Novel dihydropyrimidines as promising EGFR & HER2 inhibitors: Insights from experimental and computational studies.

Dihydropyrimidines are widely recognized for their diverse biological properties and are often synthesized by the Biginelli reactions. In this backdrop, a novel series of Biginelli dihydropyrimidines were designed, synthesized, purified, and analyzed by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. Anticancer activity against MCF-7 breast cancer cells was evaluated as part of their cytotoxicity in comparison with the normal Vero cells. The cytotoxicity of dihydropyrimidines ranges from moderate to significant. Among the 38 dihydropyrimidines screened, compounds 16, 21, and 39 exhibited significant cytotoxicity. These 3 compounds were subjected to flow cytometry studies and EGFRwt Kinase inhibition assay using lapatinib as a standard. The study included evaluation for the inhibition of EGFR and HER2 expression at five different concentrations. At a concentration of 1000 nM compound 21 showed 98.51 % and 96.79 % inhibition of EGFR and HER2 expression. Moreover, compounds 16, 21 and 39 significantly inhibited EGFRwt activity with IC50 = 69.83, 37.21 and 76.79 nM, respectively. In addition, 3D-QSAR experiments were conducted to elucidate Structure activity relationships in a 3D grid space by comparing the experimental and predicted cytotoxic activities. Molecular docking studies were performed to validate the results by in silico method. All together, we developed a new series of Biginelli dihydropyrimidines as dual EGFR/HER2 inhibitors.

The Use of Platelet-Rich Plasma in the Treatment of Diabetic Foot Ulcers: A Scoping Review.

Platelet-rich plasma (PRP) has been recognized as a method of treatment in medicine since the 1980s. It primarily functions by releasing cytokines and growth factors that promote wound healing; these growth-promoting factors released by PRP enact new processes such as angiogenesis, collagen deposition, and tissue formation that can change wound-healing outcomes. Many studies recognize that PRP aids in chronic wound healing, which is advantageous for patients who suffer from chronic diabetic foot ulcers (DFUs). This scoping review aims to examine the literature to identify the efficacy of PRP use in the healing of DFUs. The objective of this study is to explore whether PRP has a beneficial effect on healing completeness and the rate of healing on DFUs. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched randomized-controlled trials involving PRP use in diabetic patients with foot ulcers using PubMed, Medline, CINAHL Complete, and Cochrane Database of Systematic Reviews. We restricted the search to articles published during 2005-2022, full texts in the English language, articles involving patients aged 19 years or older, articles that used PRP specifically on DFUs, articles that included a control group, and articles with human subjects. The initial search yielded 119 articles after removing duplicates. The final analysis for relevance yielded eight articles. In seven of the eight studies, the PRP group showed significant results, with either faster healing, more complete healing, or a larger percentage of healed participants. In the one study that did not give conclusive evidence of accelerated healing with PRP, PRP was used as an adjunct to fat grafting and only used once. Application styles of PRP for treatment were shown to influence the level of healing in patients, with injected PRP appearing to achieve the best results compared to topical PRP application. However, this was not conclusive due to the involvement of several other variables. Two studies additionally found PRP to be useful in healing refractory DFUs, and one study found that PRP use in patients with additional comorbidities was still more effective in healing DFUs than standard wound control. This study used scoping review methodology with randomized-controlled trials to examine the literature regarding PRP use in the healing of DFUs. The evidence suggests that PRP is a useful tool in reducing healing times and improving rates of complete wound healing in DFUs. There is room for further research in the application styles of PRP before conclusive statements can be made on the efficacy of injected versus topical PRP healing, based on the findings in this study. The results of this review provide a baseline for further research on PRP use in patients with diabetes and can be used by physicians and public health experts to guide future treatment options for DFUs.

Barriers of Care to Ovarian Cancer: A Scoping Review.

