Comparative effectiveness of antitumour necrosis factor agents, biologics with an alternative mode of action and tofacitinib in an observational cohort of patients with rheumatoid arthritis in Switzerland.

BACKGROUND: Multiple biologic and targeted synthetic disease-modifying rheumatic drugs (b/tsDMARDs) are approved for the management of rheumatoid arthritis (RA), including TNF inhibitors (TNFi), bDMARDs with other modes of action (bDMARD-OMA) and Janus kinase inhibitors (JAKi). Combination of b/tsDMARDs with conventional synthetic DMARDs (csDMARDs) is recommended, yet monotherapy is common in practice. OBJECTIVE: To compare drug maintenance and clinical effectiveness of three alternative treatment options for RA management. METHODS: This observational cohort study was nested within the Swiss RA Registry. TNFi, bDMARD-OMA (abatacept or anti-IL6 agents) or the JAKi tofacitinib (Tofa) initiated in adult RA patients were included. The primary outcome was overall drug retention. We further analysed secondary effectiveness outcomes and whether concomitant csDMARDs modified effectiveness, adjusting for potential confounding factors. RESULTS: 4023 treatment courses of 2600 patients were included, 1862 on TNFi, 1355 on bDMARD-OMA and 806 on Tofa. TNFi was more frequently used as a first b/tsDMARDs, at a younger age and with shorter disease duration. Overall drug maintenance was significantly lower with TNFi compared with Tofa [HR 1.29 (95% CI 1.14 to 1.47)], but similar between bDMARD-OMA and Tofa [HR 1.09 (95% CI 0.96 to 1.24)]. TNFi maintenance was decreased when prescribed without concomitant csDMARDs [HR: 1.27 (95% CI 1.08 to 1.49)], while no difference was observed for bDMARD-OMA or Tofa maintenance with respect to concomitant csDMARDs. CONCLUSION: Tofa drug maintenance was comparable with bDMARDs-OMA and somewhat higher than TNFi. Concomitant csDMARDs appear to be required for optimal effectiveness of TNFi, but not for bDMARD-OMA or Tofa.

Long-term immunogenicity after yellow fever vaccination in immunosuppressed and healthy individuals.

BACKGROUND: The live-attenuated yellow fever vaccine (YFV) is generally contraindicated in immunosuppressed patients. Our aim was to investigate if immunosuppressive therapy impairs the long-term protection against yellow fever virus in patients who had received YFV prior to the start of their immunosuppressive therapy. METHODS: Our study examined 35 healthy individuals and 40 immunosuppressed patients with autoimmune diseases or organ transplants. All individuals had received YFV prior to the onset of their immunosuppression. We analysed the long-term influence of the immunosuppressive therapy on the YFV protective immunity by measuring neutralising antibodies (NA) with the Plaque Reduction Neutralisation Test (PRNT). We assessed risk factors for a negative PRNT result (titre below 1: 10) and their influence on the magnitude of the NA. RESULTS: A median time interval of 21.1 years (interquartile range 14.4-31.3 years) after the YFV in all patients, a total of 35 immunosuppressed patients (88%) were seropositive (PRNT ≥ 1:10) compared to 31 patients (89%) in the control group. The geometric mean titres of NA did not differ between the groups. The duration of an underlying rheumatic disease was the only risk factor found for a lower magnitude of NA. An insufficient level of NA was found in nine subjects (12%) who had received a single dose of YFV (in one subject, the number of YFV doses was unknown). CONCLUSION: The use of an immunosuppressive drug started after the administration of the YFV did not affect long-term persistence of NA. A second dose of YFV may be necessary to secure long-term immunity.

The role of neutrophil activation in determining the outcome of pregnancy and modulation by hormones and/or cytokines.

Neutrophils are often exclusively considered as a first-line innate immune defence, able to rapidly kill or trap pathogens and causing in case of over-activation tissue damage. In the female reproductive tract, however, the presence and activity of neutrophils seems to be tightly regulated. Major players in orchestrating this regulation are cyclical steroid sex hormones present during the menstrual cycle and pregnancy. This review describes the role of sex hormones in regulating directly or indirectly the functionality of neutrophils, the role of neutrophils during fertilization and pregnancy and in controlling viral, fungal and bacterial infection. This review also discusses the consequence of overt neutrophil activation in pregnancy pathologies.

