Clinical and immunological outcomes of SARS-CoV-2-infected vaccine responders, vaccine non-responders, and unvaccinated patients evaluated for neutralizing monoclonal antibody treatment at a single German tertiary care center: a retrospective cohort study with prospective follow-up.

PURPOSE: This study assessed the clinical and immunological outcomes of SARS-CoV-2-infected patients with risk factors for severe disease depending on their immunological status. METHODS: In this retrospective study with single follow-up visit, clinical outcome and humoral immunity was monitored in SARS-CoV-2 infected patients at risk. The results were compared based on the patients' initial immunological status: unvaccinated (UV), patients who did not develop neutralizing antibodies after vaccination (vaccine non-responders, VNR), and patients who expressed neutralizing antibodies after vaccination (vaccine responders, VR). Patients who lacked neutralizing antibodies (VNR and UV) were treated with nMABs. RESULTS: In total, 113 patients at risk of severe COVID-19 consented to participate in the study. VR and UV were not admitted to the hospital. During the observation period, UVs had the highest rate of SARS-CoV-2 re-infections. Three of 41 VNRs (7.3%) were hospitalized due to severe COVID-19, with two of them having undergone iatrogenic B-cell depletion. The humoral immune response after infection was significantly lower in the VNR group than in the VR group in terms of anti-N, anti-receptor-binding domain (RBD), anti-S antibody titers, and anti-S antibody avidity. In a sub-analysis of VNR, B cell-deficient non-responders had significantly lower levels of anti-N antibodies and anti-S avidity after infection than other VNRs. CONCLUSION: VNR, particularly B-cell-depleted VNR, remained at risk of hospitalization due to COVID-19. In the VR group, however, no clinical complications or severe disease were observed, despite not receiving nMAbs. Tailoring the administration of nMABs according to patient vaccination and immunological status may be advisable.

Inner retinal layer thinning in radiologically isolated syndrome predicts conversion to multiple sclerosis.

BACKGROUND AND PURPOSE: Individuals with radiologically isolated syndrome (RIS) are at increased risk of converting to multiple sclerosis (MS). Early identification of later converters is crucial for optimal treatment decisions. The purpose of this study was to assess the predictive potential of optical coherence tomography (OCT) measures in individuals with RIS regarding conversion to MS. METHODS: This prospective observational cohort study included 36 individuals with RIS and 36 healthy controls recruited from two German MS centers. All individuals received baseline OCT and clinical examination and were longitudinally followed over up to 6 years. The primary outcome measure was the conversion to MS. RESULTS: During clinical follow-up of 46 (26-58) months (median, 25%-75% interquartile range), eight individuals with RIS converted to MS. Individuals converting to MS showed a thinning of the peripapillary retinal nerve fiber layer (pRNFL) and the common ganglion cell and inner plexiform layer (GCIP) at baseline and during follow-up. Individuals with a pRNFL of 99 µm or lower or a GCIP of 1.99 mm3 or lower were at a 7.5- and 8.0-fold risk for MS conversion, respectively, compared to individuals with higher measures. After correction for other known risk factors, Cox proportional hazards regression revealed a hazard ratio of 1.08 for conversion to MS for each 1 µm decline in pRNFL. CONCLUSIONS: Reduction of the pRNFL might be a novel and independent risk factor for conversion to MS in individuals with RIS. OCT might be useful for risk stratification and therapeutic decision-making in individuals with RIS.

Perioperative management of rare coagulation factor deficiency states in cardiac surgery.

Rare bleeding disorders (RBDs) include the hereditary deficiency of fibrinogen, factor (F)II, FV, FV + FVIII, FVII, FX, FXI or FXIII. RBDs do not confer a protective effect against atheromatous plaque formation, and thus the need for cardiovascular (CV) surgery in RBD patients is expected to increase with improved healthcare access (diagnosis and management) and longevity of the population. Clinical data regarding the management of RBDs in this setting are sparse, but the perioperative care team is obliged to gain a better understanding on available biological and pharmacological hemostatic agents. Perioperative management of RBDs in CV surgery is further complicated by heparin anticoagulation, haemodilution, and consumption of procoagulant and anticoagulant proteins associated with cardiopulmonary bypass (CPB). The aims of this review are to summarize pathophysiology of RBDs and laboratory monitoring pertinent to CV surgery, available factor replacement agents, and to provide the framework for perioperative coagulation management of RBD patients.

