Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial

Background : By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01).  We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment.Methods: This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C.Discussion: Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified. TRIAL REGISTRATION: NCT02821832

UK Head and neck cancer surgical capacity during the second wave of the COVID—19 pandemic: Have we learned the lessons? COVIDSurg collaborative

Objectives The aim of this study was to evaluate the differences in surgical capacity for head and neck cancer in the UK between the first wave (March-June 2020) and the current wave (Jan-Feb 2021) of the COVID-19 pandemic. Design REDcap online-based survey of hospital capacity. Setting UK secondary and tertiary hospitals providing head and neck cancer surgery. Participants One representative per hospital was asked to report the capacity for head and neck cancer surgery in that institution. Main outcome measures The principal measures of interests were new patient referrals, capacity in outpatients, theatres and critical care; therapeutic compromises constituting delay to surgery, de-escalated surgery and therapeutic migration to non-surgical primary modality. Results Data were returned from approximately 95% of UK hospitals with a head and neck cancer surgery specialist service. 50% of UK head and neck cancer patients requiring surgery have significantly compromised treatments during the second wave: 28% delayed, 10% have received radiotherapy-based treatment instead of surgery, and 12% have received de-escalated surgery. Surgical capacity has been more severely constrained in the second wave (58% of pre-pandemic level) compared with the first wave (62%) despite the time to prepare. Conclusions Some hospitals are overwhelmed by COVID-19 and unable to offer essential cancer surgery, but all have neighbouring hospitals in their region retaining good (or even normal) capacity. It is noteworthy that very few patients have been appropriately redirected away from the hospitals most constrained by their burden of COVID-19. The paucity of an effective central or regional strategic response to this evident mismatch between demand and surgical capacity is to the detriment of our head and neck cancer patients

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics

Surgical and conservative treatment of patients with congenital scoliosis: α search for long-term results

<p>Abstract</p> <p>Background</p> <p>In view of the limited data available on the conservative treatment of patients with congenital scoliosis (CS), early surgery is suggested in mild cases with formation failures. Patients with segmentation failures will not benefit from conservative treatment. The purpose of this review is to identify the mid- or long-term results of spinal fusion surgery in patients with congenital scoliosis.</p> <p>Methods</p> <p>Retrospective and prospective studies were included, reporting on the outcome of surgery in patients with congenital scoliosis. Studies concerning a small numbers of cases treated conservatively were included too. We analyzed mid-term (5 to 7 years) and long-term results (7 years or more), both as regards the maintenance of the correction of scoliosis and the safety of instrumentation, the early and late complications of surgery and their effect on quality of life.</p> <p>Results</p> <p>A small number of studies of surgically treated patients were found, contained follow-up periods of 4-6 years that in the most cases, skeletal maturity was not yet reached, and few with follow-up of 36-44 years. The results of bracing in children with congenital scoliosis, mainly in cases with failure of formation, were also studied.</p> <p>Discussion</p> <p>Spinal surgery in patients with congenital scoliosis is regarded in short as a safe procedure and should be performed. On the other hand, early and late complications are also described, concerning not only intraoperative and immediate postoperative problems, but also the safety and efficacy of the spinal instrumentation and the possibility of developing neurological disorders and the long-term effect these may have on both lung function and the quality of life of children.</p> <p>Conclusions</p> <p>Few cases indicate the long-term results of surgical techniques, in the natural progression of scoliosis. Similarly, few cases have been reported on the influence of conservative treatment.</p> <p>In conclusion, patients with segmentation failures should be treated surgically early, according to the rate of deformity formation and certainly before the pubertal growth spurt to try to avoid cor- pulmonale, even though there is lack of evidence for that in the long-term. Furthermore, in patients with formation failures, further investigation is needed to document where a conservative approach would be necessary.</p

Brace technology thematic series: the progressive action short brace (PASB)

<p>Abstract</p> <p>Background</p> <p>The Progressive Action Short Brace (PASB) is a custom-made thoraco-lumbar-sacral orthosis (TLSO), devised in 1976 by Dr. Lorenzo Aulisa (Institute of Orthopedics at the Catholic University of the Sacred Heart, Rome, Italy). The PASB was designed to overcome the limits imposed by the trunk anatomy. Indeed, the particular geometry of the brace is able to generate internal forces that modify the elastic reaction of the spine. The PASB is indicated for the conservative treatment of lumbar and thoraco-lumbar scoliosis. The aim of this article is to explain the biomechanic principles of the PASB and the rationale underlying its design. Recently published studies reporting the results of PASB-based treatment of adolescent scoliotic patients are also discussed.</p> <p>Description and principles</p> <p>On the coronal plane, the upper margin of the PASB, at the side of the curve concavity, prevents the homolateral bending of the scoliotic curve. The opposite upper margin ends just beneath the apical vertebra. The principle underlying such configuration is that the deflection of the inferior tract of a curved elastic structure, fixed at the bottom end, causes straightening of its upper tract. Therefore, whenever the patient bends towards the convexity of the scoliotic curve, the spine is deflected. On the sagittal plane, the inferior margins of the PASB reach the pelvitrochanteric region, in order to stabilize the brace on the pelvis. The transverse section of the brace above the pelvic grip consists of asymmetrical ellipses. This allows the spine to rotate towards the concave side only, leading to the continuous generation of derotating moments. On the sagittal plane, the brace is contoured so as to reduce the lumbar lordosis. The PASB, by allowing only those movements counteracting the progression of the curve, is able to produce corrective forces that are not dissipated. Therefore, the brace is based on the principle that a constrained spine dynamics can achieve the correction of a curve by inverting the abnormal load distribution during skeletal growth.</p> <p>Results</p> <p>Since its introduction in 1976, several studies have been published supporting the validity of the biomechanical principles to which the brace is inspired. In this article, we present the outcome of a case series comprising 110 patients with lumbar and thoraco-lumbar curves treated with PASB brace. Antero-posterior radiographs were used to estimate the curve magnitude (C_M) and the torsion of the apical vertebra (T_A) at 5 time points: beginning of treatment (t₁), one year after the beginning of treatment (t₂), intermediate time between t₁and t₄(t₃), end of weaning (t₄), 2-year minimum follow-up from t₄(t₅). The average C_Mvalue was 29.3°Cobb at t₁and 13.0°Cobb at t₅. T_Awas 15.8° Perdroille at t₁and 5.0° Perdriolle at t₅. These results support the efficacy of the PASB in the management of scoliotic patients with lumbar and thoraco-lumbar curves.</p> <p>Conclusion</p> <p>The results obtained in patients treated with the PASB confirm the validity of our original biomechanical approach. The efficacy of the PASB derives not only from its unique biomechanical features but also from the simplicity of its design, construction and management.</p

