyright © 2021 The American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Aim: Three-dimensional (3D) printed models are contemporary volumetric bone graft assessment technique for secondary alveolar bone grafting (SABG) in cleft lip and palate (CLP) patients. The study aimed at evaluation of long-term stability of iliac autograft in SABG using multislice computed tomography (CT) and 3D-printed model-based volumetric analysis., Materials and Methods: Twenty-eight patients were included in this prospective clinical study. CT image (T1) was taken after orthodontic maxillary expansion, correlating with the presurgical image. Furthermore, 3D-printed model was prepared, and volumetric assessment of graft needed was ascertained with water displacement technique. SABG was carried on with the anterior iliac crest autografting procedure. After 1-year follow-up, postoperative CT analysis (T2) was followed upon., Results: The stability of bone graft at the 1-year postoperative was found to be 43.74% with mean bone loss of 56.26% (95% confidence interval; P < 0.005). The moderate scale of CLP cases has shown statistically significant bone stability compared to that of severe and mild cases. Furthermore, the 3D-printed model has shown a significant difference to that of T1 CT imaging ( P < 0.005)., Conclusion: Within the limitations of the study, it seems appropriate to conclude that 3D-printed models serves as better reference than CT imaging in the context of planning and execution of precise bone grafting in SABG., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Pharmacy and Bioallied Sciences.)

Objective: Vectorcardiographic (VCG) global electrical heterogeneity (GEH) metrics showed clinical usefulness. We aimed to assess the reproducibility of GEH metrics., Methods: GEH was measured on two 10-s 12‑lead ECGs recorded on the same day in 4316 participants of the Multi-Ethnic Study of Atherosclerosis (age 69.4 ± 9.4 y; 2317(54%) female, 1728 (40%) white, 1138(26%) African-American, 519(12%) Asian-American, 931(22%) Hispanic-American). GEH was measured on a median beat, comprised of the normal sinus (N), atrial fibrillation/flutter (S), and ventricular-paced (VP) beats. Spatial ventricular gradient's (SVG's) scalar was measured as sum absolute QRST integral (SAIQRST) and vector magnitude QT integral (VMQTi)., Results: Two N ECGs with heart rate (HR) bias of -0.64 (95% limits of agreement [LOA] -5.68 to 5.21) showed spatial area QRS-T angle (aQRST) bias of -0.12 (95%LOA -14.8 to 14.5). Two S ECGs with HR bias of 0.20 (95%LOA -15.8 to 16.2) showed aQRST bias of 1.37 (95%LOA -33.2 to 35.9). Two VP ECGs with HR bias of 0.25 (95%LOA -3.0 to 3.5) showed aQRST bias of -1.03 (95%LOA -11.9 to 9.9). After excluding premature atrial or ventricular beat and two additional beats (before and after extrasystole), the number of cardiac beats included in a median beat did not affect the GEH reproducibility. Mean-centered log-transformed values of SAIQRST and VMQTi demonstrated perfect agreement (Bias 0; 95%LOA -0.092 to 0.092)., Conclusion: GEH measurements on N, S, and VP median beats are reproducible. SVG's scalar can be measured as either SAIQRST or VMQTi., Significance: Satisfactory reproducibility of GEH metrics supports their implementation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Gemella morbillorum is increasingly implicated in infectious endocarditis. Our patient presented with anaemia and renal failure with evidence of infarcts and embolic disease. He was found to have endocarditis with an organism that could not speciate with standard culture methods requiring matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) for identification and susceptibilities. While involvement of mitral and aortic valves can be expected with Gemella , he had rare involvement of the pulmonic valve in a structurally normal heart. Although bacteriological cure was achieved, due to the locally destructive nature of Gemella , he ultimately required valve replacements for heart failure resolution. Workup for commonly implicated pathologies associated with G. morbillorum led to suspicion of gastrointestinal malignancy with findings of occult bleeding prompting an ongoing evaluation. With improved access to advanced diagnostics, G. morbillorum has been increasingly identified in infectious endocarditis. Given its destructive nature, it is important for clinicians to consider this organism is difficult to identify isolates., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: COVID-19-associated rhino-orbital-cerebral mucormycosis (ROCM) has reached epidemic proportion during India's second wave of COVID-19 pandemic, with several risk factors being implicated in its pathogenesis. This study aimed to determine the patient demographics, risk factors including comorbidities, and medications used to treat COVID-19, presenting symptoms and signs, and the outcome of management., Methods: This was a retrospective, observational study of patients with COVID-19-associated ROCM managed or co-managed by ophthalmologists in India from January 1, 2020 to May 26, 2021., Results: Of the 2826 patients, the states of Gujarat (22%) and Maharashtra (21%) reported the highest number of ROCM. The mean age of patients was 51.9 years with a male preponderance (71%). While 57% of the patients needed oxygen support for COVID-19 infection, 87% of the patients were treated with corticosteroids, (21% for > 10 days). Diabetes mellitus (DM) was present in 78% of all patients. Most of the cases showed onset of symptoms of ROCM between day 10 and day 15 from the diagnosis of COVID-19, 56% developed within 14 days after COVID-19 diagnosis, while 44% had delayed onset beyond 14 days. Orbit was involved in 72% of patients, with stage 3c forming the bulk (27%). Overall treatment included intravenous amphotericin B in 73%, functional endoscopic sinus surgery (FESS)/paranasal sinus (PNS) debridement in 56%, orbital exenteration in 15%, and both FESS/PNS debridement and orbital exenteration in 17%. Intraorbital injection of amphotericin B was administered in 22%. At final follow-up, mortality was 14%. Disease stage >3b had poorer prognosis. Paranasal sinus debridement and orbital exenteration reduced the mortality rate from 52% to 39% in patients with stage 4 disease with intracranial extension (p < 0.05)., Conclusion: : Corticosteroids and DM are the most important predisposing factors in the development of COVID-19-associated ROCM. COVID-19 patients must be followed up beyond recovery. Awareness of red flag symptoms and signs, high index of clinical suspicion, prompt diagnosis, and early initiation of treatment with amphotericin B, aggressive surgical debridement of the PNS, and orbital exenteration, where indicated, are essential for successful outcome.

