Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype.

OBJECTIVE: Mitochondrial complex-I deficiency, nuclear type 16, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) (OMIM 618238). The aim of this study was to describe a severe early prenatal manifestation of this disorder, which was previously considered to occur only postnatally. METHODS: This was a multicenter retrospective case series including five fetuses from three non-related families, which shared common sonographic abnormalities, including brain cysts, corpus callosal malformations, non-immune hydrops fetalis and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from the same family were also available for pathology examination, including electron microscopy. RESULTS: Chromosomal microarray analysis revealed no chromosomal abnormality in any of the tested cases. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygous or homozygous for likely pathogenic variants in NDUFAF5. No other causative variants were detected. The association between NDUFAF5 variants and fetal malformations was further confirmed by segregation analysis. Histological evaluation of fetal tissues and electron microscopy of the skeletal muscle, liver, proximal tubules and heart demonstrated changes that resembled postmortem findings in patients with mitochondrial depletion disorders as well as previously undescribed findings. CONCLUSIONS: Mitochondrial complex-I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development, presenting with severe congenital malformations. Mitochondrial complex-I disorders should be considered in the differential diagnosis of corpus callosal malformations and brain cysts, especially when associated with extracranial abnormalities, such as fetal growth restriction and non-immune hydrops fetalis. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Clinical utility of expanded non-invasive prenatal screening compared with chromosomal microarray analysis in over 8000 pregnancies without major structural anomaly.

OBJECTIVES: To evaluate the theoretical added value of two types of non-invasive prenatal screening (NIPS) expansions in pregnancies without major structural anomalies over the commonly used NIPS for chromosomes 13, 18, 21, X and Y (5-NIPS) and to compare them with the added value of chromosomal microarray analysis (CMA). METHODS: This was a retrospective cohort study based on CMA results of all pregnancies with normal ultrasound (including pregnancies with soft markers and with abnormal maternal serum screening) that had undergone amniocentesis between January 2013 to February 2022 and were registered in the database of the Rabin Medical Center genetic laboratory. We calculated the theoretical yield of 5-NIPS and compared the added value of expanded 5-NIPS for common microdeletions (1p36.3-1p36.2, 4p16.3-4p16.2, 5p15.3-5p15.1, 15q11.2-15q13.1 and 22q11.2) and genome-wide NIPS (including variants > 5 Mb) with the added value of CMA in the overall cohort and in subgroups according to indication for invasive testing. RESULTS: Among the 8605 examined pregnancies, 122 (1.4%) clinically significant CMA results were demonstrated. Of these, 44 (36.1%) were theoretically detectable on 5-NIPS, with the rates of 1.56% in 642 pregnancies with abnormal maternal serum screening, 0.63% in 318 pregnancies with soft markers, 0.62% in 4378 women with advanced maternal age (≥ 35 years) and 0.15% in 3267 women younger than 35 years. In addition to aneuploidies detectable on 5-NIPS, three (0.03%) cases detectable on 5-NIPS expanded for common microdeletions and nine (0.10%) cases detectable on genome-wide NIPS (excluding common microdeletions) were identified in the overall cohort. The added value of expanded NIPS tools over 5-NIPS was significantly lower compared with that of CMA, for the overall cohort and subgroups. CONCLUSIONS: 5-NIPS and even genome-wide NIPS would miss 63.9% and 54.1% of clinically significant CMA findings, respectively. The added value of 5-NIPS expanded to detect common microdeletions over 5-NIPS is about 0.035%, and the overall added value of genome-wide NIPS aimed at large CNVs is about 0.14%, both much lower compared with the added value of CMA (0.91%). These findings should assist healthcare practitioners in guiding couples towards informed decision-making regarding the choice between prenatal invasive testing and NIPS. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Analysis of autofluorescence pattern in birdshot chorioretinopathy.

