CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.

The transmembrane domain recognition complex (TRC) pathway is required for the insertion of C-terminal tail-anchored (TA) proteins into the lipid bilayer of specific intracellular organelles such as the endoplasmic reticulum (ER) membrane. In order to facilitate correct insertion, the recognition complex (consisting of BAG6, GET4 and UBL4A) must first bind to TA proteins and then to GET3 (TRC40, ASNA1), which chaperones the protein to the ER membrane. Subsequently, GET1 (WRB) and CAML form a receptor that enables integration of the TA protein within the lipid bilayer. We report an individual with the homozygous c.633 + 4A>G splice variant in CAMLG, encoding CAML. This variant leads to aberrant splicing and lack of functional protein in patient-derived fibroblasts. The patient displays a predominantly neurological phenotype with psychomotor disability, hypotonia, epilepsy and structural brain abnormalities. Biochemically, a combined O-linked and type II N-linked glycosylation defect was found. Mislocalization of syntaxin-5 in patient fibroblasts and in siCAMLG deleted Hela cells confirms this as a consistent cellular marker of TRC dysfunction. Interestingly, the level of the v-SNARE Bet1L is also drastically reduced in both of these models, indicating a fundamental role of the TRC complex in the assembly of Golgi SNARE complexes. It also points towards a possible mechanism behind the hyposialylation of N and O-glycans. This is the first reported patient with pathogenic variants in CAMLG. CAMLG-CDG is the third disorder, after GET4 and GET3 deficiencies, caused by pathogenic variants in a member of the TRC pathway, further expanding this novel group of disorders.

Treatment of breast cancer with autophagy inhibitory microRNAs carried by AGO2-conjugated nanoparticles.

Nanoparticle based gene delivery systems holds great promise. Superparamagnetic iron oxide nanoparticles (SPIONs) are being heavily investigated due to good biocompatibility and added diagnostic potential, rendering such nanoparticles theranostic. Yet, commonly used cationic coatings for efficient delivery of such anionic cargos, results in significant toxicity limiting translation of the technology to the clinic. Here, we describe a highly biocompatible, small and non-cationic SPION-based theranostic nanoparticles as novel gene therapy agents. We propose for the first-time, the usage of the microRNA machinery RISC complex component Argonaute 2 (AGO2) protein as a microRNA stabilizing agent and a delivery vehicle. In this study, AGO2 protein-conjugated, anti-HER2 antibody-linked and fluorophore-tagged SPION nanoparticles were developed (SP-AH nanoparticles) and used as a carrier for an autophagy inhibitory microRNA, MIR376B. These functionalized nanoparticles selectively delivered an effective amount of the microRNA into HER2-positive breast cancer cell lines in vitro and in a xenograft nude mice model of breast cancer in vivo, and successfully blocked autophagy. Furthermore, combination of the chemotherapy agent cisplatin with MIR376B-loaded SP-AH nanoparticles increased the efficacy of the anti-cancer treatment both in vitro in cells and in vivo in the nude mice. Therefore, we propose that AGO2 protein conjugated SPIONs are a new class of theranostic nanoparticles and can be efficiently used as innovative, non-cationic, non-toxic gene therapy tools for targeted therapy of cancer.

Real-time ultrasound elastographic evaluation of extraocular muscle involvement in Graves' ophthalmopathy.

Purpose: To evaluate the affected extraocular muscles (EOMs) of patients with Graves' ophthalmopathy (GO) using real-time ultrasound elastography (UE) and to compare these results with those of healthy subjects.Methods: This prospective, comparative case series included 70 eyes of 35 patients with moderate-to-severe GO with type 2 orbitopathy (myogenic variant) according to their computed tomography (CT) scans. Forty-six eyes of 23 healthy subjects were evaluated as the control group. The strain ratio of orbital fat to medial rectus was calculated as the ratio of the medial rectus to orbital fat tissue, and the strain ratio of orbital fat to lateral rectus was calculated as the ratio of lateral rectus to orbital fat tissue.Results: The strain ratio of orbital fat to medial rectus was 3.03 ± 1.25 (range: 1.05-5.07) in the GO group, and 0.54 ± 0.20 (range: 0.14-1.08) in the control group (p = .0001). The strain ratio of orbital fat to lateral rectus was 0.97 ± 0.29 (range: 0.56-1.55) in the GO group, and 0.63 ± 0.23 (range: 0.18-1.09) in the control group (p = .0001).Conclusion: By using real-time UE, we found the medial and the lateral recti of GO patients to be stiffer compared to those of healthy subjects.

