Precision Medicine through Next-Generation Sequencing in Inherited Eye Diseases in a Korean Cohort

In this study, we investigated medically or surgically actionable genes in inherited eye disease, based on clinical phenotype and genomic data. This retrospective consecutive case series included 149 patients with inherited eye diseases, seen by a single pediatric ophthalmologist, who underwent genetic testing between 1 March 2017 and 28 February 2018. Variants were detected using a target enrichment panel of 429 genes and known deep intronic variants associated with inherited eye disease. Among 149 patients, 38 (25.5%) had a family history, and this cohort includes heterogeneous phenotype including anterior segment dysgenesis, congenital cataract, infantile nystagmus syndrome, optic atrophy, and retinal dystrophy. Overall, 90 patients (60.4%) received a definite molecular diagnosis. Overall, NGS-guided precision care was provided to 8 patients (5.4%). The precision care included cryotherapy to prevent retinal detachment in COL2A1 Stickler syndrome, osteoporosis management in patients with LRP5-associated familial exudative vitreoretinopathy, and avoidance of unnecessary phlebotomy in hyperferritinemia-cataract syndrome. A revision of the initial clinical diagnosis was made in 22 patients (14.8%). Unexpected multi-gene deletions and dual diagnosis were noted in 4 patients (2.7%). We found that precision medical or surgical managements were provided for 8 of 149 patients (5.4%), and multiple locus variants were found in 2.7% of cases. These findings are important because individualized management of inherited eye diseases can be achieved through genetic testing.

Multiple ligament knee injuries: Clinical practice guidelines

Multiple ligament knee injuries involve tears of two or more of the four major knee ligament structures, and are commonly noted following knee dislocations. These devastating injuries are often associated with soft-tissue trauma, neurovascular deficit, and concomitant articular cartilage or meniscus tears. The complexity of presentation, and spectrum of treatment options, makes these injuries unique and extremely challenging to even the most experienced knee surgeons. A high level of suspicion, and a comprehensive clinical and radiological examination, is required to identify all injured structures. The current literature supports surgical management of these injuries, with cruciate reconstructions, and repair/augmented repair/ reconstruction of collateral ligaments. This review article analyses management principle of multiple ligament knee injuries, and formulates clinical practice guidelines with treatment algorithms essential to plan individualized management of these complex heterogeneous injuries.

How do we optimally utilize factor concentrates in persons with hemophilia?

The current mainstay of therapy for hemophilia is to replace the deficient clotting factor with the intravenous administration of exogenous clotting factor concentrates. Prophylaxis factor replacement therapy is now considered the standard of care in both pediatric and adult patients with hemophilia with a severe phenotype to protect musculoskeletal health and improve quality of life. Heterogeneity in bleeding presentation among patients with hemophilia due to genetic, environmental, and treatment-related factors has been well described. Accordingly, the World Federation of Hemophilia recommends an individualized prophylaxis regimen that considers the factors mentioned above to meet the clinical needs of the patient, which can vary over time. This review focuses on the practical points of choosing the type of factor concentrate, dose, and interval while evaluating appropriate target trough factor levels and bleeding triggers such as level of physical activity and joint status. We also discuss the use of a pharmacokinetics assessment and its incorporation in the clinic for a tailored approach toward individualized management. Overall, adopting an individualized prophylaxis regimen leads to an optimal utilization of factor concentrates with maximum efficacy and minimum waste.