PURPOSE: To characterize and correlate the different patterns of fundus autofluorescence (FAF) in patients with birdshot chorioretinopathy (BSCR), with functional and anatomical parameters. METHODS: Twenty-one BSCR patients were prospectively studied in 2013 and 2014. Each patient underwent visual acuity (VA) and visual field (SITA standard 30.2) testing as well as fluorescein and indocyanine green angiography, spectral-domain optical coherence tomography (SD-OCT) B scan, enhanced depth imaging (EDI), and fundus autofluorescence (FAF) imaging. The disease was classified as active, chronic, or quiescent. RESULTS: The patients' mean age was 60.3 ± 9.2 years and 60% were female. Disease duration was 5.7 ± 3.7 years. Autofluorescence imaging showed punctiform hyper-FAF spots in 23 out of the 29 eyes (79%), which was significantly associated with a greater visual field mean deviation (-7 ± 7 versus -3 ± 2 dB, p = 0.04). Hypo-FAF was defined as peripapillary (n = 25; 86.2%), macular (n = 10; 34.5%), lichenoid (n = 17; 58.6%), and/or diffuse (n = 13; 44.8%). Lichenoid hypo-FAF was significantly associated with worse VA (0.18 ± 0.24 vs. 0.05 ± 0.07 LogMAR, p = 0.04). Macular hypo-FAF was associated with a history of macular edema (62.5%; p = 0.06). Diffuse hypo-FAF was observed more frequently (p = 0.01) in chronic disease (66.7%) than in active (0%) or quiescent disease (27.3%). CONCLUSIONS: Autofluorescence analysis in BRSC patients contributes to evaluating disease activity and could be useful to guide follow-up and treatment.

A novel founder MSH2 deletion in Ethiopian Jews is mainly associated with early-onset colorectal cancer.

Lynch syndrome is an inherited cancer predisposition syndrome caused by germline defects in any of the mismatch repair (MMR) genes. Diagnosis of carriers makes precision prevention, early detection, and tailored treatment possible. Herein we report a novel founder deletion of 18,758 bp, mediated by Alu repeats on both sides, detected in Ethiopian Jews. The deletion, which encompasses exon 9-10 of the MSH2 coding sequence, is associated mainly with early-onset MSH2/MSH6-deficient colorectal cancer (CRC) and liposarcoma. Testing of 35 members of 5 seemingly unrelated families of Ethiopian origin yielded 10/21 (48%) carriers, of whom 9 had CRC. Age at first tumor diagnosis ranged from 16 to 89 years. Carriers from the oldest generations were diagnosed after age 45 years (mean 57), and carriers from the younger generation were diagnosed before age 45 years (mean 30). Awareness of this founder deletion is important to improve patient diagnosis, institute surveillance from an early age, and refer patients for genetic counseling addressing the risk of bi-allelic constitutional MMR deficiency syndrome.

Women's responses and understanding of polygenic breast cancer risk information.

It is estimated that polygenic factors can explain up to 18% of familial breast cancer. Clinical implementation of polygenic testing has begun, with several commercial laboratories now testing. Despite commercial implementation, there is little research investigating how women respond and understand polygenic risk information. This study aimed to explore women's experience receiving their personalised polygenic risk score (PRS) and compare responses of women at different levels of polygenic risk. Eligible participants were affected and unaffected women from families clinically assessed to be at high risk for breast cancer who had received their personalised PRS as part of the Variants in Practice Psychosocial Study (ViPPs). In-depth semi-structured interviews were conducted with 21 women (mean age 53.4 years) up to four weeks after receiving their PRS. Interviews were transcribed verbatim and analysed using thematic analysis. Eleven women received a PRS that was in the top quartile of PRS distribution and 10 in the lowest quartile. Women's lived experience with breast cancer informed how they responded to their PRS, constructed and made sense of breast cancer risk following receipt of their PRS, and integrated this new information into their breast cancer risk management. Regardless of polygenic risk level, all participants demonstrated broad knowledge of concepts related to polygenic information and were able to accurately describe the implications of their PRS. Receiving PRS did not appear to negatively impact women's reported distress levels. Our findings suggest polygenic breast cancer information is well received and understood by women at high-risk for breast cancer.

Novel WWOX deleterious variants cause early infantile epileptic encephalopathy, severe developmental delay and dysmorphism among Yemenite Jews.