A Very Rare Etiology of Hypotonia and Seizures: Congenital Glutamine Synthetase Deficiency.

Mutations in the human GLUL gene, which encodes the enzyme glutamine synthetase (GS), may cause congenital glutamine synthetase deficiency. The disease was first described in 2005 and only three patients have been reported to date. We report a fourth patient suffering from congenital GS deficiency who was found to have some distinctive clinical findings. The patient was a 30-month-old girl who was referred to us due to developmental delay and seizures which began at 5 months of age. She was seizure free for 5 months with valproic acid and vigabatrin. At presentation, she was found to have microcephaly and hypotonia. Her plasma glutamine concentration was near normal and she had mild hyperammonemia. Cranial magnetic resonance imaging (MRI) showed mild changes. Whole exome sequencing (WES) revealed a homozygous c.121C > T (p.R41C) (p.Arg41Cys) pathogenic variant of the GLUL gene. The diagnosis of this patient underlines the importance of careful evaluation of patients with borderline low glutamine levels. Treatment was begun with L-glutamine and nicotinamide and biochemical improvements have been observed at 6 months of follow-up. The outcome of this patient may provide important data about the effectiveness of glutamine and nicotinamide treatment in patients with congenital GS deficiency.

Color Doppler imaging of ocular hemodynamic changes in patients with rheumatoid arthritis unrelated to disease activity.

We aimed to investigate how orbital blood flow rates in patients with rheumatoid arthritis (RA) are affected by the active and remission phase of the disease. This prospective study included a total of 56 patients with RA (study group) and 24 control individuals (control group). All RA patients were divided into two groups, as active (Group 1) and remission (Group 2) according to the disease activity index (DAS 28) score. For each eye, retrobulbar vascular structures were evaluated [central retinal artery (CRA), posterior ciliary artery (PCA), and ophthalmic artery (OA)], respectively. The peak systolic velocity (PSV) and end-diastolic velocity (EDV) values were obtained for each artery and the vascular resistance index (RI) measurement was calculated. The median RI of the OA was 0.70 (0.57; 0.79) in the control group, 0.77 (0.55; 0.87) in group 1, and 0.73 (0.47; 0.87) in group 2. The median RI in the PCA was 0.70 (0.56; 0.82) in the control group, 0.76 (0.52; 0.88) in the group 1, and 0.74 (0.52; 0.86) in the group 2. The median RI of CRA was 0.73 (0.48; 0.81) in the control group, 0.71 (0.64; 0.81) in group 1, and 0.68 (0.61; 0.85) in group 2. The RI value was a significant difference between control and group 1 (p < 0.05). Active and remission RA patients had different effects on the flow rate of eye blood vessels.

An assessment of ocular elasticity using real time ultrasound and ocular response analyzer in active or remission rheumatoid arthritis.

PURPOSE: To investigate the elasticity of ocular structures in patients with rheumatoid arthritis (RA) without ocular involvement. METHODS: The study included 56 RA patients (study group) and 24 healthy volunteers as the control group. The rheumatoid arthritis patients were divided into two subgroups as those in active phase (Group 1, n = 25) or in remission phase (Group 2, n = 31) according to the disease activity index (DAS 28) score. The elastography values of the ratio of orbital fat-sclera (ROF/S) were measured with real-time US elastography, and corneal mechanical values were measured with the Reichert Ocular Response Analyzer in each eye. RESULTS: The mean ROF/S value was 5.2 ± 1.8 in Group 1, 0.7 ± 0.4 Group 2, and 0.6 ± 0.1 in the control group. There was a significant difference between the Group 1 and control group with regard to ROF/S (p < 0.001), but no significant difference was determined between Group 2 and control group (p > 0.05). The mean ROF/S value was a significant difference between the Group 1 and 2 (p < 0.001). ROF/S was significantly correlated with DAS-28 and C-reactive protein (CRP) (r = 0.816, p < 0.001 and r = 0.259, p = 0.006). CONCLUSIONS: ROF/S was significantly increased in patients in the active phase of RA. Findings revealed that ocular tissue structural changes may occur in the active phase and these could be related to ocular complications as a prognostic factor.

Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.

OBJECTIVE: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. METHODS: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. RESULTS: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. INTERPRETATION: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.

Optic Nerve Head Elastometry in Both Eyes of Patients with Unilateral Non-arteritic Anterior Ischaemic Optic Neuropathy - May It Be a Novel Aspect of the Pathogenesis?

In this prospective study, the biomechanical properties of optic nerve head (ONH) and cornea in both eyes of patients with non-arteritic anterior ischaemic optic neuropathy and healthy control eyes were investigated. ONH elastometry was measured with real-time elastography, and corneal elastometry was measured with ocular response analyser. Elastometry of cornea and ONH was lower in both eyes of patients with unilateral non-arteritic ischaemic optic neuropathy than in healthy control eyes. The role of these biomechanical differences in the pathogenesis of non-arteritic ischaemic optic neuropathy should be investigated further.

Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency.

BACKGROUND: Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiology. METHODS: Clinical data were retrieved retrospectively from physicians using a questionnaire survey. Plasma aminoacids, guanidinoacetate (GAA), parameters indicating oxidative stress and nitric oxide (NO) synthesis as well as asymmetric dimethylarginine (ADMA) were measured at a single study site. RESULTS: Nineteen individuals with ARG1 deficiency and 19 matched controls were included in the study. In patients, paraparesis, cognitive impairment, and seizures were significantly associated suggesting a shared underlying pathophysiology. In patients plasma GAA exceeded normal ranges and plasma ADMA was significantly elevated. Compared to controls, nitrate was significantly higher, and the nitrite:nitrate ratio significantly lower in subjects with ARG1 deficiency suggesting an advantage for NO synthesis by inducible NO synthase (iNOS) over endothelial NOS (eNOS). Logistic regression revealed no significant impact of any of the biochemical parameters (including arginine, nitrates, ADMA, GAA, oxidative stress) or protein restriction on long-term outcome. CONCLUSION: Three main hypotheses which must be evaluated in a hypothesis driven confirmatory study are delineated from this study: 1) clinical manifestations in ARG1 deficiency are not correlated with arginine, protein intake, ADMA, nitrates or oxidative stress. 2) GAA is elevated and may be a marker or an active part of the pathophysiology of ARG1 deficiency. 3) Perturbations of NO metabolism merit future attention in ARG1 deficiency.

Foetal biometry in polyhydramnios: Does femur length fall behind?

We aimed to identify the growth patterns in polyhydramnios, and therefore evaluated 108 singleton pregnancies complicated with polyhydramnios according to the changes in biparietal diameter (BPD), abdominal circumference (AC) and femur length (FL) percentiles. The pregnancy outcomes according to the growth features were analysed. In the study population, BPD and AC percentiles exhibited a significant increase (p = 0.023 and 0.05, respectively), although FL percentiles showed a significant decrease (p = 0.006) according to the changes in third trimester relative to second trimester. In the overgrown group (n = 52), the FL/BPD ratio was lower (p < 0.001), with more foetuses with FL/BPD ratios below 71 (p = 0.05). In conclusion, there was a significant increase in BPD and AC percentiles and a decrease in FL percentiles in third trimester relative to second trimester in foetuses with polyhydramnios. However, we observed a shorter FL and a lower FL/BPD ratio without associated skeletal dysplasia in overgrown foetuses.