Ovarian cancer is a leading cause of female cancer-related deaths, but patients continue to be diagnosed late. This subjects them to disease progression and possible death due to lack of early detection, despite earlier stage detection improving survival rates by significant percentages. Early detection and access to care are closely related. However, many barriers to high-quality care exist for patients and the majority of patients do not receive recommended care according to ovarian cancer treatment guidelines. In order to improve care for ovarian cancer patients and decrease healthcare disparities in accessing equitable care, it is important to acknowledge the current gaps in patient knowledge, healthcare availability, and physician practice. This scoping review explores the available evidence on ovarian cancer to identify these barriers to care in the effective treatment of ovarian cancer. Using both inclusion and exclusion criteria, results from the initial literature search were screened by the authors. After quality assessment and screening for relevance, 10 articles were included in the final review. The following themes emerged as barriers to care: hospital and physician-patient volumes, geographic distance from care facilities, patient and physician education, and demographic factors. Many patients were found to not receive guideline adherent care due to various barriers to care, whereas guideline adherent care was independently associated with factors such as patient proximity to a high-volume hospital, White race, and higher socioeconomic status. Several areas were identified as potential for increased patient and physician education, including treatment complications and patient resources. The evidence found that certain socioeconomic groups and racial minorities are often at higher risk for guideline non-adherent care. Additionally, the evidence showed a further need for physicians and healthcare providers to be provided with resources for post-cancer treatment, follow-up, and patient education. The findings of this review will provide health experts and patients with better insight into what barriers may exist so that guideline-adherent care can be better advocated for and met.

Functional and Clinical Outcomes After Plate Osteosynthesis Versus Intramedullary Nailing of a Humeral Shaft Fracture: The Results of the HUMMER Multicenter, Prospective Cohort Study.

BACKGROUND: Plate osteosynthesis (referred to throughout as plating) and intramedullary nailing (referred to throughout as nailing) are the most common operative strategies for humeral shaft fractures. However, it is undecided which treatment is more effective. This study aimed to compare functional and clinical outcomes of these treatment strategies. We hypothesized that plating would result in an earlier recovery of shoulder function and fewer complications. METHODS: From October 23, 2012, to October 3, 2018, adults with a humeral shaft fracture, OTA/AO type 12A or 12B, were enrolled in a multicenter, prospective cohort study. Patients were treated with plating or nailing. Outcome measures included the Disabilities of the Arm, Shoulder and Hand (DASH) score, Constant-Murley score, ranges of motion of the shoulder and elbow, radiographic healing, and complications until 1 year. Repeated-measure analysis was done with correction for age, sex, and fracture type. RESULTS: Of the 245 included patients, 76 were treated with plating and 169 were treated with nailing. Patients in the plating group were younger, with a median age of 43 years compared with 57 years for the nailing group (p < 0.001). The mean DASH score after plating improved faster over time, but did not differ significantly from the score after nailing at 12 months (11.7 points [95% confidence interval (CI), 7.6 to 15.7 points]) for plating and 11.2 points [95% CI, 8.3 to 14.0 points] for nailing). The Constant-Murley score and shoulder abduction, flexion, external rotation, and internal rotation displayed a significant treatment effect (p treatment ≤ 0.001), in favor of plating. The plating group had 2 implant-related complications, whereas the nailing group had 24, including 13 nail protrusions and 8 screw protrusions. Plating resulted in more postoperative temporary radial nerve palsy (8 patients [10.5%] compared with 1 patient [0.6%]; p < 0.001) and a trend toward fewer nonunions (3 patients [5.7%] compared with 16 patients [11.9%]; p = 0.285) than nailing. CONCLUSIONS: Plating of a humeral shaft fracture in adults results in faster recovery, especially of shoulder function. Plating was associated with more temporary nerve palsies, but fewer implant-related complications and surgical reinterventions, than nailing. Despite heterogeneity in implants and surgical approach, plating seems to be the preferred treatment option for these fractures. LEVEL OF EVIDENCE: Therapeutic Level II . See Instructions for Authors for a complete description of levels of evidence.

Humeral shaft fracture: systematic review of non-operative and operative treatment.