Infantile-onset Pompe disease (IOPD) is a glycogen storage disease caused by a deficiency of acid alpha-glucosidase (GAA). Treatment with recombinant human GAA (rhGAA, alglucosidase alfa) enzyme replacement therapy (ERT) significantly improves clinical outcomes; however, many IOPD children treated with rhGAA develop anti-drug antibodies (ADA) that render the therapy ineffective. Antibodies to rhGAA are driven by T cell responses to sequences in rhGAA that differ from the individuals' native GAA (nGAA). The goal of this study was to develop a tool for personalized immunogenicity risk assessment (PIMA) that quantifies T cell epitopes that differ between nGAA and rhGAA using information about an individual's native GAA gene and their HLA DR haplotype, and to use this information to predict the risk of developing ADA. Four versions of PIMA have been developed. They use EpiMatrix, a computational tool for T cell epitope identification, combined with an HLA-restricted epitope-specific scoring feature (iTEM), to assess ADA risk. One version of PIMA also integrates JanusMatrix, a Treg epitope prediction tool to identify putative immunomodulatory (regulatory) T cell epitopes in self-proteins. Using the JanusMatrix-adjusted version of PIMA in a logistic regression model with data from 48 cross-reactive immunological material (CRIM)-positive IOPD subjects, those with scores greater than 10 were 4-fold more likely to develop ADA (p<0.03) than those that had scores less than 10. We also confirmed the hypothesis that some GAA epitopes are immunomodulatory. Twenty-one epitopes were tested, of which four were determined to have an immunomodulatory effect on T effector response in vitro . The implementation of PIMA V3J on a secure-access website would allow clinicians to input the individual HLA DR haplotype of their IOPD patient and the GAA pathogenic variants associated with each GAA allele to calculate the patient's relative risk of developing ADA, enhancing clinical decision-making prior to initiating treatment with ERT. A better understanding of immunogenicity risk will allow the implementation of targeted immunomodulatory approaches in ERT-naïve settings, especially in CRIM-positive patients, which may in turn improve the overall clinical outcomes by minimizing the development of ADA. The PIMA approach may also be useful for other types of enzyme or factor replacement therapies., Competing Interests: ADG and WDM are senior officers and shareholders, and SM, FET, SK, MA, and SL are employees of EpiVax, Inc., a company specializing in immunoinformatic analysis. EpiVax, Inc. own patents to technologies utilized by associated authors in the research reported here. AKD has received grant support from Sanofi Genzyme and the lysosomal disease network. PSK has received research/grant support from Sanofi Genzyme, Valerion Therapeutics, and Amicus Therapeutics. PSK has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, JCR Pharmaceutical and Asklepios Biopharmaceutical, Inc. (AskBio). PSK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Amicus Therapeutics, and Baebies. PSK has equity in Asklepios Biopharmaceutical, Inc. (AskBio), which is developing gene therapy for Pompe disease and Maze Therapeutics, which is developing small molecule in Pompe disease. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 De Groot, Desai, Lelias, Miah, Terry, Khan, Li, Yi, Ardito, Martin and Kishnani.)