A Nomogram Model for Predicting the Response to Transcatheter Arterial Embolization in Patients With Symptomatic Hepatic Hemangioma

Background: Transcatheter arterial embolization (TAE) is regarded as an effective treatment for patients with symptomatic hepatic hemangioma. However, few studies have evaluated the efficacy of TAE alone for treating hepatic hemangioma. The aim of this study was to identify the factors that influence the response to TAE and formulate a quantitative nomogram to optimize the individualized management of hepatic hemangioma.Methods: We retrospectively studied 276 patients treated with TAE for hepatic hemangioma at our center from January 2011 to December 2019. The full cohort was randomly divided into training and validation cohorts. After assessing the potential predictive factors for the efficacy of TAE in the training cohort, a nomogram model was established and evaluated by discrimination and calibration.Results: During follow-up, the symptom relief rate was 100%. The tumor blood supply (p < 0.001), tumor number (p = 0.004), and tumor size (p = 0.006) were identified as significant predictors of the failure of tumor shrinkage in response to TAE. The nomogram model showed favorable discrimination and calibration, with a C-index of 0.775 (95% CI, 0.705–0.845) in the training cohort, which was further confirmed in the validation cohort (C-index 0.768; 95% CI, 0.680–0.856). The side effects of TAE were relatively minor and included mainly abdominal pain, nausea, vomiting, fever, and the presence of elevated hepatic transaminases.Conclusion: TAE is a safe and effective treatment for symptomatic hepatic hemangioma. The established nomogram performed well for the estimation of the effect of TAE in patients with hepatic hemangioma and can facilitate the selection of patients who would benefit most from the treatment.

An Individualized Approach to Treating Pups with Severe Hemophilia a: Which Factors Correlate with the Low Rate of Inhibitor Development?

Introduction:Development of inhibitors to replacement factor VIII (FVIII) remains a significant challenge to the management of previously untreated patients (PUPs) with severe hemophilia A. Although several determinants have been associated with the risk of inhibitor development, the impact of treatment approach remains controversial. Here we report our experience with an individualized approach to managing PUPs at a single hemophilia treatment center (HTC) in Germany. Methods:PUPs with severe hemophilia A (FVIII:C <1%) treated at the Gerinnungszentrum Rhein-Ruhr (GZRR), Germany, between January 2013 and June 2021 were followed prospectively. Our treatment approach includes early prophylactic physiotherapy, pdFVIIIconcentrate for at least the first 50 exposure days (EDs), tailored prophylaxis with individualized dose escalation according to bleeding tendency, and avoidance of prolonged on-demand treatment by avoiding treatment of minor bleeds or hematomas. Potential bleeds were examined by a hemophilia specialist and a decision made as whether to treat with pdFVIII based on the bleed location and severity. Ultrasound was performed every 3-6 months to check for joint bleeds. Where on-demand treatment was necessary, we used a high initial dose of 60-80 IU/kg with the aim of reducing the need for subsequent doses. Non-urgent surgical procedures were postponed and venous access system implants were avoided within the first 100 EDs. Inhibitor levels were measured using the modified Bethesda assay every 3-4 EDs until ED 100, and every 3 months thereafter for 2 years. Results:Data from 28 consecutive caucasian PUPs were collected. Fourteen (50%) patients had a F8 gene mutation associated with a high risk for inhibitor development. At the time of data cut-off 23 patients had received over 50 EDs of FVIII treatment, with 21 patients having over 100 EDs; the remaining patients had up to 45 EDs.Of the 28 patients, 27 started prophylaxis within the first 10 EDs. The initial prophylaxis schedule was tailored to each patient and ranged from 21 IU/kg every 10 days up to 40 IU/kg twice per week. One patient was treated on-demand for an intracranial bleed from ED 1-100. Only 3 spontaneous bleeds in 3 patients were treated; 25 patients (89%) remained free of spontaneous bleeds during prophylaxis. All three spontaneous bleeds were treated successfully with FVIII ± tranexamic acid. None of the 28 patients developed inhibitors. Discussion:Our approach to managing PUPs includes treatment with pdFVIII for at least the first 50 EDs, during which we treat bleeds only where necessary and use high doses to minimize further infusions. We had no cases of inhibitor development in our prospective cohort of 28 patients. In contrast, between 2003 and 2012, four of nine (44%) PUPs treated at our center developed inhibitors during the first 20 EDs, with two patients developing low-titer and two high-titer inhibitors. At that time we used recombinant FVIII (rFVIII) for prophylaxis in most patients and were less selective about which bleeds to treat with FVIII. Our individualized management approach, choice of pdFVIII and restricted use of FVIII for on-demand treatment therefore appear to correlate with a reduction in inhibitor incidence at our center. We usually switch patients from pdFVIII to rFVIII after at least 50 EDs due to the lower administration volume. Given the low rate of inhibitor development reported for PUPs treated with human cell line-derived rFVIII, there is a rationale to consider starting PUPs on human cell line-derived rFVIII. Conclusion:Our data support the position, that the use of an individualized management approach minimizes the risk of inhibitor development and raise important questions about how different aspects of treatment approach could impact outcomes in PUPs with severe hemophilia A. Disclosures No relevant conflicts of interest to declare.