INTRODUCTION: Humeral shaft fractures can be treated non-operatively or operatively. The optimal management is subject to debate. The aim was to compare non-operative and operative treatment of a humeral shaft fracture in terms of fracture healing, complications, and functional outcome. METHODS: Databases of Embase, Medline ALL, Web-of-Science Core Collection, and the Cochrane Central Register of Controlled Trials (CENTRAL) were systematically searched for publications reporting clinical and functional outcomes of humeral shaft fractures after non-operative treatment with a functional brace or operative treatment by intramedullary nailing (IMN; antegrade or retrograde) or plate osteosynthesis (open plating or minimally invasive). A pooled analysis of the results was performed using MedCalc. RESULTS: A total of 173 studies, describing 11,868 patients, were included. The fracture healing rate for the non-operative group was 89% (95% confidence interval (CI) 84-92%), 94% (95% CI 92-95%) for the IMN group and 96% (95% CI 95-97%) for the plating group. The rate of secondary radial nerve palsies was 1% in patients treated non-operatively, 3% in the IMN, and 6% in the plating group. Intraoperative complications and implant failures occurred more frequently in the IMN group than in the plating group. The DASH score was the lowest (7/100; 95% CI 1-13) in the minimally invasive plate osteosynthesis group. The Constant-Murley and UCLA shoulder score were the highest [93/100 (95% CI 92-95) and 33/35 (95% CI 32-33), respectively] in the plating group. CONCLUSION: This study suggests that even though all treatment modalities result in satisfactory outcomes, operative treatment is associated with the most favorable results. Disregarding secondary radial nerve palsy, specifically plate osteosynthesis seems to result in the highest fracture healing rates, least complications, and best functional outcomes compared with the other treatment modalities.

Economic evaluation of operative versus nonoperative treatment of a humeral shaft fracture: economic analyses alongside a multicenter prospective cohort study (HUMMER).

PURPOSE: Operative treatment of a humeral shaft fracture results in faster recovery than nonoperative treatment. The cost-effectiveness, in terms of costs per Quality-Adjusted Life Year (QALY) gained (Dutch threshold €20,000-€80,000) or minimal important change (MIC) in disability reduced (DASH 6.7), is unknown. The aim of this study was to determine cost-utility and cost-effectiveness of operative versus nonoperative treatment in adults with a humeral shaft fracture type 12A or 12B. METHODS: This study was performed alongside a multicenter prospective cohort study. Costs for health care and lost productivity until one year after trauma were calculated. The incremental cost-utility ratio (ICUR) was reported in costs per QALY (based on the EuroQoL-5D-3L (EQ-5D)) gained. The incremental cost-effectiveness ratio (ICER) was reported in costs per MIC (based on the DASH score at three months) reduced. RESULTS: Overall, 245 patients were treated operatively and 145 nonoperatively. In the operative group, the mean total costs per patient (€11,925 versus €8793; p < 0.001) and QALYs (0.806 versus 0.778; p < 0.001) were higher. The ICUR of operative treatment was €111,860 per QALY gained (i.e., €3132/0.028). The DASH was 7.3 points (p < 0.001) lower in the operative group. The ICER of operative treatment was €2880 per MIC in disability reduced (i.e., €3132/7.3*6.7). CONCLUSION: Due to the limited effect of treatment on quality of life measured with the EQ-5D, the ICUR of operative treatment (€111,860 per QALY gained) exceeds the threshold. However, the incremental costs of €2880 per clinically meaningful difference in DASH are much lower and suggest that operative treatment for a humeral shaft fracture is cost-effective.

A Phase I, Single Ascending Dose Study of GEM103 (Recombinant Human Complement Factor H) in Patients with Geographic Atrophy.