Renal Cell Carcinoma Metastasis to Ipsilateral Parotid and Submandibular Glands: Report of a Case with Sonoelastographic Findings.

BACKGROUND: Renal cell carcinoma (RCC) - also known as hypernephroma or grawitz tumor - accounts for 3% of the adulthood malignancies. Approximately 30-40% of the patients have metastasis at the time of the diagnosis and most common sites for metastasis are lung, regional lymph nodes, bone and liver. A total of 8-14% of the patients with RCC has head and neck metastasis. However, metastasis to major salivary glands is rarely seen. In this paper, we aimed to report a RCC case with metastasis to parotid and submandibular glands that has the same sonographic and sonoelastographic findings with the primary tumor. CASE REPORT: 66-year old woman with RCC history was referred to our radiology department for neck ultrasound (US) with painful swelling in the right parotid gland region. A well-defined, 37×21 mm sized hypoechoic heterogeneous solid mass was detected in the superficial-deep lobe of the right parotid gland. The mass was prominently hypervascular in color Doppler ultrasonography scan. Coincidentally, a 13×13 mm hypoechoic lobulated solid mass was detected in the right submandibular gland with similar sonographic findings. Real-time sonoelastography (SEL) was performed to the masses and both of them were blue-green colored that indicates hard tissue. An US and SEL evaluation was also performed to the renal mass (RCC) of the patient. The primary mass was also similar in sonographic and SEL appearance as salivary gland masses. In the patient history, she revealed chemotherapy-radiotherapy treatment 1.5 years ago due to inoperable mass in the mid-lower pole of the left kidney diagnosed as clear cell RCC with vascular invasion, liver, lung and brain metastasis. Because of known primary tumor, the masses in the salivary glands were suspected to be metastatic and a tru-cut biopsy was performed. Pathological result was reported as clear cell RCC metastasis. CONCLUSIONS: The etiology of RCC is still unknown and metastatic involvement can be seen at unexpected tissue and organs. Metastatic disease should be considered when a salivary gland mass detected in patients with RCC history. SEL examination would be helpful in differentiation of the origin of the metastatic lesion with known SEL features.

Strain ratio measurement of femoral cartilage by real-time elastosonography: preliminary results.

OBJECTIVE: The purpose of this study was to evaluate strain ratio measurement of femoral cartilage using real-time elastosonography. METHODS: Twenty-five patients with femoral cartilage pathology on MRI (study group) were prospectively compared with 25 subjects with normal findings on MRI (control group) using real-time elastosonography. Strain ratio measurements of pathologic and normal cartilage were performed and compared, both within the study group and between the two groups. RESULTS: Elastosonography colour-scale coding showed a colour change from blue to red in pathologic cartilage and only blue colour-coding in normal cartilage. In the study group, the median strain ratio was higher in pathologic cartilage areas compared to normal areas (median, 1.49 [interquartile range, 0.80-2.53] vs. median, 0.01 [interquartile range, 0.01-0.01], p < 0.001, respectively). The median strain ratio of the control group was 0.01 (interquartile range, 0.01-0.01), and there was no significant difference compared to normal areas of the study group. There was, however, a significant difference between the control group cartilage and pathologic cartilage of the study group (p < 0.001). CONCLUSIONS: Elastosonography may be an effective, easily accessible, and relatively simple tool to demonstrate pathologic cartilage and to differentiate it from normal cartilage in the absence of advanced imaging facility such as MRI. KEY POINTS: • Elastosonography uses colour-maps and strain ratios for evaluating tissue deformability. • Colour change from blue to red and increased strain ratio represent softening. • Normal cartilage shows decreased compressibility, represented by blue colour and low strain ratio. • Pathologic cartilage shows increased compressibility, represented by red colour and high strain ratio. • Elastosonography may be used for differentiating pathologic cartilage from normal cartilage.

Detection of biotinidase gene mutations in Turkish patients ascertained by newborn and family screening.

