Noninvasive imaging-guided ultrasonic neurostimulation with arbitrary 2D patterns and its application for high-quality vision restoration.

Retinal degeneration, a leading cause of irreversible low vision and blindness globally, can be partially addressed by retina prostheses which stimulate remaining neurons in the retina. However, existing electrode-based treatments are invasive, posing substantial risks to patients and healthcare providers. Here, we introduce a completely noninvasive ultrasonic retina prosthesis, featuring a customized ultrasound two-dimensional array which allows for simultaneous imaging and stimulation. With synchronous three-dimensional imaging guidance and auto-alignment technology, ultrasonic retina prosthesis can generate programmed ultrasound waves to dynamically and precisely form arbitrary wave patterns on the retina. Neuron responses in the brain's visual center mirrored these patterns, evidencing successful artificial vision creation, which was further corroborated in behavior experiments. Quantitative analysis of the spatial-temporal resolution and field of view demonstrated advanced performance of ultrasonic retina prosthesis and elucidated the biophysical mechanism of retinal stimulation. As a noninvasive blindness prosthesis, ultrasonic retina prosthesis could lead to a more effective, widely acceptable treatment for blind patients. Its real-time imaging-guided stimulation strategy with a single ultrasound array, could also benefit ultrasound neurostimulation in other diseases.

Measuring spatial visual loss in rats by retinotopic mapping of the superior colliculus using a novel multi-electrode array technique.

BACKGROUND: The retinotopic map property of the superior colliculus (SC) is a reliable indicator of visual functional changes in rodents. Electrophysiological mapping of the SC using a single electrode has been employed for measuring visual function in rat and mouse disease models. Single electrode mapping is highly laborious requiring long-term exposure to the SC surface and prolonged anesthetic conditions that can adversely affect the mapping data. NEW METHOD: To avoid the above-mentioned issues, we fabricated a fifty-six (56) electrode multi-electrode array (MEA) for rapid and reliable visual functional mapping of the SC. Since SC is a dome-shaped structure, the array was made of electrodes with dissimilar tip lengths to enable simultaneous and uniform penetration of the SC. RESULTS: SC mapping using the new MEA was conducted in retinal degenerate (RD) Royal College of Surgeons (RCS) rats and rats with focal retinal damage induced by green diode laser. For SC mapping, the MEA was advanced into the SC surface and the visual activities were recorded during full-filed light stimulation of the eye. Based on the morphological examination, the MEA electrodes covered most of the exposed SC area and penetrated the SC surface at a relatively uniform depth. MEA mapping in RCS rats (n=9) demonstrated progressive development of a scotoma in the SC that corresponded to the degree of photoreceptor loss. MEA mapping in the laser damaged rats demonstrated the presence of a scotoma in the SC area that corresponded to the location of retinal laser injury. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: The use of MEA for SC mapping is advantageous over single electrode recording by enabling faster recordings and reducing anesthesia time. This study establishes the feasibility of the MEA technique for rapid and efficient SC mapping, particularly advantageous for evaluating therapeutic effects in retinal degenerate rat disease models.

Ultrasound Flow Imaging Study on Rat Brain with Ultrasound and Light Stimulations.

Functional ultrasound (fUS) flow imaging provides a non-invasive method for the in vivo study of cerebral blood flow and neural activity. This study used functional flow imaging to investigate rat brain's response to ultrasound and colored-light stimuli. Male Long-Evan rats were exposed to direct full-field strobe flashes light and ultrasound stimulation to their retinas, while brain activity was measured using high-frequency ultrasound imaging. Our study found that light stimuli, particularly blue light, elicited strong responses in the visual cortex and lateral geniculate nucleus (LGN), as evidenced by changes in cerebral blood volume (CBV). In contrast, ultrasound stimulation elicited responses undetectable with fUS flow imaging, although these were observable when directly measuring the brain's electrical signals. These findings suggest that fUS flow imaging can effectively differentiate neural responses to visual stimuli, with potential applications in understanding visual processing and developing new diagnostic tools.