Aims and Objective: This retrospective study evaluates the importance of Mantoux test and Erythrocyte Sedimentation Rate (ESR) levels in pediatric tuberculosis and also signifies the impact of this test in treatment planning and implementation in pediatric cleft lip and palate patients., Methodology: Retrospective analyses of the records of 2010 pediatric cleft lip and palate patients below 5 years age were performed, and patients with elevated ESR subjected to Mantoux test were identified. The parameters included were age, sex, ESR levels, type of cleft, history of contact with TB & BCG vaccination, Mantoux conversion, chest X-ray findings, number of smear-positive pulmonary tuberculosis., Results: Out of 2010 patients with cleft lip and palate, 180 patients were subjected to Mantoux test due to high ESR levels. Among these, 54 (30%) patients found as Mantoux positive, in which 45 patients were identified as smear-positive pulmonary tuberculosis patients; as a result, surgery was deferred and they underwent antituberculous therapy. Most of the Mantoux-positive cases were found in patients with ESR range of 20-30 mm, i.e., 38 patients (71%), and common age group was 6 months-1 year. The most commonly involved cleft type was: unilateral cleft lip and palate having 36 patients (66.7%). The overall incidence of tuberculosis was 2%., Conclusion: Although the correlation of Mantoux test with elevated ESR was not significant in our study, it could be of value as a screening tool along with the Mantoux test, which is sensitive but nonspecific in the diagnosis of active tuberculosis. Together, they could be a valuable screening tool in any community or hospital for diagnosis of the disease., Competing Interests: Conflict of interestThe authors declare that there is no conflict of interest., (© The Association of Oral and Maxillofacial Surgeons of India 2020.)

Purpose: To assess the magnitude of benefit to early treatment initiation, enabled by newborn screening or prenatal diagnosis, in patients with cross-reactive immunological material (CRIM)-negative infantile Pompe disease (IPD), treated with enzyme replacement therapy (ERT) and prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and intravenous immunoglobulin (IVIG)., Methods: A total of 41 CRIM-negative IPD patients were evaluated. Among patients who were treated with ERT + ITI (n = 30), those who were invasive ventilator-free at baseline and had ≥6 months of follow-up were stratified based on age at treatment initiation: (1) early (≤4 weeks), (2) intermediate (>4 and ≤15 weeks), and (3) late (>15 weeks). A historical cohort of 11 CRIM-negative patients with IPD treated with ERT monotherapy served as an additional comparator group., Results: Twenty patients were included; five, seven, and eight in early, intermediate, and late treatment groups, respectively. Genotypes were similar across the three groups. Early-treated patients showed significant improvements in left ventricular mass index, motor and pulmonary outcomes, as well as biomarkers creatine kinase and urinary glucose tetrasaccharide, compared with those treated later., Conclusion: Our preliminary data suggest that early treatment with ERT + ITI can transform the long-term CRIM-negative IPD phenotype, which represents the most severe end of the Pompe disease spectrum.

Objective: Critical illness causes a decrease in serum free triiodothyronine (T 3 ) levels. This condition, known as nonthyroidal illness syndrome (NTIS), is associated with poor outcomes. The association of NTIS and outcomes in patients in the intensive care unit (ICU) requiring mechanical ventilation has not been well studied. This study aimed to determine the impact of NTIS on the outcomes of these patients., Methods: This prospective study included 162 patients in the ICU who underwent mechanical ventilation. Serum free T 3 levels were tested on the day of initiation of mechanical ventilation. The rates of in-hospital mortality and ventilator-free days (VFDs) at day 28 after the initiation of mechanical ventilation were compared between patients with low (<2.3 pg/mL) and normal (≥2.3 pg/mL) free T 3 levels. Patients who died while on mechanical ventilation were assigned a VFD of 0., Results: Low T 3 was present in 60% of study patients. The in-hospital mortality rate of the entire cohort was 39%, and the mean and median VFDs at day 28 were 13.5 and 21 days, respectively. Compared to patients with normal free T 3 , patients with low free T 3 had higher in-hospital mortality (52% vs 19%, P < .001) and less mean and median VFDs at day 28 (10.7 vs 18 and 0 vs 23, respectively. P < .001 for both mean and median VFDs)., Conclusions: The presence of low T 3 due to NTIS in patients in the ICU requiring mechanical ventilation is associated with poor outcomes.