UNLABELLED: The incidence of biotinidase deficiency in Turkey is currently one of the highest in the world. To expand upon the information about the biotinidase gene (BTD) variations in Turkish patients, we conducted a mutation screening in a large series (n = 210) of probands with biotinidase deficiency, using denaturing high-performance liquid chromatography and direct DNA sequencing. The putative effects of novel mutations were predicted by computational program. Twenty-six mutations, including six novels (p.C143F, p.T244I, c.1212-1222del11, c.1320delG, p.V457L, p.G480R) were identified. Nine of the patients were symptomatic at the initial clinical assessment with presentations of seizures, encephalopathy, and lactic acidemia. The most common mutation in this group of symptomatic patients was c.98-104 del7ins3. Among the screened patients, 72 have partial and 134 have profound biotinidase deficiency (BD) of which 106 are homozygous for BTD mutations. The common mutations (p.R157H, p.D444H, c.98-104del7ins3, p.T532M) cumulatively accounted for 72.3% of all the mutant alleles in the Turkish population. CONCLUSION: The identification of common mutations and hot spot regions of the BTD gene in Turkish patients is important for mutation screening in the Turkish population and helps to ascertain carriers, may have impact on genetic counseling and implementing prevention programs.

Transabdominal Sonographic Study of the Cavum Vergae Detection Rate in Healthy Third-Trimester Fetuses.

OBJECTIVES: We aimed to measure the thickness and volume of the cavum vergae by sonography in fetuses at gestational ages of 25 to 41 weeks to determine the relationship of cavum vergae thickness and volume with gestational age and biparietal diameter and to estimate the rate of cavum vergae closure in relation to gestational age. METHODS: A total of 336 patients in their third trimester of pregnancy had transabdominal sonography. The fetal cavum vergae was scanned in the coronal and axial planes. The thickness of the anteroposterior diameter of the cavum vergae and the largest inner surface were measured after marking the internal borders of the structure, and then longitudinal and vertical sizes were obtained. The values obtained were multiplied by each other and then by 0.52 to obtain the cavum vergae volume. RESULTS: In 55 of 322 cases, the cavum vergae volume and thickness could not be calculated because the cavum vergae was closed. In the remaining cases, the cavum vergae volume and thickness and biparietal diameter were measured. Although the degree of correlation between cavum vergae thickness and volume increased with increasing gestational age, there was no correlation between cavum vergae thickness and volume at 37 to 41 weeks. There was a positive but weak statistically significant correlation between biparietal diameter and cavum vergae volume (P= .05), but there was no statistically significant correlation between biparietal diameter and cavum vergae thickness. The cavum vergae closure rate increased significantly as gestational age increased (P < .001). CONCLUSIONS: Cavum vergae closure increases as gestational age increases. However, we did not find any relationships between cavum vergae thickness and volume, gestational age, and biparietal diameter.

Choroid plexus separation in fetuses without ventriculomegaly: Natural course and postnatal outcome.

PURPOSE: To evaluate fetuses with choroid plexus separation without ventriculomegaly in terms of fetal malformations, behavior of the separation during follow-up, and postnatal outcome. METHODS: In total, 172 fetuses with choroid plexus separation without ventriculomegaly were included in this prospective study. Fetal sonography was performed at 2- to 4-week intervals, and detailed physical and neurologic examinations were performed after their delivery. Fetuses were categorized into normal and abnormal subgroups according to the outcome. RESULTS: Sixteen fetuses (9.3%) were included in the abnormal-outcome group and 156 fetuses (90.7%) were included in the normal-outcome group. Both the initial mean lateral ventricular diameter (9.3 mm versus 8.6 mm) and the initial mean choroid plexus separation (4.8 mm versus 3.3 mm) were greater in the abnormal group than in the normal group (p < 0.001 for both comparisons). We found that 4.0 mm was the best cutoff point of choroid plexus separation to detect a major anomaly, with 87.5% sensitivity and 93.6% specificity. CONCLUSIONS: Choroid plexus separation without ventriculomegaly often resolves within the third trimester and does not affect postnatal outcome. It can be associated with various fetal malformations; however, with a comprehensive examination, all fetal malformations can be detected prenatally. Follow-up sonography studies would be useful, especially in the case of suspected corpus callosum agenesis.