Investigation of the interaction of thymine drugs with Be12O12 and Ca12O12 nanocages: A quantum chemical study.

Based on the DFT in a Wb97xd/6-311+G* level of theory, the interaction of thymine derivatives with Be12O12 and Ca12O12 nanocages was investigated. It was found that adsorption energies of thymine molecules on the Be12/Ca12-O12 surface was around -43.16, -60.06 and -29.62, -50.71, -45.95, -30.27 kcal/mol, for thymine (TH1), 1-amino thymine (TH2) and thymine glycol (TH3), respectively and this result supported the drug's adsorption. Additionally, according to the FMOs and MEP studies, a charge transfer from TH's to nanocages. Additionally, both molecular orbitals demonstrate that the LUMO and HOMO are primarily found on the BeO's surface.

TD-DFT, DFT, docking, MD simulations, and concentration-dependent SERS investigations of a bioactive trifluoromethyl derivative having human acetylcholinesterase and butyrylcholinesterase in silver colloids.

CONTEXT: Various concentrations of (E)-4-methoxy-N'-(2-(trifluoromethyl)benzylidene) benzohydrazide (EMT) adsorbed on colloidal silver nanoparticles were studied using SERS and results were compared to the normal Raman spectrum. DFT calculations were used to validate experimental findings. Theoretically, the structures of the EMT and EMT-Ag6 systems were optimized. The UV-Vis spectral analysis's red shift and lower intensity behavior show that EMT has chemisorbed onto Ag nanoparticles. Charge transfer (CT) from Ag to EMT is highlighted by FMO analysis. The CT interaction in EMT and EMT-Ag6 was further verified by MEP and Mulliken charge analyses. The EMT was adsorbed on Ag nanoparticles with tilted orientation and orientation changes with colloidal concentration, according to SERS spectrum analysis. Docking EMT with 4PQE and 5DYW binding affinities are found to be -9.7 and -8.1 kcal/mol. MD simulations give the competence of 5DYW-EMT and 4PQE-EMT in their intended binding interactions and their ability to establish enduring associations with the protein of interest. METHODS: DFT was used to optimize the molecular structures of EMT and EMT-Ag6 using B3LYP/6-311++G* (LANL2DZ basis set for Ag). A molecular dynamics simulation study was conducted on the 4PQE-EMT and 5DYW-EMT systems using the Desmond software for 100 ns.

Non-Invasive Hybrid Ultrasound Stimulation of Visual Cortex In Vivo.

The optic nerve is the second cranial nerve (CN II) that connects and transmits visual information between the retina and the brain. Severe damage to the optic nerve often leads to distorted vision, vision loss, and even blindness. Such damage can be caused by various types of degenerative diseases, such as glaucoma and traumatic optic neuropathy, and result in an impaired visual pathway. To date, researchers have not found a viable therapeutic method to restore the impaired visual pathway; however, in this paper, a newly synthesized model is proposed to bypass the damaged portion of the visual pathway and set up a direct connection between a stimulated visual input and the visual cortex (VC) using Low-frequency Ring-transducer Ultrasound Stimulation (LRUS). In this study, by utilizing and integrating various advanced ultrasonic and neurological technologies, the following advantages are achieved by the proposed LRUS model: 1. This is a non-invasive procedure that uses enhanced sound field intensity to overcome the loss of ultrasound signal due to the blockage of the skull. 2. The simulated visual signal generated by LRUS in the visual-cortex-elicited neuronal response in the visual cortex is comparable to light stimulation of the retina. The result was confirmed by a combination of real-time electrophysiology and fiber photometry. 3. VC showed a faster response rate under LRUS than light stimulation through the retina. These results suggest a potential non-invasive therapeutic method for restoring vision in optic-nerve-impaired patients using ultrasound stimulation (US).

Inhaled pirfenidone solution (AP01) for IPF: a randomised, open-label, dose-response trial.