Objectives: The purpose of this paper is to consider the anatomical basis and surgical technique along with the utility of buccal fat pad (BFP) for the reconstruction in cleft lip and palate patients., Methods: We reviewed 27 cases of CLAP treated with BFP over three year period in our institution which included 2 cases of primary palatoplasty & 25 cases of secondary palatoplasty. Inclusion criteria consisted of patients operated by a single surgeon with a minimum follow up of 2yrs. Exclusion criteria included all syndromic cleft lip and palate patients. Predictor variables recorded were demographic characters, follow up period, type of cleft, type of surgical procedure, site & dimension of the fistula. Outcome variables of the study were post-operative fistula formation, post-operative hemorrhage & speech assessment., Results: The study included 8 female & 19 male patients with mean age group 3.75 ± 1.75yrs. Cleft of soft palate & Lt. CLAP were the most common type of cleft. The surgical technique used was: BFP with V-Y pushback palatoplasty for primary palate repair, BFP with Furlow's technique for VPI correction, and BFP in conjugation with rotation flap, straight-line closure or redohardpalatoplasty for fistula closure. All cases showed satisfactory healing with favorable speech assessment outcomes for 18 patients (67%)., Conclusion: BFP along with other types of flap is the choice of treatment in cases of moderate defect owing to its favorable anatomic location & high vascularity. The size limitation of the BFP must be known to permit a successful outcome., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Context: Log odds of positive lymph nodes (LODDS) have been recently demonstrated as a very promising staging model and have outperformed AJCC pN, lymph node ratio (LNR) category in major cancers. Literature is scarce concerning the prognostic ability of LODDS in oral squamous cell carcinoma (OSCC) patients., Aims: The present study was aimed to evaluate the importance of LODDS in predicting locoregional recurrence and overall survival (OS) in patients with OSCC compared to LNR., Settings and Design: The retrospective study was carried out on 194 patients with OSCC cases treated by surgery ± adjuvant therapy from 2008 to 2014 at our institution., Subjects and Methods: Demographical and clinicopathological details of study cases were recorded. LNR and LODDS were calculated and expressed as a percentage and mean ± standard deviation., Statistical Analysis Used: The OS analysis was done by the Kaplan-Meier curve followed by log-rank (mantel-cox) test. Univariate and multivariate survival analysis was done to analyze the prognostic ability of LNR% and LODDS after adjusting the clinicopathological parameters by the Cox proportional hazards model., Results: Patients with cut off values of LODDS >-1.2 and LNR% >4 had significantly lower mean OS ( P ≤ 0.001). Multivariate analysis indicated that only mean LODDS >-1.2 was significantly associated with poor OS. Although there was a correlation with locoregional recurrence, LODDS and LNR failed to be the independent predictors of locoregional recurrence., Conclusions: LODDS was an independent reliable prognostic indicator for patients with OSCCs than conventional staging systems and LNR., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Oral and Maxillofacial Pathology.)

Immune tolerance induction (ITI) with a short-course of rituximab, methotrexate, and/or IVIG in the enzyme replacement therapy (ERT)-naïve setting has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD) lacking endogenous acid-alpha glucosidase (GAA), known as cross-reactive immunologic material (CRIM)-negative. In the context of cancer therapy, rituximab administration results in sustained B-cell depletion in 83% of patients for up to 26-39 weeks with B-cell reconstitution beginning at approximately 26 weeks post-treatment. The impact of rituximab on serum immunoglobulin levels is not well studied, available data suggest that rituximab can cause persistently low immunoglobulin levels and adversely impact vaccine responses. Data on a cohort of IPD patients who received a short-course of ITI with rituximab, methotrexate, and IVIG in the ERT-naïve setting and had ≥6 months of follow-up were retrospectively studied. B-cell quantitation, ANC, AST, ALT, immunization history, and vaccine titers after B-cell reconstitution were reviewed. Data were collected for 34 IPD patients (25 CRIM-negative and 9 CRIM-positive) with a median age at ERT initiation of 3.5 months (0.1-11.0 months). B-cell reconstitution, as measured by normalization of CD19%, was seen in all patients ( n = 33) at a median time of 17 weeks range (11-55 weeks) post-rituximab. All maintained normal CD19% with the longest follow-up being 248 weeks post-rituximab. 30/34 (88%) maintained negative/low anti-rhGAA antibody titers, even with complete B-cell reconstitution. Infections during immunosuppression were reported in five CRIM-negative IPD patients, all resolved satisfactorily on antibiotics. There were no serious sequelae or deaths. Of the 31 evaluable patients, 27 were up to date on age-appropriate immunizations. Vaccine titers were available for 12 patients after B-cell reconstitution and adequate humoral response was observed in all except an inadequate response to the Pneumococcal vaccine ( n = 2). These data show the benefits of short-course prophylactic ITI in IPD both in terms of safety and efficacy. Data presented here are from the youngest cohort of patients treated with rituximab and expands the evidence of its safety in the pediatric population., (Copyright © 2020 Desai, Baloh, Sleasman, Rosenberg and Kishnani.)

The aim of the study is to assess the occlusion in mandibular condyle fractures using T-Scan and analyze the data obtained. Twenty patients underwent non-surgical management for condylar fractures were treated with Erich arch bar and guiding elastics, and periodically subjected to T-Scan III evaluations. The data obtained was analyzed with the clinical evaluation conducted. There were 18 males and 2 females. Mean age of the patients was 25.4 ± 7.4 years. There were statistically no significant changes in Centre of Force values, in Bite Force at First Contact (P < 0.05) during the study period. There were significant differences in Maximum Bite Force between preoperative and postoperative values, preoperative and sixth-month values, postoperative and first-month values, first-month and sixth-month values. There were significant (P < 0.05) differences in Bite Force at Maximum Intercuspation between preoperative and third month, preoperative and sixth-month values, postoperative and sixth-month values, first-month and consequent follow-ups. Subjective evaluation of occlusion revealed significant differences (P < 0.05) between preoperative and 1-month, preoperative and postoperative, postoperative and 1-month values. All patients improved by the end of 6 months with regards to their mouth opening. The center of force does not alter significantly in post trauma period. Mouth opening improves significantly at the end of 6-month period post-operative. Improvement in maximum bite force and maximum intercuspation take place simultaneously. Mouth opening improved significantly. Subjective evaluation of occlusion does not change significantly after the third month evaluation. Longer follow-ups would help us in understanding when or if the bite forces equilibrate after a condylar trauma.