Biological agents in monotherapy for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease, which results in joint destruction and permanent disability. The advent of disease-modifying antirheumatic drugs (DMARDs) has made a profound impact on the outcome and prognosis of RA. Methotrexate (MTX) is a central agent in RA therapy, and is used either alone or in combination with biological DMARDs. However, a large proportion of RA patients (20%-40%) either do not respond to or are unable to tolerate MTX or the alternative agents used in place of MTX (including leflunomide, sulfasalazine, azathioprine, hydroxycholoquine and combination DMARDs). For these patients, monotherapy with biological DMARDs is a key treatment option that balances tolerability with improved clinical outcomes. This article reviews the data for four biological agents approved for use as monotherapy in Switzerland (adalimumab, certolizumab pegol, etanercept and tocilizumab) in order to formulate a consensus statement on their roles in biologic monotherapy of RA.

A learning-enabled neuron array IC based upon transistor channel models of biological phenomena.

We present a single-chip array of 100 biologically-based electronic neuron models interconnected to each other and the outside environment through 30,000 synapses. The chip was fabricated in a standard 350 nm CMOS IC process. Our approach used dense circuit models of synaptic behavior, including biological computation and learning, as well as transistor channel models. We use Address-Event Representation (AER) spike communication for inputs and outputs to this IC. We present the IC architecture and infrastructure, including IC chip, configuration tools, and testing platform. We present measurement of small network of neurons, measurement of STDP neuron dynamics, and measurement from a compiled spiking neuron WTA topology, all compiled into this IC.

Computing with networks of spiking neurons on a biophysically motivated floating-gate based neuromorphic integrated circuit.

Results are presented from several spiking network experiments performed on a novel neuromorphic integrated circuit. The networks are discussed in terms of their computational significance, which includes applications such as arbitrary spatiotemporal pattern generation and recognition, winner-take-all competition, stable generation of rhythmic outputs, and volatile memory. Analogies to the behavior of real biological neural systems are also noted. The alternatives for implementing the same computations are discussed and compared from a computational efficiency standpoint, with the conclusion that implementing neural networks on neuromorphic hardware is significantly more power efficient than numerical integration of model equations on traditional digital hardware.

[Comparison of laser treatment of patients with the replace with "computer-based laser" between experienced and unexperienced operators]. / Vergleich der laserbehandlung mit einem computergestützten lasersystem durch einen erfahrenen versus einen unerfahrenen behandelnden arzt.

INTRODUCTION: The aim of this study was to compare individual accuracy and speed of laser application using the Navilas laser system in patients with diabetic and vascular macular oedema. METHODS: The Navilas laser system was used by an experienced retina specialist and a relatively inexperienced ophthalmologist. Obtained results were retrospectively assessed with regard to precision and speed of laser application. RESULTS: Precision of laser therapy was quite similar, 88 % and 84 % for experienced and inexperienced operators, respectively. The treatment procedure took on average 5.5 minutes and 5.34 minutes for experienced and inexperienced operators, respectively. CONCLUSIONS: Precision and duration of therapy using the Navilas laser system do not seem to be correlated with the individual experience of the treating physician.

Refractory neuro-Behçet treated by tocilizumab: a case report.

A patient with central nervous system involvement of Behçet's disease was refractory to conventional immunosuppressive therapy and showed secondary failure of the anti-TNF agent infliximab. This presented as a progressive weakness of the legs and reduction in walking distance. The cerebrospinal fluid showed signs of inflammation including a vastly elevated IL-6 concentration. Given this result, the anti-IL-6 receptor antibody tocilizumab was administered and a good improvement of inflammatory parameters and a satisfactory increase of the walking distance were achieved.

[Traumatic proptosis]. / Traumatische Proptosis.

The emergency consultation of a female patient revealed a left-sided prolapse of the eyeball with visual loss. The patient had fallen against an object hitting the left eye 40 min prior to the consultation. Motility of the eye was severely restricted and retinoscopy was impossible due to a corneal edema. The pupil was moderately dilated and non-reactive. The ocular pressure was 50 mmHg. Spontaneous repositioning was unsuccessful and an immediate lateral canthotomy was performed. The follow-up control showed that the patient had recovered good visual acuity with a reduction of intraocular pressure and pain. The latest findings were uneventful.