INTRODUCTION: Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue. Reduced doses may be suboptimal in slowing disease progression. METHODS: This phase 1b, randomised, open-label, dose-response trial at 25 sites in six countries (Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618001838202) assessed safety, tolerability and efficacy of inhaled pirfenidone (AP01) in IPF. Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%-90% predicted, and intolerant, unwilling or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulised AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks. RESULTS: We present results for week 24, the primary endpoint and week 48 for comparability with published trials of antifibrotics. Week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study. Ninety-one patients (50 mg once per day: n=46, 100 mg two times per day: n=45) were enrolled from May 2019 to April 2020. The most common treatment-related adverse events (frequency, % of patients) were all mild or moderate and included cough (14, 15.4%), rash (11, 12.1%), nausea (8, 8.8%), throat irritation (5, 5.5%), fatigue (4, 4.4%) and taste disorder, dizziness and dyspnoea (three each, 3.3%). Changes in FVC % predicted over 24 and 48 weeks, respectively, were -2.5 (95% CI -5.3 to 0.4, -88 mL) and -4.9 (-7.5 to -2.3,-188 mL) in the 50 mg once per day and 0.6 (-2.2 to 3.4, 10 mL) and -0.4 (-3.2 to 2.3, -34 mL) in the 100 mg two times per day group. DISCUSSION: Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01. Mean FVC % predicted remained stable in the 100 mg two times per day group. Further study of AP01 is warranted. TRIAL REGISTRATION NUMBER: ACTRN12618001838202 Australian New Zealand Clinical Trials Registry.

Development of a Surgical Technique for Subretinal Implants in Rats.

Retinal degeneration, such as age-related macular degeneration (AMD), is a leading cause of blindness worldwide. A myriad of approaches have been undertaken to develop regenerative medicine-based therapies for AMD, including stem cell-based therapies. Rodents as animal models for retinal degeneration are a foundation for translational research, due to the broad spectrum of strains that develop retinal degeneration diseases at different stages. However, mimicking human therapeutic delivery of subretinal implants in rodents is challenging, due to anatomical differences such as lens size and vitreous volume. This surgical protocol aims to provide a guided method for transplanting implants into the subretinal space in rats. A user-friendly comprehensive description of the critical steps has been included. This protocol has been developed as a cost-efficient surgical procedure for reproducibility across different preclinical studies in rats. Proper miniaturization of a human-sized implant is required prior to conducting the surgical experiment, which includes adjustments to the dimensions of the implant. An external approach is used instead of an intravitreal procedure to deliver the implant to the subretinal space. Using a small sharp needle, a scleral incision is performed in the temporal superior quadrant, followed by paracentesis to reduce intraocular pressure, thereby minimizing resistance during the surgical implantation. Next, a balanced salt solution (BSS) injection through the incision is carried out to achieve focal retinal detachment (RD). Lastly, insertion and visualization of the implant into the subretinal space are conducted. Post-operative assessment of the subretinal placement of the implant includes imaging by spectral domain optical coherence tomography (SD-OCT). Imaging follow-ups ascertain the subretinal stability of the implant, before the eyes are harvested and fixated for histological analysis.

Comparison of Conventional Methods with Newer Diagnostic Modalities to Detect Genital Tuberculosis in Infertile Women.

Background: Genital tuberculosis is one of the leading causes of female infertility. Paucibacillary nature of the disease in the female genital system often makes its diagnosis difficult. No single test has been able to accurately diagnose genital tuberculosis. In this study we aim to compare conventional diagnostic tests for tuberculosis like Acid Fast Bacilli (AFB) Staining, Lowenstein Jensen (LJ) Culture and Histopathology with newer tests like PCR, MGIT 960, GeneXpert. Methods: This study included 67 infertile women from Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi. They were subjected to detailed history and routine investigations, namely Haemogram, ESR, Mantoux test, Chest X-ray and pelvic ultrasound to look for the findings of tuberculosis. A premenstrual endometrial aspirate was taken and was subjected to the AFB Staining, LJ Culture, Histopathology, PCR, MGIT 960, Gene Xpert, and the test results were compared. Result and Conclusion: 35.8% (24/67) of women were diagnosed with genital tuberculosis using the diagnostic criteria. With culture as the gold standard, the positivity of genital TB was 19.4% (13/67). Majority of infertile patients with low index of suspicion clinically were positive for genital tuberculosis. Therefore, all the patients of infertility should be routinely evaluated for genital tuberculosis. PCR and MGIT 960 have shown promising results in the newer methods. LJ culture and histopathology are still the most reliable and available diagnostic methods. The usefulness of AFB Staining and GeneXpert remains questionable.