Purpose: To establish the safety, tolerability, pharmacokinetics, and pharmacodynamics of an intravitreal injection of recombinant human complement factor H (CFH), GEM103, in individuals with genetically defined age-related macular degeneration (AMD) and geographic atrophy (GA). Design: Phase I single ascending-dose, open-label clinical trial (ClinicalTrials.gov identifier, NCT04246866). Participants: Twelve individuals 50 years of age or older with a confirmed diagnosis of foveal GA in the study eye. Methods: Participants were assigned to the increasing dose cohorts and received 1 50-µl intravitreal injection of GEM103 at doses of 50 µg/eye, 100 µg/eye, 250 µg/eye, or 500 µg/eye; dose escalation was dependent on the occurrence of dose-limiting toxicities. Main Outcome Measures: Safety assessments included ocular and systemic adverse events (AEs), ocular examinations, clinical laboratory and vital signs, and serum antidrug antibody levels. Biomarkers, measured in the aqueous humor (AH), included CFH and complement activation biomarkers factor Ba and complement component 3a. Results: No dose-limiting toxicities were reported, enabling escalation to the maximum study dose. No anti-GEM103 antidrug antibodies were detected during the study. Four participants experienced AEs; these were nonserious, mild or moderate in severity, and unrelated to GEM103. The AEs in 2 of these participants were related to the intravitreal injection procedure. No clinically significant ophthalmic changes and no ocular inflammation were observed. Visual acuity was maintained and stable throughout the 8-week follow-up period. No choroidal neovascularization occurred. CFH levels increased in a dose-dependent manner after GEM103 administration with supraphysiological levels observed at week 1; levels were more than baseline for 8 weeks or more in all participants receiving single doses of 100 µg or more. Complement activation biomarkers were reduced 7 days after dose administration. Conclusions: A single intravitreal administration of GEM103 (up to 500 µg/eye) was well tolerated in individuals with GA. Of the few mild or moderate AEs reported, none were determined to be related to GEM103. No intraocular inflammation or choroidal neovascularization developed. CFH levels in AH were increased and stable for 8 weeks, with pharmacodynamic data suggesting that GEM103 restored complement regulation. These results support further development in a repeat-dose trial in patients with GA with AMD.

Prevalence and Determinants of Depression among Multi Drug Resistant (MDR) TB cases registered under National Tuberculosis Elimination Program in Ahmedabad City.

Background: Multidrug-resistant tuberculosis (MDR-TB) increases the risk of depression, lowers treatment compliance leading to poor outcomes. Objectives: To (1) document the prevalence of depression among MDR-TB cases registered at tuberculosis units (TUs) of Ahmedabad city and (2) assess determinants of depression. Methodology: Adult MDR-TB patients registered at all (23) TUs of Ahmedabad city, were studied using semi-structured questionnaire along with Gujarati translated version of the Hamilton Depression Rating Scale (HAM-D) to assess the severity of depression based on 17 items. The sample size at 95% level of significance, was 251. Probability proportional to size sampling was adopted for selecting participants from each of the 23 TUs. Proportions and odds ratio with confidence interval with probability value were calculated. Results: Of 251, only 185 (73.7%) cases could be contacted. Mortality proportion among selected cases was 18.7%. More than one-fifth (22%) had ≥1 comorbidity and 9.7% had another active TB case in the family. 161 (87.1) experienced ≥1 adverse event. Financial, social, or psychological stressors were reported by 22% of cases. Based on the HAM-D scale, 16.2% suffered from depression, determinants of depression by univariate analysis showed significant association with recent family issues, discrimination, financial/other troubling issues, and the presence of adverse drug event. Conclusion: MDR-TB cases are more vulnerable for developing depression as the prevalence was 16.2% among them. Hence, cases need to be monitored closely for depression at TU as well at community level.

Functional and clinical outcome after operative versus nonoperative treatment of a humeral shaft fracture (HUMMER): results of a multicenter prospective cohort study.

PURPOSE: The best treatment of humeral shaft fractures in adults is still under debate. This study aimed to compare functional and clinical outcome of operative versus nonoperative treatment in adult patients with a humeral shaft fracture. We hypothesized that operative treatment would result in earlier functional recovery. METHODS: From October 23, 2012 to October 03, 2018, adults with a humeral shaft fracture AO type 12A or 12B were enrolled in a prospective cohort study in 29 hospitals. Patients were treated operatively or nonoperatively. Outcome measures were the Disabilities of the Arm, Shoulder, and Hand score (DASH; primary outcome), Constant-Murley score, pain (Visual Analog Score, VAS), health-related quality of life (Short Form-36 (SF-36) and EuroQoL-5D-3L (EQ-5D)), activity resumption (Numeric Rating Scale, NRS), range of motion (ROM) of the shoulder and elbow joint, radiologic healing, and complications. Patients were followed for one year. Repeated measure analysis was done with correction for age, gender, and fracture type. RESULTS: Of the 390 included patients, 245 underwent osteosynthesis and 145 were primarily treated nonoperatively. Patients in the operative group were younger (median 53 versus 62 years; p < 0.001) and less frequently female (54.3% versus 64.8%; p = 0.044). Superior results in favor of the operative group were noted until six months follow-up for the DASH, Constant-Murley, abduction, anteflexion, and external rotation of the shoulder, and flexion and extension of the elbow. The EQ-US, and pronation and supination showed superior results for the operative group until six weeks follow-up. Malalignment occurred only in the nonoperative group (N = 14; 9.7%). In 19 patients with implant-related complications (N = 26; 10.6%) the implant was exchanged or removed. Nonunion occurred more often in the nonoperative group (26.3% versus 10.10% in the operative group; p < 0.001). CONCLUSION: Primary osteosynthesis of a humeral shaft fracture (AO type 12A and 12B) in adults is safe and superior to nonoperative treatment, and should therefore be the treatment of choice. It is associated with a more than twofold reduced risk of nonunion, earlier functional recovery and a better range of motion of the shoulder and elbow joint than nonoperative treatment. Even after including the implant-related complications, the overall rate of complications as well as secondary surgical interventions was highest in the nonoperative group. TRIAL REGISTRATION: NTR3617 (registration date 18-SEP-2012).