The Effect of Platelet-rich Fibrin Matrix on Rotator Cuff Healing in a Rat Model.

The purpose of the current study was to determine if the application of platelet-rich fibrin matrix could improve regeneration of the tendon-bone insertion site in a rat rotator cuff repair model. 25 Lewis syngeneic rats underwent bilateral tenotomy and repair of the supraspinatus tendon. 10 separate rats were used for PRFM harvest. All left (control) shoulders underwent transosseous rotator cuff repair, while all right (treatment) shoulders were repaired similarly with PRFM augmentation. 9 rats were sacrificed at 2-weeks and ten at 4-weeks for biomechanical testing. 3 separate rats were sacrificed at 2-weeks and 4-weeks each for histologic analysis of the insertion site. At 2 weeks, the experimental group repairs were significantly stronger in ultimate load to failure (P=0.01), stress (P=0.03), and stiffness (P=0.03). Differences in biomechanical testing were not found between the groups at 4 weeks. Histological analysis revealed less collagen organization and cartilage formation at the insertion site in the experimental group. Semiquantitative histologic analysis confirmed our qualitative assessment of the specimens. PRFM does not recapitulate the native enthesis, but rather induces an exuberant and disordered healing response that is characterized by fibrovascular scar tissue.

Population Pharmacokinetics and Pharmacodynamics of Lampalizumab Administered Intravitreally to Patients With Geographic Atrophy.

Intravitreally administered lampalizumab is an investigational complement inhibitor directed against complement factor D (CFD) for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration. We sought to develop an integrated ocular and systemic pharmacokinetic/pharmacodynamic model for lampalizumab in patients with GA using the data from the clinical phase I and II studies. The kinetics of lampalizumab and CFD disposition were well described by the combined ocular/serum target-mediated drug disposition model using a quasi-steady-state approximation. This model takes into account the drug, target, and drug-target complex clearance, their transfer rates between ocular and serum compartments, and turnover kinetics of CFD. The constructed model provided a prediction of target occupancy in ocular tissues and supported that the two dosing regimens (10 mg q4w and 10 mg q6w) selected for the phase III studies are expected to be efficacious and able to achieve near-complete target engagement in the vitreous humor.

Estimating the burden of early onset dementia; systematic review of disease prevalence.

Dementia is more common in older age but a number of people develop symptoms at a younger age and are said to have early onset dementia (EOD). Those with EOD face different challenges to those with onset later in life. It has been difficult to quantify this disease burden. This is a systematic review of papers reporting on the prevalence of EOD. A search of Medline and Embase was performed. This was followed by a hand search of the references of these papers. Eleven suitable studies were included. All of the data was from more economically developed countries. The studies were heterogeneous in their design hindering direct comparison. The majority of the papers looked at all types of dementia although many gave a breakdown of the prevalence of different subgroups. A variety of diagnostic criteria was employed. Figures of 38 to 260 per 100,000 are quoted by papers looking at various different types of dementia together with an onset of between 30 and 64 or up to 420 per 100,000 for those aged 55-64. Prevalence rises as age approaches 65. Epidemiological data for prevalence rates for EOD are sparse. EOD remains a rare condition with low case numbers. Assimilation and comparison of results from existing studies is difficult due to methodological heterogeneity. Cross-national standardization of methodology should be a priority for future research in this area.

Mechanical effects of defect closure following BPTB graft harvest for ACL reconstruction.

Anterior cruciate ligament injury affects roughly 120,000 athletes in the United States every year. One of the most common techniques is the use of a bone-patellar tendon-bone graft. Graft harvest creates a sizeable defect in the remaining patellar tendon. Closure of this defect is based on surgeon preference. To date there has been no study on the effects of defect closure on the mechanical properties of remaining donor patellar tendon. The goal of this study was to investigate the effect of closure on both the strength and stiffness of the remaining patellar tendon. 7 pairs of fresh frozen cadaver patellar tendons were matched by tendon dimensions. Bone-patellar tendon-bone grafts were harvested from all of the specimens and then half of the paired tendons underwent defect closure. All of the donor tendons were then tested in a servohydraulic load frame to failure at a constant displacement rate at room temperature. This study found no differences in the load at failure, the engineering failure stress, stiffness or in the engineering modulus between the donor tendons that underwent defect closure versus those that did not.