Depression and anxiety among parents of phenylketonuria children.

OBJECTIVE: To investigate the existence of depression and/or anxiety with underlying risk factors among parents of children with classical phenylketonuria (PKU). METHODS: This cross-sectional study was conducted in the Division of Pediatric Metabolism, Ankara Children`s Hospital, Dokuz Eylul University, Kirikkale University, and Erzurum Local Research Hospital, Turkey, between January and July 2014. Parents of 61 patients and 36 healthy controls completed the self-report questionnaires. We used Beck Depression Inventory (BDI) to assess the parental depression and State-Trait Anxiety Inventory S-T (STAI S-T) to assess parental anxiety. RESULTS: Depression and anxiety scores were significantly higher in the case group (BDI: 12.3 ± 9.1; STAI-S: 38.2 ± 9.6; STAI-T: 43.2 ± 6.9) than controls (BDI: 5.4 ± 4.1 p=0.000; STAI-S: 31.8 ± 7.6 p=0.001; STAI-T: 37.0 ± 7.2 p=0.000). Mothers of the patients had higher scores than the other parental groups (BDI: p=0.000, STAI-S: p=0.001 and STAI-T: p=0.000). Logistic regression analysis showed that low educational level of the parent was the only independent factor for depression (OR: 9.96, 95% CI: 1.89-52.35, p=0.007) and state anxiety (OR: 6.99, 95% CI: 1.22-40.48, p=0.030) in the case group. CONCLUSION: A subset of parents with PKU patients have an anxiety or depressive disorder. Supportive services dealing with the parents of chronically ill children such as PKU are needed in order to reduce the level of anxiety.

Recurrence of carbamoyl phosphate synthetase 1 (CPS1) deficiency in Turkish patients: characterization of a founder mutation by use of recombinant CPS1 from insect cells expression.

Carbamoyl phosphate synthetase 1 (CPS1) deficiency due to CPS1 mutations is a rare autosomal-recessive urea cycle disorder causing hyperammonemia that can lead to death or severe neurological impairment. CPS1 catalyzes carbamoyl phosphate formation from ammonia, bicarbonate and two molecules of ATP, and requires the allosteric activator N-acetyl-L-glutamate. Clinical mutations occur in the entire CPS1 coding region, but mainly in single families, with little recurrence. We characterized here the only currently known recurrent CPS1 mutation, p.Val1013del, found in eleven unrelated patients of Turkish descent using recombinant His-tagged wild type or mutant CPS1 expressed in baculovirus/insect cell system. The global CPS1 reaction and the ATPase and ATP synthesis partial reactions that reflect, respectively, the bicarbonate and the carbamate phosphorylation steps, were assayed. We found that CPS1 wild type and V1013del mutant showed comparable expression levels and purity but the mutant CPS1 exhibited no significant residual activities. In the CPS1 structural model, V1013 belongs to a highly hydrophobic ß-strand at the middle of the central ß-sheet of the A subdomain of the carbamate phosphorylation domain and is close to the predicted carbamate tunnel that links both phosphorylation sites. Haplotype studies suggested that p.Val1013del is a founder mutation. In conclusion, the mutation p.V1013del inactivates CPS1 but does not render the enzyme grossly unstable or insoluble. Recurrence of this particular mutation in Turkish patients is likely due to a founder effect, which is consistent with the frequent consanguinity observed in the affected population.

Early effects of inactivated (CoronaVac) SARS-CoV-2 vaccine on retrobulbar vascular blood flow and retinal vascular density.