[Iatrogenic burns in neonates]. / Iatrogene brandwonden bij pasgeborenen.

BACKGROUND: Despite the availability of different medical tools to simplify blood withdrawal, an old-fashioned method is still frequently being used in neonatal infants: the use of warm elements such as a warm washcloth or a glove filled with warm water, wrapped around an extremity. Use of these warm elements may easily cause contact burns in neonates. Unfortunately, not seldom we see and treat neonates with these burn injuries. CASE DESCRIPTION: We present the case of a neonate, who was referred to our outpatient clinic with an iatrogenic contact burn. The patient received topical treatment and wound dressings for over a month time. Scars remained. CONCLUSION: We would like to raise awareness among care givers on this type of injuries. To prevent these iatrogenic burns injuries, we advise to use alternative methods to simplify blood withdrawal.

Functional Evaluation of Levator Scapulae Tendon to Supraspinatus in Adult Brachial Plexus Injuries.

Introduction Brachial plexus injuries are severe life-altering injuries. The surgical method to restore shoulder abduction in adult upper brachial plexus injuries involves the usage of nerve grafts and nerve transfers targeting the suprascapular and/or the axillary nerve. When the primary nerve surgery has been unsuccessful or recovery has been incomplete or with a late presentation, muscle transfer procedures are needed to provide or improve shoulder abduction. Levator scapulae to supraspinatus is a transfer to improve shoulder abduction in posttraumatic brachial plexus injuries. Material and Methods The study included 13 patients with the age ranging from 17 to 47 years with a mean age of 30 years. All these patients had preop shoulder abduction of Medical Research Council (MRC) grade ≤3. All had a minimum of MRC grade 4 of active elbow flexion. Eleven patients had primary surgery. Only patients with a minimum of 1 year postoperative follow-up were included. All 13 patients underwent levator scapulae transfer only. Results All patients had a stable shoulder postoperatively. The average increase in active shoulder abduction was from 6.15°(median: 0°) preoperatively to 61.92°(median: 60°), with an average gain in shoulder abduction of 49.61°(median: 50°). Conclusions Transfer of levator scapulae tendon to the supraspinatus is an option to improve shoulder abduction in posttraumatic brachial plexus. In conditions where supraspinatus alone is not functioning, levator scapulae is the best available transfer, considering its strength and maintaining the form of the shoulder unlike trapezius transfer. In patients with previous surgery where supraspinatus has recovered partially but not functionally significant, this tendon transfer can be considered for the augmentation of the existing shoulder abduction.

Characterization of Methyl and Ethyl Esters of Amino-Acids as Corneal Permeation Enhancers