The effect of landscape structure on the distribution of brown hare Lepus europaeus in farmlands of Germany and Poland.

Habitat management should be an important part of the brown hare (Lepus europaeus) conservation, but the habitat requirements of this species are not fully recognised. The aim of our research was to estimate these requirements by analysing the effect of various agricultural landscape structure features on the distribution of hares in five agricultural areas in Germany and Poland. The local density of hares was assessed in the spring and autumn of 2006 by using the method of spotlight-strip counts on 9-15 subareas in each research region. The structure of agricultural landscape has been described for each subarea: the share of grain, other crops and grasses as well as the density of crop edges and uncultivated places with wild vegetation. The density of hares was considerably higher in Germany than in Poland (18.8-48.4 vs. 4.1-9.5 indiv./km(2)). The hare density was positively correlated with non-grain crops in an area, with crop edges in two areas and with wild vegetation without trees in two areas, and negatively correlated with grassfields in two areas. The occurrence of wild vegetation without trees affected the hare density only in the study areas, where this habitat was relatively rare (<3 km/km(2)). It was suggested that proper projects aimed at habitat management for brown hares should be elastic, i.e. the projects should be modified depending on the structure of local landscapes. Moreover, the protection and creation of structures with wild vegetation among cropland seem to be considerable methods of brown hare or generally wildlife conservation; therefore, such measures should be an important part of agro-environmental packages.

Benign extraosseous cartilage tumours of the hand and wrist.

Benign extraosseous cartilage tumours of the hand and wrist comprise soft tissue chondromas, synovial chondromatosis and tenosynovial chrondromatosis. These tumours can significantly affect patients as they are often painful, functionally limiting and cosmetically displeasing. Although each tumour is generally considered to be a distinct entity, they share radiological and histopathological similarities. Occasionally, all three tumours may be seen in the same patient. This is an important consideration because of the risk of recurrence that may not necessarily occur at the same anatomical site but instead extend to different sites, such as a tendon sheath and/or joint.

Incremental patterns in the amount of informal and formal care among non-demented and demented elderly persons: results from a 3-year follow-up population-based study.

OBJECTIVE: Elderly care includes complex interactions between formal services, informal care, morbidity and disabilities. Studies of the incremental effects of formal and informal care are rare and thus the objective was to describe the longitudinal patterns in formal and informal care given to non-demented and demented persons living in a rural area in Sweden. METHODS: Transitions in the Kungsholmen-Nordanstig Project (n=919) was followed up 3 years later (n=579), presented as different combinations of informal and formal care, institutionalization and mortality. Number of hours spent on care was examined by the Resource Utilization in Dementia instrument (RUD). Bootstrapped descriptive statistics and regression models were applied. RESULTS: The overall mortality during follow-up was 34%, and 15% had been institutionalized. Of those who lived at home, those receiving only formal care had been institutionalized to the greatest extent (29%; p<0.05). In terms of hours, informal care decreased amongst demented. The ratio between demented and non-demented was greater at baseline, both regarding informal care (10:1 and 3:1, respectively) and formal care (5:1 and 4:1, respectively). People with mild cognitive decline and no home support at baseline had a great risk of being receiver of care (formal or informal) or dead at follow-up. CONCLUSIONS: The amount of informal care was lower for demented persons still living at home at follow-up than at baseline, probably due to selection effects (institutionalization and mortality). Mild cognitive decline of non-users of care at baseline was strongly associated with receiving care or being dead at follow-up.

Pantothenate utilization by Plasmodium as a target for antimalarial chemotherapy.