The human WW Domain Containing Oxidoreductase (WWOX) gene was originally described as a tumor suppressor gene. However, recent reports have demonstrated its cardinal role in the pathogenesis of central nervous systems disorders such as epileptic encephalopathy, intellectual disability, and spinocerebellar ataxia. We report on six patients from three unrelated families of full or partial Yemenite Jewish ancestry exhibiting early infantile epileptic encephalopathy and profound developmental delay. Importantly, four patients demonstrated facial dysmorphism. Exome sequencing revealed that four of the patients were homozygous for a novel WWOX c.517-2A > G splice-site variant and two were compound heterozygous for this variant and a novel c.689A > C, p.Gln230Pro missense variant. Complementary DNA sequencing demonstrated that the WWOX c.517-2A > G splice-site variant causes skipping of exon six. A carrier rate of 1:177 was found among Yemenite Jews. We provide the first detailed description of patients harboring a splice-site variant in the WWOX gene and propose that the clinical synopsis of WWOX related epileptic encephalopathy should be broadened to include facial dysmorphism. The increased frequency of the c.517-2A > G splice-site variant among Yemenite Jews coupled with the severity of the phenotype makes it a candidate for inclusion in expanded preconception screening programs.

The long-term clinical and radiological outcomes in patients who suffer recurrent injuries to the anterior cruciate ligament after reconstruction.

AIMS: The aim of this study was to investigate the long-term clinical and radiological outcome of patients who suffer recurrent injuries to the anterior cruciate ligament (ACL) after reconstruction and require revision surgery. PATIENTS AND METHODS: From a consecutive series of 200 patients who underwent primary reconstruction following rupture of the ACL, we identified 36 who sustained a further rupture, 29 of whom underwent revision surgery. Patients were reviewed prospectively at one, two, seven, 15 and about 20 years after their original surgery. Primary outcome measures were the number of further ruptures, the posterior tibial slope (PTS), and functional and radiological outcomes. These were compared with a gender and age matched cohort of patients who underwent primary ACL reconstruction only. RESULTS: At a mean follow-up of 18.3 years (14.3 to 20.2), 29 patients had undergone revision surgery and within this revision group 11 had sustained more than three ruptures of the ACL (3 to 6). The mean age at the time of revision reconstruction was 26.4 years (14 to 54). The mean PTS was significantly higher in those patients who suffered a further injury to the ACL (11°) compared with the control group (9°) (p < 0.001). The mean PTS in those patients who sustained more than three ruptures was 12°. CONCLUSION: Patients who suffer recurrent injuries to the ACL after reconstruction have poorer functional and radiological outcomes than those who suffer a single injury. The causes of further injury are likely to be multifactorial but an increased PTS appears to have a significant association with recurrent ACL injuries. Cite this article: Bone Joint J 2017;99-B:337-43.

Total knee arthroplasty with an oxidised zirconium femoral component: ten-year survivorship analysis.

AIMS: Oxidised zirconium was introduced as a material for femoral components in total knee arthroplasty (TKA) as an attempt to reduce polyethylene wear. However, the long-term survival of this component is not known. METHODS: We performed a retrospective review of a prospectively collected database to assess the ten year survival and clinical and radiological outcomes of an oxidised zirconium total knee arthroplasty with the Genesis II prosthesis. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS) and a patient satisfaction scale were used to assess outcome. RESULTS: A total of 303 consecutive TKAs were performed in 278 patients with a mean age of 68 years (45 to 89). The rate of survival ten years post-operatively as assessed using Kaplan-Meier analysis was 97% (95% confidence interval 94 to 99) with revision for any reason as the endpoint. There were no revisions for loosening, osteolysis or failure of the implant. There was a significant improvement in all components of the WOMAC score at final follow-up (p < 0.001). The mean individual components of the KOOS score for symptoms (82.4 points; 36 to 100), pain (87.5 points; 6 to 100), activities of daily life (84.9 points; 15 to 100) and quality of life (71.4 points; 6 to 100) were all at higher end of the scale. DISCUSSION: This study provides further supportive evidence that the oxidised zirconium TKA gives comparable rates of survival with other implants and excellent functional outcomes ten years post-operatively. TAKE HOME MESSAGE: Total knee arthroplasty with an oxidised zirconium femoral component gives comparable long-term rates of survival and functional outcomes with conventional implants.