Angiomyxoma of the pelvis in women. Clinical cases

Aggressive pelvic angiomyxoma belongs to one of the rare types of mesenchymal pelvic tumors found in premenopause patients. Currently, this pathology is mainly treated via surgical intervention. Alternatively, it may also be managed by using radiation or hormone therapy. The final diagnosis is usually established by histological examination of removed tumor, because biopsy analysis during examination may not always provide a high diagnostic value. This tumor type is able to relapse, even after 100 % surgically removed intervention. Immunohistochemistry examination reveals expression of progesterone and estrogen receptors. One of the hormone therapy options with good long-term effect is based on using gonadotropin-releasing hormone drugs. Taking into consideration slow tumor growth and hormonal sensitivity, one of the options for managing disease relapse is patient follow-up, especially in perimenopausal subjects. Single clinical cases have been published related to pelvic angiomyxoma so that it results in introducing individualized management for every certain patient, but unified therapeutic approaches have not been developed yet.

Identification of Novel GCK and HNF4α Gene Variants in Japanese Pediatric Patients with Onset of Diabetes before 17 Years of Age

Background. Maturity-onset diabetes of the young (MODY) is commonly misdiagnosed as type 1 or type 2 diabetes. Common reasons for misdiagnosis are related to limitations in genetic testing. A precise molecular diagnosis is essential for the optimal treatment of patients and allows for early diagnosis of their asymptomatic family members. Objective. The aim of this study was to identify rare monogenic variants of common MODY genes in Japanese pediatric patients. Methods. We investigated 45 Japanese pediatric patients based on the following clinical criteria: development of diabetes before 17 years of age, a family history of diabetes, testing negative for glutamate decarboxylase-65 (GAD 65) antibodies and insulinoma-2-associated autoantibodies (IA-2A), no significant obesity, and evidence of endogenous insulin production. Genetic screening for MODY1 (HNF4α), MODY2 (GCK), MODY3 (HNF1α), and MODY5 (HNF1β) was performed by direct sequencing followed by multiplex ligation amplification assays. Results. We identified 22 missense variants (3 novel variants) in 27 patients (60.0%) in the GCK, HNF4α, and HNF1α genes. We also detected a whole exon deletion in the HNF1β gene and an exon 5–6 aberration in the GCK gene, each in one proband (4.4%). There were a total of 29 variations (64.4%), giving a relative frequency of 53.3% (24/45) for GCK, 2.2% (1/45) for HNF4α, 6.7% (3/45) for HNF1α, and 2.2% (1/45) for HNF1β genes. Conclusions. Clinicians should consider collecting and assessing detailed clinical information, especially regarding GCK gene variants, in young antibody-negative patients with diabetes. Correct molecular diagnosis of MODY better predicts the clinical course of diabetes and facilitates individualized management.