A New Optokinetic Testing Method to Measure Rat Vision.

Optokinetic nystagmus (OKN) is a reflexive eye movement initiated by the motion of visual stimuli in the field of vision. The head-tracking movement associated with OKN is commonly used as a measure of visual function in rodents. To record OKN responses in normal and experimental rats, a simple and inexpensive apparatus has been developed. This setup uses two tablet screens to display the OKN visual stimulus consisting of high contrast black and white stripes generated using the OKN Stripes Visualization Web Application, a freely available software. The rat is placed inside a clear Plexiglass holder that limits movement so that the rat's head continuously faces the OKN display screen. The position of the rat holder can be changed to adjust the distance between the rat and the display screen. A micro-camera positioned above the rat holder is used to record the rat's visual activities. These recordings can be used for quantitative assessments. Based on the presence or absence of clear head-tracking, the OKN responses at different spatial frequencies can be determined. The collected data demonstrates a novel technique for reliable measurement of visual acuity in normal and retinal degenerate rats.

Imaging Approach to Pulmonary Infections in the Immunocompromised Patient.

Pulmonary infections are the major cause of morbidity and mortality in immunocompromised patients and almost one-third of intensive care unit patients with pulmonary infections belong to the immunocompromised category. Multiple organisms may simultaneously infect an immunocompromised patient and the overwhelming burden of mixed infections further predisposes critically ill patients to acute hypoxemic respiratory failure. Notwithstanding that lung ultrasound is coming into vogue, the primary imaging investigation is a chest radiograph, followed by thoracic CT scan. This review based on our experience at tertiary care teaching hospitals provides insights into the spectrum of imaging features of various pulmonary infections occurring in immunocompromised patients. This review is unique as, firstly, the imaging spectrum described by us is categorized on basis of the etiological infective agent, comprehensively and emphatically correlated with the clinical setting of the patient. Secondly, a characteristic imaging pattern is emphasized in the clinical setting-imaging-pattern conglomerate, to highlight the most likely diagnosis possible in such a combination. Thirdly, the simulating conditions for a relevant differential diagnosis are discussed in each section. Fourthly, not only are the specific diagnostic and tissue sampling techniques for confirmation of the suspected etiological agent described, but the recommended pharmaco-therapeutic agents are also enumerated, so as to provide a more robust insight to the radiologist. Last but not the least, we summarize and conclude with a diagnostic algorithm, derived by us from the characteristic illustrative cases. The proposed algorithm, illustrated as a flowchart, emphasizes a diagnostic imaging approach comprising: correlation of the imaging pattern with clinical setting and with associated abnormalities in the thorax and in other organs/systems, which is comprehensively analyzed in arriving at the most likely diagnosis. Since a rapid evaluation and emergent management of such patients is of pressing concern not only to the radiologist, but also for the general physicians, pulmonologists, critical care specialists, oncologists and transplant surgery teams, we believe our review is very informative to a wide spectrum reader audience.

Role of GeneXpertMTB/RIF in the diagnosis of cutaneous tuberculosis.