Follow-up after surgery for hemorrhagic AMD.

INTRODUCTION: The long-term functional results of macular hematoma (MH) surgery in exudative AMD are often limited. The goal of this study was to compare visual outcomes of monthly versus bimestrial follow-up in these patients. METHODS: Retrospective, interventional case series. Population : 21 eyes of 21 patients with SMH associated with exudative AMD. INCLUSION CRITERIA: first SMH associated with exudative AMD, with 1-year postoperative follow-up. EXCLUSION CRITERIA: blood located exclusively underneath the retinal pigment epithelium on OCT imaging, SMH due to different etiology, lost to follow-up, ≤5 postoperative visits and a different surgical protocol as described. Patients were divided into two groups according to the number of postoperative visits (number of intravitreal injections [IVT] combined with the number of consultations, only one visit was recorded when IVT and consultation occurred on the same day) during the 1-year postoperative follow-up: group 1 had ≥11 visits (n=8); group 2 had 6 to 10 visits (n=13). All eyes underwent vitrectomy with subretinal injection of recombinant tissue plasminogen activator, fluid-gas exchange and anti-VEGF intravitreal injection. The main outcome was change in best-corrected visual acuity (BCVA). RESULTS: Considering visual acuity (VA) change between 1-month and 1-year postoperative follow-up examinations, group 1 had statistically significant greater VA changes (logMAR -0.29±0.44 vs logMAR 0.42±0.73; P=0.016; P=0.016). In patients that had exudative recurrences (ER), group 1 received more anti-VEGF IVT than group 2 (P=0.045). CONCLUSION: Our results showed that monthly follow-up, between the IVT series, is highly recommended to preserve postoperative VA in patients undergoing surgery for SMH associated with AMD.

Elastic coupling between spin-crossover particles and cellulose fibers.

Composite materials made of cellulose fibers and spin crossover micro-particles were investigated by magnetic measurements and dynamic mechanical analysis (DMA). The storage modulus of the cellulose handsheet (0.6 GPa at room T) is significantly enhanced in the composite (1.7 GPa). The latter also displays a reversible increase of ca. 10% when switching the magnetic spin state of the particles from the low spin (LS) to the high spin (HS) form. Around the spin transition temperature a loss modulus peak is also observed, highlighting the strong viscoelastic coupling between the particles and the cellulose matrix. These results pave the way for the development of a novel family of actuator materials based on spin crossover-polymer composites.

Enhanced luminescence stability with a Tb-spin crossover nanocomposite for spin state monitoring.

[Fe(Htrz)2(trz)]BF4@SiO2 nanorods were synthesized using a reverse emulsion technique and a Tb(3+) complex was chemically bound to the silica surface. This Tb-spin crossover nanocomposite demonstrates high luminescence stability under continuous thermal cycling. A reabsorption mechanism is determined to be responsible for the luminescence intensity variation during the spin state switching of the iron complex.

Ursodeoxycholic acid modulates cyclosporin A oral absorption in liver transplant recipients.

The aim was to study the ursodeoxycholic acid (UDC) effect on the cyclosporin A (CsA) pharmacokinetics after oral administration of the microemulsion formulation Neoral (CsA-ME) in liver transplant recipients, and test the potential protective effect of this bile acid on liver and renal CsA-ME-induced toxicity. At entry into the study, 12 patients who underwent orthotopic liver transplantation received CsA-ME, for at least 6 months. They then received a cotreatment CsA-ME plus UDC (13.8 mg x kg(-1) x day(-1)) for three months. Blood concentrations of CsA were measured using a monoclonal antibody specific for the parent compound. The kinetic data were analysed by a mathematical model incorporating a time dependent rate coefficient for CsA intestinal absorption, before and after UDC treatment. Changes in serum markers of hepatic and renal injury were assessed. Individual serum bile acids were determined by chromatography. Serum levels of UDC increased from 3 to about 45% of total serum bile acids after UDC treatment. The estimated model parameters indicate that UDC administration modulates CsA intestinal absorption. In the nine non-cholestatic patients, UDC reduced the absorption rate and the bioavailability of CsA without modifying the elimination rate constant of CsA and the CsA pre-drug levels. In contrast, in the three cholestatic patients, the bioavailability tended to be higher and the absorption rate faster when CsA was combined with UDC. UDC significantly decreased elevated gamma-glutamyl transferase and creatinine serum levels and induced some clinical improvements such as disappearance of headaches in four patients. In conclusion, a 3-month UDC treatment modifies CsA intestinal absorption without affecting CsA elimination rate constant. On the other hand, UDC supplementation appears to improve CsA tolerability.