@#Introduction: Amino acids are important role-playing components in the maintenance of the normal functions of parts of eye like retina and conjunctiva. In the current study the methyl and ethyl esters of amino acids such as lysine, phenyl alanine and valine were used to enhance the corneal permeation of ketorolac tromethamine. Methods: The amino-acid esters were coupled with the drug ketorolac tromethamine to obtain the test products and were characterized by various analytical techniques. The characterized test products were used to formulate the test ophthalmic solutions of Ketorolac tromethamine such as KPD-1, KPD-1A, KPD-2, KPD-2A, KPD-3 and KPD-3A with methyl and ethyl esters of corresponding amino-acids. These test products were subjected percentage corneal hydration and to permeation studies by using Franz diffusion cell mounted with freshly isolated goat cornea. Results: All the test results were compared with those of the standard Ketorolac tromethamine ophthalmic solution and observed that all the test solutions have exhibited less percentage corneal hydration and enhanced corneal permeation of ketorolac tromethamine. Conclusion: From all the results it can be concluded that the NonsteroidalAnti-Inflammatory Ketorolac has enhanced trans-corneal permeation and reduced corneal hydration when formulated with amino acid transporters by the pro-drug approach in ophthalmic solutions as the formulated pro-drugs have revealed high vitreal drug concentration.

Trichilemmal Carcinoma of Scalp Masquerading as Squamous Cell Carcinoma: A Report of a Rare Case with Histogenesis and Literature Review.

Trichilemmal carcinoma is a rare malignant adnexal neoplasm of follicular type usually seen over the sun-exposed areas of elderly people. We present a report of a 60-year-old male with ulceroproliferative lesion over the occipital region of the scalp for 2 months, clinically diagnosed as squamous cell carcinoma. A wide local excision was done, and histopathological examination showed atypical clear cells with abrupt keratinization. The histogenesis and other differential diagnoses are discussed.

[Frostbite due to recreational nitrous oxide use]. / Bevriezingswonden door recreatief lachgasgebruik.

BACKGROUND: There is a new type of injury that is observed increasingly often: frostbite of the thighs that has occurred as result of holding a cylinder containing nitrous oxide in position between the legs during recreational use of said substance. Because skin symptoms are often mild in the first few days after the event, the severity of the injury is often not recognized. However, patients can suffer serious scarring from this type of injury. CASE DESCRIPTION: We present two cases involving young patients who were referred to the burns unit with lesions sustained through nitrous oxide use. Upon inspection we observed deep frostbite wounds, which necessitated operative treatment. The patients had to undergo multiple operations and remained under our care for management of their scars. CONCLUSION: It is important to recognize this injury and to consult one of the burns units to treat these patients in a timeline and appropriate manner.

Rasch analysis of the Disabilities of the Arm, Shoulder and Hand (DASH) instrument in patients with a humeral shaft fracture.

BACKGROUND: The Disabilities of the Arm, Shoulder and Hand (DASH) instrument was developed to assess the disability experienced by patients with any musculoskeletal condition of the upper extremity and to monitor change in symptoms and upper-limb function over time. The 30 items are scored on a 5-point rating scale. The Dutch-language version of the DASH instrument (DASH-DLV) has been examined with the classical test theory in patients with a humeral shaft fracture. This study aimed to examine the DASH-DLV with a more rigorous and extensive analysis by applying the Rasch model. METHODS: Data of 400 patients included in a multicenter, prospective study comparing operative and nonoperative treatment of adult patients with a humeral shaft fracture were used. The person-item map, item fit statistics, reliability, response category ordering, and dimensionality were examined. Raw data were converted to linear measures using the Rasch model. RESULTS: The DASH-DLV showed a good fit to the Rasch model, except for item 26 ("Tingling [pins and needles] in your arm, shoulder or hand"). The person reliability was 0.92. In general, the category functioning of the 5-point rating scale was working well. Dimensionality analysis revealed that the DASH-DLV is a unidimensional scale. Differential item functioning for sex was not detected, and only item 26 exhibited differential item functioning as a function for age. CONCLUSION: The DASH-DLV fits the stringent Rasch model in a clinical situation with a group of adult patients with a humeral shaft fracture. Adequate measurement for scientific research can be obtained to evaluate longitudinal intervention research.

Ameloblastic Fibroma Mimicking Dentigerous Cyst: A Diagnostic Dilemma.

Ameloblastic fibroma is a rare, slow-growing odontogenic mixed tumor with neoplastic epithelial and ectomesenchymal tissue, which does not show inductive changes to form enamel and dentin. It is frequently found in the first two decades of life. It is often confused with ameloblastoma and dentigerous cyst due to the presence of an impacted tooth and can be distinguished histologically. Ameloblastic fibroma can be differentiated from ameloblastoma by the presence of myxoid appearance of connective tissue. A case of an 11-year-old female with a slow-growing swelling on the left side of mandible in the molar ramus region has been presented which was diagnosed as ameloblastic fibroma postenucleation.