BACKGROUND: cutaneous involevemtn is an important extrapulmonary manifestation of tuberculosis. It is a paucibacillary condition and has diverse clinical presentations. Sufficient data is not available regarding role of GeneXpertMTB/RIF in cutanoues tuberculosis. METHODS: in this study, BacT/Alert3D and response to antitubercular therapy were taken as gold standard and performance of GeneXpertMTB/RIF was evaluated against it in clinically and histopathologically suspected cases of cutaneous tuberculosis. RESULTS: forty seven patients were included in the study of which commonest presentation was scrofuloderma (42.6%) followed by lupus vulgaris (40.4%). Granulomatous inflammation on histopathology was seen in 75.5% patients on skin biopsy. Sic patients had extracutaneous focus of tuberculosis. In 14 (29.79%), culture of skin biopsy was positive for M. tuberculosis and all showed complete response to ATT in 6 months. GeneXpertMTB/RIF detected M. tuberculsois in 4 samples. CONCLUSION: GeneXpertMTB/RIF is not a reliable tool for diagnosis of cutaneous tuberculosis. Clinic-histopathological correlation along with response to ATT is needed for confirmation of diagnosis of cutaneous tuberculosis.

Stem Cell-based Treatment Strategies for Degenerative Diseases of the Retina.

BACKGROUND: The main cause of progressive vision impairment in retinal degenerative diseases is the dysfunction of photoreceptors and the underlying retinal pigment epithelial cells. The inadequate regenerative capacity of the neural retina and lack of established therapeutic options demand the development of clinical-grade protocols to halt the degenerative process in the eye or replace the damaged cells by using stem cell-derived products. Recently, stem cell-based regenerative therapies have been at the forefront of clinical investigations for retinal dystrophies. OBJECTIVE: This article will review different stem cell-based therapies currently employed for retinal degenerative diseases, recent clinical trials, and major challenges in the translation of these therapies from bench to bedside. METHODOLOGY: A systematic literature review was conducted to identify potentially relevant articles published in MEDLINE/PubMed, Embase, ClinicalTrials.gov, Drugs@FDA, European Medicines Agency, and World Health Organization International Clinical Trials Registry Platform. RESULTS: Transplantation of healthy cells to replace damaged cells in the outer retina is a clinically relevant concept because the inner retina that communicates with the visual areas of the brain remains functional even after the photoreceptors are completely lost. Various methods have been established for the differentiation of pluripotent stem cells into different retinal cell types that can be used for therapies. Factors released from transplanted somatic stem cells showed trophic support and photoreceptor rescue during the early stages of the disease. Several preclinical and phase I/II clinical studies using terminally differentiated photoreceptor/retinal pigment epithelial cells derived from pluripotent stem cells have shown proof of concept for visual restoration in Age-related Macular Degeneration (AMD), Stargardt disease, and Retinitis Pigmentosa (RP). CONCLUSION: Cell replacement therapy has great potential for vision restoration. The results obtained from the initial clinical trials are encouraging and indicate its therapeutic benefits. The current status of the therapies suggests that there is a long way to go before these results can be applied to routine clinical practice. Input from the ongoing multicentre clinical trials will give a more refined idea for the future design of clinical-grade protocols to transplant GMP level HLA matched cells.

Long-Term Transplant Effects of iPSC-RPE Monolayer in Immunodeficient RCS Rats.

Retinal pigment epithelium (RPE) replacement therapy is evolving as a feasible approach to treat age-related macular degeneration (AMD). In many preclinical studies, RPE cells are transplanted as a cell suspension into immunosuppressed animal eyes and transplant effects have been monitored only short-term. We investigated the long-term effects of human Induced pluripotent stem-cell-derived RPE (iPSC-RPE) transplants in an immunodeficient Royal College of Surgeons (RCS) rat model, in which RPE dysfunction led to photoreceptor degeneration. iPSC-RPE cultured as a polarized monolayer on a nanoengineered ultrathin parylene C scaffold was transplanted into the subretinal space of 28-day-old immunodeficient RCS rat pups and evaluated after 1, 4, and 11 months. Assessment at early time points showed good iPSC-RPE survival. The transplants remained as a monolayer, expressed RPE-specific markers, performed phagocytic function, and contributed to vision preservation. At 11-months post-implantation, RPE survival was observed in only 50% of the eyes that were concomitant with vision preservation. Loss of RPE monolayer characteristics at the 11-month time point was associated with peri-membrane fibrosis, immune reaction through the activation of macrophages (CD 68 expression), and the transition of cell fate (expression of mesenchymal markers). The overall study outcome supports the therapeutic potential of RPE grafts despite the loss of some transplant benefits during long-term observations.