Antibody response of Mexican infants to Haemophilus influenzae type b capsular polyribosylribitol phosphate. Differences between natural and vaccine induced (oligosaccharide-CRM197 conjugated vaccine) immunization.

In this study we compared natural vs. induced Haemophilus influenzae type b (Hib) anti-capsular polyribosylribitol phosphate (PRP) antibody response in a low socioeconomic population. One hundred twenty five 2-month-old children received the complete HbOC vaccine immunization scheme and a booster dose at 15 months of age. One hundred twenty five non-immunized children served as the control group. Serum Hib anti-PRP antibody titers were determined by ELISA in all children. We found at the end of the primary immunization scheme an antibody concentration of 27.28 micrograms/ml in the immunized group vs. 7.48 micrograms/ml in the control group. The antibody response was mainly of the IgG1 class in both groups. After the booster dose the antibody concentration was 30.14 g/ml in the vaccinated group vs. 6.06 micrograms/ml in the control group (p < 0.01). Ninety nine percent of immunized and non-immunized infants had titers greater than 1 microgram/ml. These results confirm that immunization with the HbOC vaccine induces an important increase in anti-PRP specific antibody titer, but they also demonstrate that natural exposure induces responses higher than those referred as protective (1 microgram/ml).

The health and well-being of adolescents: a school-based population study of the self-report Child Health Questionnaire.

PURPOSE: To evaluate a new generic measure of adolescent health status, the self-report version of the Child Health Questionnaire (CHQ), and provide population-based data. Furthermore, we aimed to examine the impact of common adolescent illness and health concerns on their health and well-being. METHODS: A stratified, two-stage, random cluster sampling design was used to obtain a cross-sectional sample of subjects through schools. A written questionnaire included the 80-item 12-scale self-report CHQ and items measuring health concerns, illnesses/health conditions, and sociodemographics. RESULTS: A total of 2361 adolescents participated (response rate of 70%). Reliability was high: Tests of internal consistency and discriminant validity reported 90% of item-scale correlations >.4; all scales had Cronbach alpha coefficients >.7. Adolescents with illnesses/conditions or health concerns reported lower scores and larger differences for content-related scales, supporting content and construct validity. Statistically significant age and gender trends were observed for Mental Health, Self-Esteem, General Health, and Family Cohesion scales. Health status worsened as health concerns increased (X(2) linear trend, p =.00) with deterioration in health of 5-20% on all scales for emotional health concerns (40% of sample). CONCLUSIONS: The self-report CHQ is a reliable and seemingly valid measure of health and well-being for adolescent health research, although additional measures may be required where scales have high ceiling values. The significantly lower scores reported by adolescents with illness and/or health concerns lend support to the use of standardized health measures and longitudinal research to further examine the impact of adolescent comorbidities and their causal determinants.

Competitive inhibitors of yeast phosphoglucose isomerase: synthesis and evaluation of new types of phosphorylated sugars from the synthon D-arabinolactone-5-phosphate.