AIMS: We aimed to investigate the early effects of inactivated SARS-CoV-2 vaccine on retrobulbar vascular blood flow and retinal vascular density in healthy subjects. METHODS: Thirty-four eyes of 34 healthy volunteers who received the CoronaVac (Sinovac Life Sciences, China) were included in this prospective study. Resistive index (RI), pulsatility index (PI) and peak systolic velocity (PSV) of the ophthalmic artery (OA), central retinal artery (CRA), and the temporal and nasal posterior ciliary arteries (PCA) were evaluated with color Doppler ultrasonography (CDUS) before vaccination, at the 2nd and 4th weeks after vaccination. Superficial capillary plexus (SCP) and deep capillary plexus (DCP) vessel density (VD), foveal avascular zone (FAZ), and choriocapillaris blood flow (CCF) measurements were made using optical coherence tomography angiography (OCTA). RESULTS: When compared to the pre-vaccination values, there was no significant change in OA-PSV, temporal-nasal PCA-PSV, CRA-EDV, temporal-nasal PCA-EDV at 2nd and 4th weeks after vaccination. However statistically significant reductions were found in the OA-RI, OA-PI, CRA-RI, CRA-PI, temporal-nasal PCA-RI, temporal-nasal PCA-PI values, CRA-PSV at post-vaccination 2nd week (p<0.05 for all). While there was sustained reduction in OA-RI, OA-PI, CRA-PSV, and nasal PCA-RI values at 4th week after vaccination, the change in CRA-RI, CRA-PI, temporal PCA-RI, temporal-nasal PCA-PI values were not significant compared to pre-vaccination values. There was no statistically significant difference in the SCP-VD, DCP-VD, FAZ and CCF measurements. CONCLUSIONS: Our findings demonstrating that CoronaVac vaccine did not affect retinal vascular density in the early period, but it caused alterations in the retrobulbar blood flow.

Immunosuppressive Medication Adherence in Patients With Hepatocellular Cancer Who Have Undergo Liver Transplantation: A Case Control Study.

BACKGROUND: We aimed to compare the adherence to immunosuppressive medication use in patients who underwent liver transplantation (LT) due to hepatocellular carcinoma (HCC) and non-HCC reasons. METHODS: The study population was determined as 242 patients with HCC and 1290 patients with non-HCC who had LT performed in our institute between March 2002 and November 2021; all these patients were contacted by phone in March 2022. The sample size was calculated using the MedCalc software program, and the number of patients required in each group was determined as 111 patients. Furthermore, we used the sample.int function, a random integer generator in the R (version 4.1.2) software program. Whereas demographic and clinical parameters were determined as independent variables, the immunosuppressive medication adherence scale (IMAS) score was determined as a dependent variable. Patients were evaluated by the IMAS. This 11-item IMAS scale evaluates the lowest compliance score as 11 and the highest as 55. RESULTS: Out of a total number of 221 patients, 161 (72%) were men and 60 (27.1%) were women, with a median age of 58 years (IQR: 14); one patient in the non-HCC group was excluded due to lack of data. Among the HCC and non-HCC groups, significant differences were found in terms of the variables of age (P = .003), IMAS score (P < .001), sex (P = .001), working status (P = .004), chronic diseases (P = .008), tacrolimus alone (P < .001), tacrolimus plus everolimus (P < .001), and often medication changes (P < .001). A statistically significant correlation was found between the IMAS score and whether the patients had HCC (P < .001) and frequently changing immunosuppressive drugs (P = .023). CONCLUSION: This study showed that patients with frequent drug changes or non-HCC etiology had better adherence to immunosuppressive drug use.

Detection of other inborn errors of metabolism in hyperphenylalaninemic babies picked up on narrow-spectrum screening programs.

In many countries, neonatal screening programs have been unable to expand and have been limited to a few diseases. We highlight herein the opportunity available for the early detection of some inborn errors of metabolism (IEMs) in those countries in which newborn screening programs are limited. All the newborns that are referred to us for hyperphenylalaninemia are examined physically and their blood samples are checked by both high-performance liquid chromatography (HPLC) for blood phenylalanine levels and by amino acid analyzer for the measurement of blood amino acid concentrations. Seven patients who had been referred to our unit for hyperphenylalaninemia were eventually diagnosed with another IEM. A careful physical examination of the babies sent for positive screening test result combined with the utilization of low expense screening techniques at the experienced referring centers might facilitate otherwise missed opportunities for the early detection of some IEMs.