In the absence of an effective vaccine against malaria suitable for widespread deployment, the control of this lethal infectious disease relies heavily on antimalarial chemotherapies. The most virulent of the parasites that cause malaria (Plasmodium falciparum) has, however, developed resistance to all antimalarial agents in clinical use, and there is a desperate need for new antimalarial agents that target previously unexploited parasite processes. P. falciparum requires an extracellular supply of pantothenate to support its proliferation during the erythrocytic stage of its development in humans. This requirement highlights the mechanisms involved in the utilization (uptake and metabolism) of pantothenate as potential targets for chemotherapeutic attack. Here we review the evidence demonstrating pantothenate to be an essential nutrient for P. falciparum and data from studies investigating whether this parasite has the capacity to utilize exogenous supplies of the cofactor (coenzyme A; CoA) for which pantothenate serves as a precursor. The results of recent studies aimed at characterising the mechanisms by which pantothenate is taken up by the P. falciparum-infected erythrocyte and intracellular parasite, and metabolised to CoA, are described. The unique properties that may be exploited to develop selective inhibitors of pantothenate utilization by P. falciparum-infected erythrocytes are highlighted. The molecular identity of P. falciparum pantothenate transporters and CoA biosynthesis enzymes remain unconfirmed. We consider the possible identities, and emphasize the importance of generating these proteins in pure, functionally active form. The tools currently available for identifying inhibitors of pantothenate utilization that may be potent antiplasmodial agents are also discussed.

Uncontrolled diabetes increases the risk of Alzheimer's disease: a population-based cohort study.

AIMS/HYPOTHESIS: Diabetes has been related to Alzheimer's disease with inconsistent findings. We aimed to clarify the association of diabetes with different dementing disorders taking into account glycaemic control, and to explore the link between glucose dysregulation and neurodegeneration. METHODS: A dementia-free cohort (n = 1,248) aged >or=75 years was longitudinally examined to detect dementia, Alzheimer's disease and vascular dementia (VaD) cases (Diagnostic and Statistical Manual of Mental Disorders, revised third edition [DSM-III-R] criteria). The Alzheimer's disease diagnoses were subdivided into Alzheimer's disease with stroke and Alzheimer's disease without hypertension, heart disease and stroke. Diabetes was ascertained based on medical history, or hypoglycaemic medication use, or a random blood glucose level >or=11.0 mmol/l, which included undiagnosed diabetes when neither a history of diabetes nor hypoglycaemic drugs use was present. Uncontrolled diabetes was classified as a random blood glucose level >or=11.0 mmol/l in diabetic patients. Borderline diabetes was defined as a random blood glucose level of 7.8-11.0 mmol/l in diabetes-free individuals. Cox models were used to estimate HRs. RESULTS: During the 9 year follow-up, 420 individuals developed dementia, including 47 with VaD and 320 with Alzheimer's disease (of the 320 Alzheimer's disease cases, 78 had previous, temporally unrelated stroke, and 137 had no major vascular comorbidities). Overall diabetes was only related to VaD (HR 3.21, 95% CI 1.20-8.63). Undiagnosed diabetes led to an HR of 3.29 (95% CI 1.20-9.01) for Alzheimer's disease. Diabetic patients with random blood glucose levels <7.8 mmol/l showed no increased dementia risk. Uncontrolled and borderline diabetes were further associated with Alzheimer's disease without vascular comorbidities. CONCLUSIONS/INTERPRETATION: Uncontrolled diabetes increases the risk of Alzheimer's disease and VaD. Our findings suggest a direct link between glucose dysregulation and neurodegeneration.

The impact of chronic multimorbidity and disability on functional decline and survival in elderly persons. A community-based, longitudinal study.

OBJECTIVE: We aimed to disentangle the effect of chronic multimorbidity and disability on 3-year functional decline and survival in the elderly. DESIGN: Prospective cohort study with a mean of follow-up of 2.8 years. SETTING: Swedish elderly persons from the Kungsholmen Project (1987-2000). SUBJECTS: A total of 1099 subjects, 77-100 years old, living in the community and institutions. MAIN OUTCOME MEASUREMENTS: Medical diagnoses (based on clinical examination, drug use, medical records and blood tests), and functional assessment (according to Katz Index) at baseline were investigated in relation to functional decline and death occurring during follow-up. RESULTS: At baseline, 12.1% of participants had disability, and 52.3% were affected by multimorbidity. During follow-up, 363 persons died and 85 worsened in functioning. The number of chronic conditions incrementally increased the risk of functional decline [hazard ratio (HR) increased from 1.5 in subjects with one disease to 6.2 in persons with 4+ diseases]. However, this was not the case for mortality, as the HR of death was the same for people with one disease as well as 4+ diseases (HR=2.3). Baseline disability had the highest impact on survival, independently of number of diseases [HR=8.1; 95% confidence interval (CI)=4.8-13.7 in subjects with one disease and HR=7.7; 95% CI=4.7-12.6 in those with 2+ diseases]. CONCLUSIONS: In the elderly subjects, chronic disability rather than multimorbidity emerged as the strongest negative prognostic factor for functionality and survival.