The Influence of SDM-Based Individualized Management Model on the Health Outcome and Quality of Life of Maintenance Hemodialysis Patients

Background Chronic kidney disease is a common clinical problem that endangers human physical and mental health and life safety. It eventually evolves into end-stage renal disease, and the incidence has increased year by year. It has been reported that the incidence of chronic kidney disease in China is about 10 %, and most patients need to carry out dialysis to maintain life. Objective To observe the influence of an individualized management model based on shared decision-making (SDM) between doctors, nurses and patients on the health outcomes and quality of life of maintenance hemodialysis patients. Methods A total of 100 end-stage renal disease patients treated with maintenance hemodialysis intervention in the Department of Nephrology, Changyisha City Fourth Hospital from May 2020 to May2021 were selected. According to the order of admission, they were randomly divided into control groups (n=50)) And the observation group (n=50). The control group received conventional management mode intervention, and the observation group received SDM-based individualized management mode intervention. The blood pressure and fluid control of the two groups were recorded, and the self-management behavior scale for hemodialysis patients (SMSH), the satisfaction survey questionnaire for patient participation in medical decision-making, and the kidney disease-related quality of life scale (KDTA) were used to evaluate the self-management ability of the two groups. Satisfaction and quality of life. Results After the intervention, fluid intake, weight gain between dialysis intervals, and the number of dialysis-related complications in the observation group decreased significantly (P<0.05), while the number of dialysis-related complications in the control group decreased (P<0.05), but fluid The intake and weight gain between dialysis intervals were similar to those before the intervention (P>0.05), and the fluid control in the observation group improved more significantly than the control group after the intervention (P<0.05). After the intervention, the systolic and diastolic blood pressure of the observation group decreased significantly (P<0.05), and the systolic and diastolic blood pressure of the control group were similar to those before the intervention (P>0.05). The blood pressure of the observation group improved more significantly than the control group after the intervention (P<0.05). After the intervention, the two groups of SMSH scale scores (problem solving, self-care, partnership, emotional processing, etc.), satisfaction scores (information, communication and negotiation, decision-making, total satisfaction and confidence, etc.), quality of life scores (symptoms, kidney disease, etc.) The impact of kidney disease, the burden of kidney disease, work status, cognitive function, social quality, sleep, social support, etc.) have been greatly improved (P<0.05), and the SMSH scale score, satisfaction score, quality of life of the observation group after intervention The score improved more significantly than the control group (P<0.05). Conclusion Intervention of maintenance hemodialysis patients based on an individualized management model of SDM can improve the self-management ability and satisfaction of patients, improve the quality of life, and reduce the occurrence of adverse events and complications.

Identifying Chinese Medicine Patterns of Tension-Type Headache and Understanding Its Subgroups

Tension-type headache (TTH) is common among adults. Individualized management strategies are limited due to lack of understanding of subtypes of TTH. Chinese medicine (CM) uses the pattern differentiation approach to subtype all health conditions. There is, however, a lack of evidence-based information on CM patterns of TTH. This study aimed to identity common CM patterns of TTH. TTH sufferers were invited for a survey, consisting of a validated Chinese Medicine Headache Questionnaire (CMHQ), Migraine Disability Assessment Test, and Perceived Stress Scale. The CMHQ consisted of information about headache, aggravating and relieving factors, and accompanying symptoms. Principal component analysis was used for factor extraction and TwoStep cluster analyses for identifying clusters. ANOVA was used to compare cluster groups with disability and stress. In total, 170 eligible participants took part in the survey. The commonest headache features were continuous pain (64%); fixed location (74%); aggravated by overwork (74%), stress (74%), or mental strain (70%); and relieved by sleeping (78%). The commonest nonpain symptoms were fatigue (71%) and neck stiffness (70%). Four clusters, differing in their key signs and symptoms, could be assigned to three different CM patterns including ascendant hyperactivity of liver yang (cluster 1), dual qi and blood deficiency (cluster 2), liver depression forming fire (cluster 3), and an unlabelled group (cluster 4). Additionally, over 75% participants in clusters 1 and 2 have episodic TTH, over one-third participants in cluster 3 have chronic TTH, and a majority of participants in cluster 4 have infrequent TTH. The three patterns identified also differed in levels of disability and some elements of coping as measured with PSS. The three CM patterns identified are common clinical presentations of TTH. The new information will contribute to further understanding of the subtypes of TTH and guide the development of targeted intervention combinations for clinical practice and research.