Objectives: To report the respiratory function of school-aged children with infantile Pompe disease (IPD) who started enzyme replacement therapy (ERT) in infancy and early childhood., Study Design: This is a retrospective chart review of pulmonary function tests of: (a) patients with IPD 5 to 18 years of age, (b) who were not ventilator dependent, and (c) were able to perform upright and supine spirometry. Subjects were divided into a younger (5-9 years) and older cohort (10-18 years) for the analysis. Upright and supine forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were analyzed., Results: Fourteen patients, all cross-reactive immunologic material (CRIM)-positive, met the inclusion criteria and were included in this study. Mean upright and supine FVC were 70.3% and 64.9% predicted, respectively, in the 5- to 9-year-old cohort; and 61.5% and 52.5% predicted, respectively, in the 10- to 18-year-old group. Individual patient trends showed stability in FVC overtime in six of the 14 patients. MIPs and MEPs were consistent with inspiratory and expiratory muscle weakness in the younger and older age group but did not decline with age., Conclusion: Data from this cohort of CRIM-positive patients with IPD showed that ERT is able to maintain respiratory function in a subgroup of patients whereas others had a steady decline. There was a statistically significant decline in FVC from the upright to a supine position in both the younger and older age groups of CRIM-positive ERT-treated patients. Before ERT, patients with IPD were unable to maintain independent ventilation beyond the first few years of life., (© 2020 Wiley Periodicals, Inc.)

Diabetes mellitus continues to increase in epidemic proportions globally as well as in India. Poor glycemic control in long-standing diabetes mellitus eventually leads to chronic complications such as retinopathy, nephropathy, neuropathy, and cardiovascular disease. Diabetic retinopathy is emerging as an important cause of avoidable visual impairment and blindness in India across all strata of society. Much of this vision loss can be prevented by improving control of known risk factors, annual fundus screening, with prompt treatment of individuals with sight-threatening retinopathy. The Queen Elizabeth Diamond Jubilee Trust has made a significant contribution by supporting such a program across India, including Goa. The newly established medical retina clinic at Goa Medical College now provides facilities for screening, a detailed evaluation of advanced retinopathy, and therapeutic modalities such as laser and intravitreal injections. The peripheral centers are equipped to screen all people with diabetes mellitus and refer those with sight-threatening retinopathy to the medical college. The provision of a foot scanner to evaluate the risk of foot ulcers and microalbuminuria assessment as part of the nephropathy screening would encompass the entire gamut of diabetic microvascular complications. The next decade would provide evidence if this initiative, with the enthusiastic partnership of the state government, results in reduction of blindness in the people of Goa and an overall reduction in diabetes-related morbidity and mortality., Competing Interests: None

Pompe disease is an autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase resulting in intralysosomal glycogen accumulation in multiple tissue types, especially cardiac, skeletal, and smooth muscle. Enzyme replacement therapy (ERT) with alglucosidase alfa has led to improved clinical outcomes and prolonged survival in patients with Pompe disease. While ERT has changed the natural course of Pompe disease, with many long-term survivors, several factors affect the response to ERT. Previous studies in Pompe disease have shown that IgG antibodies to ERT can lead to a decline in muscle strength, pulmonary function, and overall and ventilator-free survival. Additionally, antibody responses to ERT can also cause hypersensitivity reactions. Various strategies to prevent or eliminate the IgG antibody response have been attempted in patients with Pompe disease. A detailed literature search was performed to compile data regarding the consequences of IgG antibodies, clinical approaches to prevent or eliminate IgG antibodies in patients with Pompe disease, and to expand our understanding of new modalities being developed in non-clinical settings. All qualifying articles describing the impact of IgG antibodies on the response to ERT, immunomodulation in patients with Pompe disease, and non-clinical settings identified via a PubMed database search were included in the review. Here, we provide a comprehensive review of combination- and single-agent therapies that have been investigated in the context of immune tolerance induction to ERT in Pompe disease to date. Immunomodulation strategies that successfully induce immune tolerance to ERT have improved overall survival, especially reflected in the decreased number of ventilator-dependent or deceased cross-reactive immunologic material (CRIM)-negative infantile Pompe disease (IPD) patients due to development of IgG antibodies when treated with ERT alone. Immunomodulation in CRIM-positive patients at the time they receive ERT also results in a decrease in the development of IgG antibodies compared to cases treated with ERT alone. Lessons learned from current approaches, alongside results from trials of novel immunomodulation strategies, may provide important insights into the development of next-generation therapies., Competing Interests: Conflicts of Interest: AK Desai has received grant support from Sanofi Genzyme and the Lysosomal Disease Network. C Li and AS Rosenberg have no financial or proprietary interest in the material presented herein. PS Kishnani has received grant support from Sanofi Genzyme, Valerion Therapeutics, Shire Pharmaceuticals, and Amicus Therapeutics. PS Kishnani has received consulting fees and honoraria from Sanofi Genzyme, Shire Pharmaceuticals, Amicus Therapeutics, Vertex Pharmaceuticals, and Asklepios BioPharmaceutical, Inc. (AskBio). PS Kishnani is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme. PS Kishnani has equity in AskBio, which is developing gene therapy for Pompe disease.