The use of retrievable inferior vena cava filters in orthopaedic patients.

This study was undertaken to evaluate the safety and efficacy of retrievable inferior vena cava filters in high-risk orthopaedic patients. A total of 58 patients had a retrievable inferior vena cava filter placed as an adjunct to chemical and mechanical prophylaxis, most commonly for a history of previous deep-vein thrombosis or pulmonary embolism, polytrauma, or expected prolonged immobilisation. In total 56 patients (96.6%) had an uncomplicated post-operative course. Two patients (3.4%) died in the peri-operative period for unrelated reasons. Of the 56 surviving patients, 50 (89%) were available for follow-up. A total of 32 filters (64%) were removed without complication at a mean of 37.8 days (4 to 238) after placement. There were four filters (8%) which were retained because of thrombosis at the filter site, and four (8%) were retained because of incorporation of the filter into the wall of the inferior vena cava. In ten cases (20%) the retrievable filter was left in place to continue as primary prophylaxis. No patient had post-removal thromboembolic complications. A retrievable inferior vena cava filter, as an adjunct to chemical and mechanical prophylaxis, was a safe and effective means of reducing the acute risk of pulmonary embolism in this high-risk group of patients. Although most filters were removed without complications, thereby avoiding the long-term complications that have plagued permanent indwelling filters, a relatively high percentage of filters had to be left in situ.

Mannan-binding lectin MBL2 gene polymorphism in chronic hepatitis C: association with the severity of liver fibrosis and response to interferon therapy.

Hepatitis C virus (HCV) is a major cause of hepatic disease and of liver transplantation worldwide. Mannan-binding lectin (MBL), encoded by the MBL2 gene, can have an important role as an opsonin and complement activating molecule in HCV persistence and liver injury. We assessed the MBL2 polymorphism in 102 Euro-Brazilian patients with moderate and severe chronic hepatitis C, paired for gender and age with 102 HCV seronegative healthy individuals. Six common single nucleotide polymorphisms in the MBL2 gene, three in the promoter (H/L, X/Y and P/Q) and three in exon 1 (A, the wild-type, and B, C or D also known as O) were evaluated using real-time polymerase chain reaction with fluorescent hybridization probes. The concentration of MBL in plasma was measured by enzyme-linked immunosorbent assay. The frequency of the YA/YO genotype was significantly higher in the HCV patients compared with the controls (P = 0.022). On the other hand, the genotypes associated with low levels of MBL (XA/XA, XA/YO and YO/YO) were decreased significantly in the patients with severe fibrosis (stage F4), when compared with the patients with moderate fibrosis (stage F2) (P = 0.04) and to the control group (P = 0.011). Furthermore, MBL2 genotypes containing X or O mutations were found to be associated with non-responsiveness to pginterferon and ribavirin treatment (P = 0.023). MBL2 polymorphisms may therefore be associated not only with the development of chronic hepatitis C, but also with its clinical evolution and response to treatment.

Education and dementia: what lies behind the association?