[Fractures associated with dimonshed bone density, thypercalciuria and osteolysis. Is the diagnosis an osteoporosis or a syndrome?]. / Frakturen bei verminderter Knochendichte, Hyperkalziurie und Osteolysen - Osteoporose oder Syndrom?

At first osteomalacia was presumed clinically and radiologically in a 49-year old female patient. Radiologically there were multiple suspected neoplastic osseous infiltrations, which was not confirmed by subsequent investigations. There were no indications of osteomalacia or malabsorption in the laboratory exams. The multiple microfractures and osteolysis of the fingers, the toes, the wrist and the tarsus detected with varius imaging techniques were ascribed to an acroosteolysis. Osteoporosis of both femoral necks was also present in dual photon X-ray absorptiometry densitometry. Cheney Syndrom (HCS) was diagnosed clinically and radiologically and a treatment with bisphosphonates was introduced.

[Mononeuritis multiplex under the TNF-alpha inhibitor infliximab]. / Mononeuritis multiplex unter dem TNF-alpha-Hemmer Infliximab.

A 21-year-old patient with ankylosing spondylitis under treatment with the TNF-alpha inhibitor infliximab developed a multifocal, demyelinating axonal neuropathy affecting several peripheral nerves simultaneously (mononeuritis multiplex). This represents an additional rare peripheral nervous system side effect of infliximab therapy. The underlying cause is unknown. Intravenous immunoglobulin therapy (0.4 g/kg per day for five days) led to a complete regression of muscle paresis and sensory defects in this case.

Floating gate synapses with spike-time-dependent plasticity.

This paper describes a single transistor floating-gate synapse device that can be used to store a weight in a nonvolatile manner, compute a biological EPSP, and demonstrate biological learning rules such as Long-Term Potentiation, LTD, and spike-time dependent plasticity. We also describe a highly scalable architecture of a matrix of synapses to implement the described learning rules. Parameters for weight update in the 0.35 um process have been extracted and can be used to predict the change in weight based on time difference between pre- and post-synaptic spike times.

Neural dynamics in reconfigurable silicon.

A neuromorphic analog chip is presented that is capable of implementing massively parallel neural computations while retaining the programmability of digital systems. We show measurements from neurons with Hopf bifurcations and integrate and fire neurons, excitatory and inhibitory synapses, passive dendrite cables, coupled spiking neurons, and central pattern generators implemented on the chip. This chip provides a platform for not only simulating detailed neuron dynamics but also uses the same to interface with actual cells in applications such as a dynamic clamp. There are 28 computational analog blocks (CAB), each consisting of ion channels with tunable parameters, synapses, winner-take-all elements, current sources, transconductance amplifiers, and capacitors. There are four other CABs which have programmable bias generators. The programmability is achieved using floating gate transistors with on-chip programming control. The switch matrix for interconnecting the components in CABs also consists of floating-gate transistors. Emphasis is placed on replicating the detailed dynamics of computational neural models. Massive computational area efficiency is obtained by using the reconfigurable interconnect as synaptic weights, resulting in more than 50 000 possible 9-b accurate synapses in 9 mm(2).

Early postoperative recovery of idiopathic macular hole in a young adult.

BACKGROUND: Idiopathic macular holes usually develop in the elderly. We report the case of a spontaneous macular hole in a 23-year-old man. HISTORY AND SIGNS: The patient noticed decreased central vision in his left eye since 5 days without any history of trauma or intraocular inflammation. On examination the best corrected visual acuity was 20/20 in the right eye and 20/50 in the left. Fundus biomicroscopy and OCT showed a full-thickness macular hole. Microperimetry demonstrated a scotoma within the macular hole. THERAPY AND OUTCOME: 2 months later the patient underwent pars plana vitrectomy, ILM-peeling with trypan blue staining and fluid-air exchange followed by face down positioning for 12 h a day for 2 days. On the 4th post-surgical day visual acuity was 20/32 and OCT showed a complete closure of the macular hole. During the further follow-up visual acuity in the left eye improved to 20/20. OCT examination showed a restored foveal depression, and microperimetry demonstrated an increased foveal sensitivity in the area of the previous scotoma. CONCLUSIONS: The aetiology of the macular hole in this patient is unclear. It is most likely an idiopathic macular hole in a young person. Post-surgical follow-up OCTs and microperimetry disclosed an early recovery of the foveal anatomy and function.