Enzyme replacement therapy (ERT) with rhGAA has improved clinical outcomes in infantile Pompe disease (IPD). A subset of CRIM-positive IPD patients develop high and sustained antibody titers (HSAT; ≥51,200) and/or sustained intermediate titer (SIT; ≥12,800 and <51,200), similar to CRIM-negative patients. To date there has been no systematic study to analyze the extent of IgG antibody response in CRIM-positive IPD. Such data would be critical and could serve as a comparator group for potential immune modulation approaches. A retrospective analysis of the dataset from the original rhGAA clinical trials final reports was conducted. CRIM-positive patients who received ERT monotherapy and had >6 months of antibody titer data available, were included in the study. Patients were classified based on their longitudinal antibody titers into HSAT, SIT, and low titer (LT; <12,800) groups. Of the 37 patients that met inclusion criteria, five (13%), seven (19%), and 25 (68%) developed HSAT, SIT, and LT, respectively. Median peak titers were 204,800 (51,200-409,600), 25,600 (12,800-51,200), and 800 (200-12,800) for HSAT, SIT, and LT groups, respectively. Median last titers were 102,400 (51,200-409,600), 1600 (200-25,600), and 400 (0-12,800) at median time since ERT initiation of 94 weeks (64-155 weeks), 104 weeks (86-144 weeks), and 130 weeks (38-182 weeks) for HSAT, SIT, and LT groups, respectively. 32% (12/37) of CRIM-positive IPD patients developed HSAT/SIT which may lead to limited ERT response and clinical decline. Further Studies are needed to identify CRIM-positive IPD patients at risk of developing HSAT/SIT, especially with the addition of Pompe disease to the newborn screening.

Purpose: To investigate immune tolerance induction with transient low-dose methotrexate (TLD-MTX) initiated with recombinant human acid α-glucosidase (rhGAA), in treatment-naïve cross-reactive immunologic material (CRIM)-positive infantile-onset Pompe disease (IOPD) patients., Methods: Newly diagnosed IOPD patients received subcutaneous or oral 0.4 mg/kg TLD-MTX for 3 cycles (3 doses/cycle) with the first 3 rhGAA infusions. Anti-rhGAA IgG titers, classified as high-sustained (HSAT; ≥51,200, ≥2 times after 6 months), sustained intermediate (SIT; ≥12,800 and <51,200 within 12 months), or low (LT; ≤6400 within 12 months), were compared with those of 37 CRIM-positive IOPD historic comparators receiving rhGAA alone., Results: Fourteen IOPD TLD-MTX recipients at the median age of 3.8 months (range, 0.7-13.5 months) had a median last titer of 150 (range, 0-51,200) at median rhGAA duration ~83 weeks (range, 36-122 weeks). One IOPD patient (7.1%) developed titers in the SIT range and one patient (7.1%) developed titers in the HSAT range. Twelve of the 14 patients (85.7%) that received TLD-MTX remained LT, versus 5/37 HSAT (peak 51,200-409,600), 7/37 SIT (12,800-51,000), and 23/37 LT (200-12,800) among comparators., Conclusion: Results of TLD-MTX coinitiated with rhGAA are encouraging and merit a larger longitudinal study.

Purpose: In the present study, we have highlighted the occurrence of different palatal fistulas and evaluated the difficulty level in planning the treatment, thereby enabling the prediction of the prognosis preoperatively., Materials and Methods: The present retrospective study included 62 nonsyndromic cases with primary surgery and palatal fistula repair performed in our unit. Data were collected on the fistula incidence, site, and size, cleft type, fistula closure method. All these were categorized, analyzed, and scored according to the difficulty index reported by Richardson et al. The data were statistically analyzed using χ 2 analysis and Fisher's exact test., Results: The incidence of palatal fistula was 4.58%, with the transverse type (74%) the predominant type. The difficulty index was grade 1 and 2 for 33 (53.2%) and 29 (46.8%) patients, respectively. The recurrence rate was 35.4%, with 6.4 and 28.9% observed in the grade 1 and grade 2 groups, respectively (P = .019). The surgical techniques included tongue flap, redo palatoplasty, rotation flap, and a combination of rotation with a buccal fat pad. The incidence of recurrence was dependent on the type of surgical management and the difficulty index score (P = .047)., Conclusions: Palatal fistula closure is a technically difficult procedure with a high recurrence rate. Thus, the difficulty level index for closure must be evaluated to predict the outcomes of the procedure before surgery. Also, further studies are required to introduce a standardized classification system of fistula complexity to address the difficulty in their management., (Copyright © 2018 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