BACKGROUND: Low education seems to be associated with an increased risk of dementia and Alzheimer disease (AD). People with low education have unhealthier lifestyles and more cardiovascular risk factors, but it is unclear how this affects the association between education and dementia. METHODS: Participants of the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study were derived from random, population-based samples previously studied in a survey in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1,449 individuals (72%) aged 65 to 79 participated in a re-examination in 1998. RESULTS: Compared to individuals with formal education of 5 years or less, those with 6 to 8 years of education had OR of 0.57 (95% CI 0.29 to 1.13), and those with 9 years of education or more had OR of 0.16 (95% CI 0.06 to 0.41) for dementia. The corresponding ORs for AD were 0.49 (0.24 to 1.00) and 0.15 (0.05 to 0.40). The associations remained unchanged after adjustments for several demographic, socioeconomic, vascular, and lifestyle characteristics. The results were similar among both men and women. ApoE4 did not modify the association, but the risk of dementia and AD was very low among ApoE4 noncarriers with high education. CONCLUSIONS: The association between low education and dementia is probably not explained by the unhealthy lifestyles of the less educated compared with higher educated persons. Higher educated persons may have a greater cognitive reserve that can postpone the clinical manifestation of dementia. Unhealthy lifestyles may independently contribute to the depletion of this reserve or directly influence the underlying pathologic processes.

Does obesity influence the outcome after the operative treatment of ankle fractures?

Many orthopaedic surgeons believe that obese patients have a higher rate of peri-operative complications and a worse functional outcome than non-obese patients. There is, however, inconsistency in the literature supporting this notion. This study was performed to evaluate the effect of body mass index (BMI) on injury characteristics, the incidence of complications, and the functional outcome after the operative management of unstable ankle fractures. We retrospectively reviewed 279 patients (99 obese (BMI > or = 30) and 180 non-obese (BMI < 30) patients who underwent surgical fixation of an unstable fracture of the ankle. We found that obese patients had a higher number of medical co-morbidities, and more Orthopaedic Trauma Association type B and C fracture types than non-obese patients. At two years from the time of injury, however, the presence of obesity did not affect the incidence of complications, the time to fracture union or the level of function. These findings suggest that obese patients should be treated in line with standard procedures, keeping in mind any known associated medical co-morbidities.

Combating oncogene activation associated with retrovirus-mediated gene therapy of X-linked severe combined immunodeficiency

A successful gene therapy clinical trial that also encountered serious adverse effects has sparked extensive study and debate about the future directions for retrovirus-mediated interventions. Treatment of X-linked severe combined immunodeficiency with an oncoretrovirus harboring a normal copy of the gc gene was applied in two clinical trials, essentially curing 13 of 16 infants, restoring a normal immune system without the need for additional immune-related therapies. Approximately 3 years after their gene therapy, tragically, 3 of these children, all from the same trial, developed leukemia as a result of this experimental treatment. The current understanding of the mechanism behind this leukemogenesis involves three critical and cooperating factors, i.e., viral integration, oncogene activation, and the function of the therapeutic gene. In this review, we will explore the causes of this unwanted event and some of the possibilities for reducing the risk of its reoccurrence.

Combating oncogene activation associated with retrovirus-mediated gene therapy of X-linked severe combined immunodeficiency.

A successful gene therapy clinical trial that also encountered serious adverse effects has sparked extensive study and debate about the future directions for retrovirus-mediated interventions. Treatment of X-linked severe combined immunodeficiency with an oncoretrovirus harboring a normal copy of the gammac gene was applied in two clinical trials, essentially curing 13 of 16 infants, restoring a normal immune system without the need for additional immune-related therapies. Approximately 3 years after their gene therapy, tragically, 3 of these children, all from the same trial, developed leukemia as a result of this experimental treatment. The current understanding of the mechanism behind this leukemogenesis involves three critical and cooperating factors, i.e., viral integration, oncogene activation, and the function of the therapeutic gene. In this review, we will explore the causes of this unwanted event and some of the possibilities for reducing the risk of its reoccurrence.

The posterior Monteggia lesion with associated ulnohumeral instability.

The type II Monteggia (posterior) lesion is a rare injury which is sometimes associated with ulnohumeral instability. We have reviewed 23 of 28 patients with this injury. A clinical and radiographic assessment was undertaken at follow-up. Functional outcome scores, including the Broberg and Morrey Index and the Disabilities of the Arm, Shoulder or Hand (DASH), were used. The results from the six patients with associated posterior ulnohumeral dislocation were compared with 17 without ulnohumeral injury. Those with dislocation had reduced movement of the elbow and had outcome scores indicative of greater disability compared to those without associated dislocation.