Tissue Engineering Strategies for Retina Regeneration.

The retina is a complex and fragile photosensitive part of the central nervous system which is prone to degenerative diseases leading to permanent vision loss. No proven treatment strategies exist to treat or reverse the degenerative conditions. Recent investigations demonstrate that cell transplantation therapies to replace the dysfunctional retinal pigment epithelial (RPE) cells and or the degenerating photoreceptors (PRs) are viable options to restore vision. Pluripotent stem cells, retinal progenitor cells, and somatic stem cells are the main cell sources used for cell transplantation therapies. The success of retinal transplantation based on cell suspension injection is hindered by limited cell survival and lack of cellular integration. Recent advances in material science helped to develop strategies to grow cells as intact monolayers or as sheets on biomaterial scaffolds for transplantation into the eyes. Such implants are found to be more promising than the bolus injection approach. Tissue engineering techniques are specifically designed to construct biodegradable or non-degradable polymer scaffolds to grow cells as a monolayer and construct implantable grafts. The engineered cell construct along with the extracellular matrix formed, can hold the cells in place to enable easy survival, better integration, and improved visual function. This article reviews the advances in the use of scaffolds for transplantation studies in animal models and their application in current clinical trials.

Knowledge acquisition and retention after a high flow training programme in Peru: a quasi-experimental single group pre-post design.

OBJECTIVE: Respiratory infections remain the leading infectious cause of death in children under 5 and disproportionately affect children in resource-limited settings. Implementing non-invasive respiratory support can reduce respiratory-related mortality. However, maintaining competency after deployment can be difficult. Our objective was to evaluate the effectiveness of a comprehensive multidisciplinary high-flow training programme in a Peruvian paediatric intensive care unit (PICU). DESIGN: Quasi-experimental single group pre-post intervention study design. SETTING: Quaternary care PICU in a resource-constrained setting in Lima, Peru. PARTICIPANTS: Attending physicians, fellows, paediatric residents, registered nurses, respiratory therapists and medical technicians working in the PICU were invited to participate. INTERVENTIONS: Concurrent with initial high-flow deployment, we implemented a training programme consisting of lectures, case-based discussion and demonstrations with baseline, 3-month and 12-month training sessions. Pre-training and post-training assessment surveys were distributed surrounding all training sessions. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was achieving minimum competency (median score of 80%) on the high flow training assessment tool. Secondary outcomes included knowledge acquisition (differences in pre-baseline and post-baseline training assessments), short-term retention (differences in post-baseline and pre-3-month refresher training assessments) and long-term retention (differences in post-3-month refresher and pre-12-month refresher training assessments). RESULTS: Eighty participants (50% nurses, 15% ICU physicians and 34% other providers) completed the baseline assessment. Participants showed improvement in overall score and all subtopics except the clinical application of knowledge after baseline training (p<0.001). Participants failed to retain minimum competency at 3-month and 12-month follow-up assessments (70% (IQR: 57-74) and 70% (IQR: 65-74), respectively). After repeat training sessions, overall knowledge continued to improve, exceeding baseline performance (78% (IQR: 70-87), 83% (IQR: 74-87) and 87% (IQR: 83-91) at baseline, 3 and 12 months, respectively). CONCLUSION: This study suggests the need for repeat training sessions to achieve and maintain competency after the implementation of new technology.

Factors Associated with Health-Related Quality of Life in Children with Intestinal Failure.