In Pompe disease, anti-drug antibodies (ADA) to acid alpha-glucosidase (GAA) enzyme replacement therapy contribute to early mortality. Assessing individual risk for ADA development is notoriously difficult in (CRIM-positive) patients expressing endogenous GAA. The individualized T cell epitope measure (iTEM) scoring method predicts patient-specific risk of developing ADA against therapeutic recombinant human GAA (rhGAA) using individualized HLA-binding predictions and GAA genotype. CRIM-negative patients were six times more likely to develop high ADA titers than CRIM-positive patients in this retrospective study, whereas patients with high GAA-iTEM scores were 50 times more likely to develop high ADA titers than patients with low GAA-iTEM scores. This approach identifies high-risk IOPD patients requiring immune tolerance induction therapy to prevent significant ADA response to rhGAA leading to a poor clinical outcome and can assess ADA risk in patients receiving replacement therapy for other enzyme or blood factor deficiency disorders., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: This study aims to determine whether a resource- and culturally appropriate lifestyle intervention programme in South Asian countries, provided to women with gestational diabetes (GDM) after childbirth, will reduce the incidence of worsening of glycaemic status in a manner that is affordable, acceptable and scalable., Methods: Women with GDM (diagnosed by oral glucose tolerance test using the International Association of the Diabetes and Pregnancy Study Groups criteria) will be recruited from 16 hospitals in India, Sri Lanka and Bangladesh. Participants will undergo a repeat oral glucose tolerance test at 6 ± 3 months postpartum and those without Type 2 diabetes, a total sample size of 1414, will be randomly allocated to the intervention or usual care. The intervention will consist of four group sessions, 84 SMS or voice messages and review phone calls over the first year. Participants requiring intensification of the intervention will receive two additional individual sessions over the latter half of the first year. Median follow-up will be 2 years. The primary outcome is the proportion of women with a change in glycaemic category, using the American Diabetes Association criteria: (i) normal glucose tolerance to impaired fasting glucose, or impaired glucose tolerance, or Type 2 diabetes; or (ii) impaired fasting glucose or impaired glucose tolerance to Type 2 diabetes. Process evaluation will explore barriers and facilitators of implementation of the intervention in each local context, while trial-based and modelled economic evaluations will assess cost-effectiveness., Discussion: The study will generate important new evidence about a potential strategy to address the long-term sequelae of GDM, a major and growing problem among women in South Asia. (Clinical Trials Registry of India No: CTRI/2017/06/008744; Sri Lanka Clinical Trials Registry No: SLCTR/2017/001; and ClinicalTrials.gov Identifier No: NCT03305939)., (© 2018 Diabetes UK.)

Patients with Pompe disease have realized significant medical benefits due to enzyme replacement therapy (ERT) infusions with alglucosidase alfa. However, regular infusions are time-consuming. Utilizing recommended infusion rates, infusion duration is 3h 45min for a patient receiving the standard dose of 20mg/kg, not including additional time needed for preparation of ERT, assessment of vital signs, intravenous access, and post-infusion monitoring. Recent studies have demonstrated increased effectiveness of higher dose of ERT (40mg/kg) in infantile-onset Pompe disease (IOPD), which increases the infusion duration to 6h 36min. Increased infusion durations compound the psychosocial burden on patients and families and potentially further disrupt family activities and obligations. We developed a stepwise infusion rate escalation protocol to administer higher dose ERT safely while decreasing infusion duration, which has been implemented in 15 patients to date. Reported here in detail are five patients with IOPD on 40mg/kg/weekly ERT in whom infusion duration was decreased with individualized, stepwise rate escalation. All patients tolerated rate escalations above the recommended rates without experiencing any infusion associated reactions and experienced a reduction in infusion duration by 1h and 24min with a corresponding increase in reported satisfaction. Our experience with ERT rate escalation is presented., Synopsis: A careful stepwise method of enzyme replacement therapy (ERT) rate escalation can safely reduce infusion duration in patients with Pompe disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Newborn screening (NBS) has led to early diagnosis and early initiation of treatment for infantile onset Pompe Disease (IOPD). However, guidelines for management of late onset Pompe disease (LOPD) via NBS, especially with the IVS c.-32-13T>G are not clear. This IVS variant is noted in 68-90% cases with LOPD and has been presumed to result in "adult" disease in compound heterozygosity, with a few cases with earlier onset and a mild to no phenotype in homozygosity. Our study evaluates newborns with LOPD having IVS variant with a diligent multidisciplinary approach to determine if they have an early presentation., Methods: Seven children with LOPD identified by NBS with IVS variant (3 compound heterozygous, and 4 homozygous) were evaluated with clinical, biochemical (CK, AST, ALT, and urinary Glc 4 ), cardiac evaluation, physical therapy (PT), occupational, and speech/language therapy., Results: All seven patients demonstrated motor involvement by age 6months; the three patients with c.-32-13 T>G variant in compound heterozygosity had symptoms as neonates. Patients with c.-32-13 T>G variant in compound heterozygosity had more involvement with persistent hyperCKemia, elevated AST and ALT, swallowing difficulties, limb-girdle weakness, delayed motor milestones, and were initiated on ERT. The patients with c.-32-13T>G variant in homozygosity had normal laboratory parameters, and presented with very subtle yet LOPD specific signs, identified only by meticulous assessments., Conclusion: This patient cohort represents the first carefully phenotyped cohort of infants with LOPD with the "late-onset" GAA variant c.-32-13T>G detected by NBS in the USA. It emphasizes not only the opportunity for early detection of skeletal and other muscle involvement in infants with c.-32-13T>G variant but also a high probability of overlooking or underestimating the significance of clinically present and detectable features. It can thus serve as a valuable contribution in the development of evaluation and treatment algorithms for infants with LOPD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Complementary and alternative medicine (CAM) is often used alongside conventional medical care, yet few patients disclose CAM use to medical doctors. Our objectives were to (1) assess Latino herbal use, (2) explore the most commonly used herbs for common ailments, and (3) examine patients' disclosure of herb use to their physicians. Self-administered questionnaires were collected from 318 Latino patients seeking treatment at community health centers. Descriptive statistical analysis was conducted to determine the frequency of stated objectives among the participants. Fisher's exact test was used to compare differences among CAM users and non-users. Most respondents (90%) reported using herbs. Less than a third (31%) of those herb users felt comfortable speaking English to their physician. A majority (74.8%) of the respondents utilizing herbs reported never disclosing their herbal use to their healthcare providers, and of those that did, majority (63%) were under the age of 36 years. Of those that disclosed their herbal use, only 31% perceived receiving a positive reaction about herbal use from their providers. Chamomile, cinnamon, Aloe vera, spearmint, and key lime were the top used herbs in this population. Herbal use disclosure reflects a greater sense of trust and communication between patient and provider. Therefore, a need exists to increase provider competency for patients using herbs in order to improve consistency of care and facilitate healthy patients and communities, especially among Spanish-speaking Latinos in Southern California.