Designed as competitive inhibitors of the isomerization reaction catalyzed by the potential chemotherapeutic target phosphoglucose isomerases (PGI), D-arabinonamide-5-phosphate and D-arabinohydrazine-5-phosphate were synthesized and fully characterized. These new types of phosphorylated sugar derivatives were easily and efficiently obtained in a one-step procedure from the promising synthon D-arabinono-1,4-lactone 5-phosphate. These two compounds proved to be new good competitive inhibitors of yeast PGI with the substrate D-fructose-6-phosphate, though not as strong as D-arabinohydroxamic acid-5-phosphate. Overall, our results are in accord with the postulated 1,2-cis-enediolate species as a probable high-energy intermediate of the PGI-catalyzed reaction.

A convenient preparation of aldonohydroxamic acids in water and crystal structure of L-erythronohydroxamic acid.

Hydroxamic acids derived from aldonic acids, namely aldonohydroxamic acids, have become an increasingly important class of inhibitors of enzymes involved in the metabolism of carbohydrates. We now report the straightforward preparation of various types of aldonohydroxamic acids by a new methodology involving the use of commercial 50% aqueous hydroxylamine as the source of the free base hydroxylamine that reacts directly with the corresponding aldonolactone dissolved in water. The reaction proceeds almost instantaneously in water at room temperature, yielding generally pure products in quantitative yield. To date, this methodology is probably the most facile and efficient way to synthesize aldonohydroxamic acids. We also determined by X-ray diffraction analysis the first crystal structure of a free aldonohydroxamic acid reported to date. Crystals of L-erythronohydroxamic acid belonged to the monoclinic system, space group P2(1), a=5.511(3), b=7.556(1), c=8.071(3) A, beta=109.10 degrees, and Z=2.

The influence of reverse-thread screw femoral fixation on laxity measurements after anterior cruciate ligament reconstruction with hamstring tendon.

In arthroscopically assisted anterior cruciate ligament reconstruction using hamstring tendon graft, the graft rotates slightly as the femoral screw is inserted. Its final position tends to be in the anterior half of the tunnel in right knees, resulting in clinical laxity. To perform identical procedures on left and right knees, a reverse-thread screw was designed for femoral fixation in right knees. We prospectively studied 80 patients undergoing right-knee anterior cruciate ligament reconstruction with hamstring tendon autograft. Thirty-six patients underwent reconstruction with a standard screw and 44 underwent reconstruction with a reverse-thread screw. The same technique, performed by the same surgeon, was used on all patients. At 12 months' follow-up, the average side-to-side differences on arthrometry testing were 2.00 mm for the standard screw group and 0.95 mm for the reverse-thread screw group using a manual maximum test, and 1.66 mm and 1.00 mm, respectively, using the 20-pound test. Both differences were statistically significant. Of the standard group, 23% had a manual maximum difference of 3 mm or more, compared with 8% of the reverse-thread group. A significant difference was found between these two groups for Lachman test (77% with grade 0 for the standard group compared with 92% for the reverse group) but pivot shift and Lysholm knee score were not significantly different. The use of a reverse-thread screw for femoral fixation in right-knee anterior cruciate ligament reconstructions in men significantly decreased laxity at 12 months after surgery compared with standard screw fixation.

Endoscopic reconstruction of the anterior cruciate ligament with an ipsilateral patellar tendon autograft. A prospective longitudinal five-year study.

A total of 90 patients with an isolated rupture of the anterior cruciate ligament (ACL) had a reconstruction using the ipsilateral patellar tendon secured with round-headed cannulated interference screws. Annual review for five years showed three failures of the graft (two traumatic and one atraumatic); none occurred after two years. Ten patients sustained a rupture of the contralateral ACL. At five years, 69% of those with surviving grafts continued to participate in moderate to strenuous activity. Using the International Knee Documentation Committee assessment, 90% reported their knee as being normal or nearly normal and had a median Lysholm knee score of 96 (64 to 100). Most patients (98%) had a pivot shift of grade 0 with the remaining 2% being grade 1; 90% of the group had a Lachman test of grade 0. The incidence of subsequent meniscectomy was similar in the reconstructed joint to that in the contralateral knee. Radiological examination was normal in 63 of 65 patients. Our study supports the view that reconstruction of the ACL is a reliable technique allowing full rehabilitation of the previously injured knee. In the presence of normal menisci there is a low incidence of osteoarthritic change despite continued participation in sporting activity.