OBJECTIVE: To evaluate disease-specific and age-related factors contributing to health-related quality of life (HRQOL). in children with intestinal failure. STUDY DESIGN: A prospective study of HRQOL was performed in a regional intestinal rehabilitation program. Parent-proxy Pediatric Quality of Life Inventory surveys were administered annually to families of 91 children with intestinal failure over a 6-year period. Survey data was stratified by age and compared with pediatric HRQOL data in healthy and chronically ill populations. Linear mixed-effect models using multivariable regression were constructed to identify associations with HRQOL. RESULTS: A total of 180 surveys were completed by 91 children and their families. HRQOL scores were lowest for children ages 5-7 years (P < .001) and 8-12 years (P < .01), and these changes were primarily related to school dimension scores. In multivariable regression, age of 5 years and older and developmental delay were independently associated with lower HRQOL scores. The trend toward lower HRQOL scores parallels reference data from healthy and chronically ill children, although patients with intestinal failure scored lower than both populations at school age. CONCLUSIONS: Children with intestinal failure experience lower parent-proxy HRQOL scores in the 5-7 and 8-12 year age groups primarily related to school dimension scores. Multicenter data to validate these findings and identify interventions to improve QOL for children with intestinal failure are needed.

Predictors of Hand Contracture in Early Systemic Sclerosis and the Effect on Function: A Prospective Study of the GENISOS Cohort.

OBJECTIVE: To identify baseline features that predict progression of hand contractures and to assess the effect of contractures on functional status in the prospective GENISOS cohort. METHODS: Rate of decline in hand extension, as an indicator of hand contracture, was the primary outcome. We assessed longitudinal hand extension measurements, modified Health Assessment Questionnaire (MHAQ) score, Medical Outcomes Study Short Form-36 (SF-36) physical function score, and demographic, clinical, and serological variables. Subjects with ≥ 2 hand measurements at least 6 months apart were included. RESULTS: A total of 1087 hand measurements for 219 patients were available over an average of 8.1 ± 4.8 years. Hand extension decreased on average by 0.11 cm/year. Antitopoisomerase I antibody (ATA) positivity and higher modified Rodnan Skin Score (mRSS) were predictive of faster decline in hand extension (p = 0.009 and p = 0.046, respectively). In a subgroup analysis of 62 patients with ≤ 2 years from SSc onset, ATA and diffuse disease type were associated with faster decline in hand extension; anticentromere positivity was associated with slower rate of decline. Although the rate of decline in patients with disease duration ≤ 2 years was numerically higher, the difference was not statistically significant. Hand extension continued to decline in a linear fashion over time and was inversely related to overall functional status. CONCLUSION: ATA was predictive of contracture development in both early disease (≤ 2 yrs) and in the overall cohort. Hand extension declined linearly over time and was inversely associated with MHAQ and SF-36 scores. ATA positivity and higher baseline mRSS were predictive of faster decline in hand extension.

Comparative Evaluation of Molecular Tests Vis-à-Vis Culture and Treatment Response in the Diagnosis of Cutaneous Tuberculosis.

The clinical diagnosis of cutaneous tuberculosis (CT) was based on criteria of reinfection and reactivation. Laboratory tests are mandatory but have limitations, thus demanding continuous innovation. In our study, we took punch biopsies from lesions on 48 patients. Half of these biopsies underwent histopathologic investigation, and the other half were analysed using the BACT Alert 3D system, the Amplified Mycobacterium Tuberculosis Direct Test (AMTDT), and DNA amplification by polymerase chain reaction (PCR) using primers specific for the M. tuberculosis 16SrRNA complex. Patients were given antitubercular therapy for 6 weeks. A positive response was indicative of CT. Histopathology was suggestive, although no acid-fast bacilli could be demonstrated. In vitro culture recovery of M. tuberculosis was possible in six (12.5%); only two (4%) were positive on AMTDT, and 14 (29%) on real-time PCR. Regression of skin lesions was remarkable after antitubercular therapy, irrespective of a laboratory result. AMTDT and real-time PCR are seen to be of low value in the diagnosis of CT. They are limited by high cost, their paucibacillary nature, and technical errors. On comparing has AMTDT and PCR, the latter was found to be superior. High percentages of negative results were also investigated; extensive involvement of skin has yielded positive PCR results, probably due to low immunity and high bacterial load.