Background: Cross-reactive immunological material-negative (CRIM-negative) infantile Pompe disease (IPD) patients develop an immune response against enzyme replacement therapy (ERT) with alglucosidase alfa that nullifies ERT efficacy. Prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG successfully prevents development of deleterious rhGAA IgG antibodies; however, safety, likelihood of success, and long-term efficacy of ITI in a larger cohort remain unknown., Methods: Clinical data were analyzed for 19 CRIM-negative IPD patients who received ITI with rituximab, methotrexate, and IVIG in the ERT-naive setting (ERT+ITI) and compared to a historical cohort of 10 CRIM-negative IPD patients on ERT monotherapy., Results: ITI was safely tolerated, although infections were reported in 4 patients. Fourteen (74%) ERT+ITI patients were alive, with a median age of 44.2 months at their final assessment. The eldest survivor was 103.9 months old, with 100.2 months of follow-up after initiation of ERT+ITI. Death (n = 5) occurred at a median age of 29.2 months and was unrelated to the administration of ITI. Fifteen patients either did not seroconvert (n = 8) or maintained low titers (n = 7; defined as titers of ≤6,400 throughout the course of ERT) following ERT+ITI. Only one patient developed high and sustained antibody titers (defined as titers of ≥51,200 at or beyond 6 months on ERT). Left ventricular mass index (LVMI) decreased from a median of 248.5 g/m2 at baseline to 76.8 g/m2 at a median time from ERT+ITI initiation to 59 weeks. ERT+ITI significantly improved overall survival (P = 0.001), eliminated/reduced antibodies at values of ≤6,400 at week 52 on ERT (P = 0.0004), and improved LVMI at week 52 on ERT (P = 0.02) when compared with ERT monotherapy., Conclusion: Evidence from this international cohort of CRIM-negative IPD patients further supports the safety, feasibility, and efficacy of ITI in the prevention of immune responses to ERT., Trial Registration: Clinicaltrials.gov NCT01665326., Funding: This research was supported in part by the Lysosomal Disease Network, a part of NIH Rare Diseases Clinical Research Network, and by a grant from Genzyme, a Sanofi company.

Objective: To assess the accuracy of different sonographic estimated fetal weight (EFW) cutoffs, and combinations of EFW and biometric measurements for predicting small for gestational age (SGA) in fetal gastroschisis., Study Design: Gastroschisis cases from two centers were included. The sensitivity, specificity, positive and negative predictive values (PPV and NPV) were calculated for different EFW cutoffs, as well as EFW and biometric measurement combinations., Results: Seventy gastroschisis cases were analyzed. An EFW<10% had 94% sensitivity, 43% specificity, 33% PPV and 96% NPV for SGA at delivery. Using an EFW cutoff of <5% improved the specificity to 63% and PPV to 41%, but decreased the sensitivity to 88%. Combining an abdominal circumference (AC) or femur length (FL) z-score less than -2 with the total EFW improved the specificity and PPV but decreased the sensitivity., Conclusion: A combination of a small AC or FL along with EFW increases the specificity and PPV, but decreases the sensitivity of predicting SGA.