Lorentz violating kinematics: Threshold theorems

Recent tentative experimental indications, and the subsequent theoretical speculations, regarding possible violations of Lorentz invariance have attracted a vast amount of attention. An important technical issue that considerably complicates detailed calculations in any such scenario, is that once one violates Lorentz invariance the analysis of thresholds in both scattering and decay processes becomes extremely subtle, with many new and naively unexpected effects. In the current article we develop several extremely general threshold theorems that depend only on the existence of some energy momentum relation E(p), eschewing even assumptions of isotropy or monotonicity. We shall argue that there are physically interesting situations where such a level of generality is called for, and that existing (partial) results in the literature make unnecessary technical assumptions. Even in this most general of settings, we show that at threshold all final state particles move with the same 3-velocity, while initial state particles must have 3-velocities parallel/anti-parallel to the final state particles. In contrast the various 3-momenta can behave in a complicated and counter-intuitive manner.Comment: V1: 32 pages, 6 figures, 3 tables. V2: 5 references adde

Antinociceptive activity of Mentha piperita leaf aqueous extract in mice

Mentha piperita L. (Labiatae) is an herbaceous plant, used in folk medicine for the treatment of several medical disorders.In the present study, the aqueous extract of Mentha piperita leaf, at the i.p doses 200 and 400 mg/kg, showed significant analgesic effects against both acetic acid-induced writhing and hot plate-induced thermal stimulation in mice, with protection values of 51.79% and 20.21% respectively. On the contrary, the Mentha piperita leaf aqueous extract did not exhibit anti-inflammatory activity against carrageenan induced paw oedema.These findings indicate that Mentha piperita has a potential analgesic effect that may possibly have mediated centrally and peripherally, as well as providing a pharmacological evidence for its traditional use as a pain reliever

Phase transitions in biological membranes

Native membranes of biological cells display melting transitions of their lipids at a temperature of 10-20 degrees below body temperature. Such transitions can be observed in various bacterial cells, in nerves, in cancer cells, but also in lung surfactant. It seems as if the presence of transitions slightly below physiological temperature is a generic property of most cells. They are important because they influence many physical properties of the membranes. At the transition temperature, membranes display a larger permeability that is accompanied by ion-channel-like phenomena even in the complete absence of proteins. Membranes are softer, which implies that phenomena such as endocytosis and exocytosis are facilitated. Mechanical signal propagation phenomena related to nerve pulses are strongly enhanced. The position of transitions can be affected by changes in temperature, pressure, pH and salt concentration or by the presence of anesthetics. Thus, even at physiological temperature, these transitions are of relevance. There position and thereby the physical properties of the membrane can be controlled by changes in the intensive thermodynamic variables. Here, we review some of the experimental findings and the thermodynamics that describes the control of the membrane function.Comment: 23 pages, 15 figure

Innovative gait robot for the repetitive practice of floor walking and stair climbing up and down in stroke patients

<p>Abstract</p> <p>Background</p> <p>Stair climbing up and down is an essential part of everyday's mobility. To enable wheelchair-dependent patients the repetitive practice of this task, a novel gait robot, G-EO-Systems (EO, Lat: I walk), based on the end-effector principle, has been designed. The trajectories of the foot plates are freely programmable enabling not only the practice of simulated floor walking but also stair climbing up and down. The article intended to compare lower limb muscle activation patterns of hemiparetic subjects during real floor walking and stairs climbing up, and during the corresponding simulated conditions on the machine, and secondly to demonstrate gait improvement on single case after training on the machine.</p> <p>Methods</p> <p>The muscle activation pattern of seven lower limb muscles of six hemiparetic patients during free and simulated walking on the floor and stair climbing was measured via dynamic electromyography. A non-ambulatory, sub-acute stroke patient additionally trained on the G-EO-Systems every workday for five weeks.</p> <p>Results</p> <p>The muscle activation patterns were comparable during the real and simulated conditions, both on the floor and during stair climbing up. Minor differences, concerning the real and simulated floor walking conditions, were a delayed (prolonged) onset (duration) of the thigh muscle activation on the machine across all subjects. Concerning stair climbing conditions, the shank muscle activation was more phasic and timely correct in selected patients on the device. The severely affected subject regained walking and stair climbing ability.</p> <p>Conclusions</p> <p>The G-EO-Systems is an interesting new option in gait rehabilitation after stroke. The lower limb muscle activation patterns were comparable, a training thus feasible, and the positive case report warrants further clinical studies.</p