Early foveal recovery after macular hole surgery.

AIMS: To evaluate morphological and functional recovery after macular hole surgery using pars plana vitrectomy (PPV), inner limiting membrane (ILM) peeling, air-tamponade and short-time limited face-down positioning. DESIGN: Retrospective, interventional, non-comparative consecutive case series. PATIENTS: Thirty eyes in 30 patients (30 eyes) with unilateral full-thickness macular hole (stage II-IV). INTERVENTION: All eyes underwent PPV, ILM peeling and fluid-air exchange followed by postoperative face-down positioning for 2 days. MAIN OUTCOME MEASURES: Best corrected visual acuity, optical coherence tomography (OCT) assessment of macular integrity, and biomicroscopy at days 3 and 7, and months 1, 3, 6 and 12. RESULTS: On postoperative day 3, OCT demonstrated macular hole closure in 28 eyes (93%). One eye required vitrectomy 7 weeks after initial surgery due to retinal detachment. CONCLUSIONS: In the present case series, PPV with Trypan Blue-assisted ILM peeling, short-acting internal tamponade and thus shorter face-down positioning was associated with a 93% macular hole closure rate.

Zygnematalean zygospores: morphological features and use in species identification.

Suitable morphological characteristics for identification of zygnematalean algae were determined using a combination of classical light microscopy (LM) techniques, fluorescence microscopy (with blue and green excitation), scanning electron microscopy (SEM) and specialized culture methods. Characteristics of spore germination, growth and reproduction under culture conditions identified Zygnema chalybeo-spermum in a mixture of zygnematalean spores collected from a small fishpond in Czechia. Reproduction in general, particularly aplanospore formation and lateral conjugation was more frequent and occurred earlier in a nutrient poor medium than in a nutrient rich medium, where vegetative growth was more vigorous. Variability in spore size was wide and influenced by the origin (sexual and/or asexual) of the spores. Asexual spores, particularly partenospores were rounded and significantly smaller than sexual ones. Thus spore morphology alone (size and shape) is not a particularly helpful characteristic for species identification. The mesospore of mature spores contained lipids and a sporopolenin-like material (algaenan), which showed green autofluorescence with blue excitation. The mesospore ornamentation, the only characteristic found that is suitable for identification purposes, can be observed easily in LM and SEM after exospore removal by KOH treatment. Detailed LM and SEM observations of the zygospores of all Zygnema species thus could provide basic data necessary for the preparation of an atlas and key for species identification which, after completion with molecular methods, brings clarification into the genetic relationships between morphospecies.

Combination therapy of PDT and triamcinolone in CNV associated with fundus flavimaculatus.

BACKGROUND: Photodynamic therapy (PDT) performed in this rare condition showed promising results according to 3 other case reports. HISTORY AND SIGNS: A 47-year-old female patient with fundus flavimaculatus developed metamorphopsia and minimal vision deterioration (20/25) in her left eye. Fluorescein angiography revealed all signs of classic choroidal neovascularisation (CNV). THERAPY AND OUTCOME: After the first PDT treatment with a spot adapted to the size of the juxtafoveal CNV (1.5 mm) and standard parameters visual acuity (VA) dropped to 20/63, more leakage and progression to subfoveal CNV was observed. 3 months after the second PDT VA was 20/80 and FA revealed persistent leakage. Given the results of the combination treatment in age-related macular degeneration and the poor outcome seen after PDT alone in this case, PDT and intravitreal injection of 4 mg triamcinolone acetonide on the same day was applied. 3, 6 and 9 months after treatment VA stabilised at 20/63 and FA showed confirmed regression of the CNV and, thus, no leakage, but scarring. CONCLUSIONS: To the best of our knowledge this is the first published report of CNV secondary to fundus flavimaculatus in which PDT alone failed to stop leakage and progression of the CNV. However therapy combined with triamcinolone acetonide was successful.

[Hearing loss after lumbar myelography]. / Hörverlust nach Myelographie.

Hearing loss is a possible sequel of myelography. We describe a case of bilateral hearing loss of -60 dB, which recovered completely after an epidural blood patch. In hearing loss or tinnitus in association with a possible cerebrospinal fluid loss after a diagnostic or therapeutic puncture of the lumbar dural sack, an epidural blood patch is a viable and recommended therapeutic option.