Final results of the phase 1/2, open-label clinical study of intravenous recombinant human N-acetyl-α-d-glucosaminidase (SBC-103) in children with mucopolysaccharidosis IIIB.

Mucopolysaccharidosis IIIB is caused by a marked decrease in N-acetyl-α-d-glucosaminidase (NAGLU) enzyme activity, which leads to the accumulation of heparan sulfate in key organs, progressive brain atrophy, and neurocognitive decline. In this open-label study, 11 eligible patients aged 2 to <12 years (developmental age ≥ 1 year) were sequentially allocated to recombinant human NAGLU enzyme (SBC-103) in 3 staggered- and escalating-dose groups (0.3 mg/kg [n = 3], 1.0 mg/kg [n = 4], or 3.0 mg/kg [n = 4]) by intravenous infusion every 2 weeks for 24 weeks, followed by a 4-week interruption (Part A), treatment at 1.0 and/or 3.0 mg/kg every 2 weeks starting at week 28 (Part B), and treatment at 5.0 or 10.0 mg/kg every 2 weeks (Part C) for approximately 2 total years in the study. The primary objective of the study was safety and tolerability evaluation; secondary objectives included evaluation of SBC-103 effects on total heparan sulfate levels in cerebrospinal fluid (CSF), brain structural magnetic resonance imaging (cortical gray matter volume), and neurocognitive status (age equivalent/developmental quotient). During the study, 13 treatment-emergent serious adverse events (SAEs) occurred in 3 patients; 32 infusion-associated reactions (IARs) occurred in 8 patients. Most AEs were mild and intravenous treatment with SBC-103 was well tolerated. Mean (SD) changes from baseline at 52 weeks in Part C for the 5.0 and 10.0 mg/kg doses, respectively, were: -4.7% (8.3) and - 4.7% (14.7) for heparan sulfate levels in CSF, -8.1% (3.5) and - 10.3% (9.4) for cortical gray matter volume, +2.3 (6.9) points and +1.0 (9.2) points in cognitive age equivalent and -8.9 (10.2) points and -14.4 (9.2) points in developmental quotient. In summary, SBC-103 was generally well tolerated. Changes in heparan sulfate levels in CSF were small and were not maintained from earlier study time points, there was no clear evidence overall of clinically meaningful improvement in neurocognitive function at the higher doses investigated, and no dose-dependent effects were observed.

Noninvasive prenatal testing (NIPT) detects variant of Turner syndrome not detectable by fluorescent in situ hybridization.

Introduction: Noninvasive prenatal testing (NIPT) is a reliable screening method for fetal aneuploidy detection of trisomy 18, 13, 21 along with few sex chromosome abnormalities monosomy X, XXX, XXY (Klinefelter), XYY (Jacob) syndromes and certain microdeletions which include cri-du-chat, DiGeorge, 1p36, Angelman, and Prader-Willi syndromes in comparison to the available screening methods. Prenatal screening of Turners syndrome is possible by ultrasound in certain conditions only. Recently benefits of early detection and treatment of Turners syndrome has been emphasized, enforcing on accurate and early screening prenatally.Case details: The current case emphasizes on the reliability of NIPT testing which comes with an advantage of early screening. A 24-year-old primi gravida was referred for NIPT as she tested for high risk on biochemical screening. The Panorama™ NIPT results showed low risk for trisomies, 21, 18, and 13 but high risk of monosomy X and was advised confirmatory amniocentesis. The fluorescence in situ hybridization (FISH) report revealed no numerical abnormality detected for any of the five chromosomes tested. On receiving this discordant report, the sample was rerun for NIPT, to rule out any laboratory-related issues. The result obtained on a rerun was consistent with the first report and showed monosomy X again. The karyotype report was available three weeks later and a rare variant of Turners syndrome was identified.Discussion: Panorama™ NIPT considers single nucleotide polymorphisms spread across the chromosomes for analysis, different variants of aneuploidy can be picked up in comparison to FISH, similar to the current case wherein it could not as it was a centromeric probe. Reported first case of X chromosome variant detected by NIPT confirmed by karyotyping, missed by FISH.