COVID-19 vaccines and adverse events of special interest: A multinational Global Vaccine Data Network (GVDN) cohort study of 99 million vaccinated individuals.

BACKGROUND: The Global COVID Vaccine Safety (GCoVS) Project, established in 2021 under the multinational Global Vaccine Data Network™ (GVDN®), facilitates comprehensive assessment of vaccine safety. This study aimed to evaluate the risk of adverse events of special interest (AESI) following COVID-19 vaccination from 10 sites across eight countries. METHODS: Using a common protocol, this observational cohort study compared observed with expected rates of 13 selected AESI across neurological, haematological, and cardiac outcomes. Expected rates were obtained by participating sites using pre-COVID-19 vaccination healthcare data stratified by age and sex. Observed rates were reported from the same healthcare datasets since COVID-19 vaccination program rollout. AESI occurring up to 42 days following vaccination with mRNA (BNT162b2 and mRNA-1273) and adenovirus-vector (ChAdOx1) vaccines were included in the primary analysis. Risks were assessed using observed versus expected (OE) ratios with 95 % confidence intervals. Prioritised potential safety signals were those with lower bound of the 95 % confidence interval (LBCI) greater than 1.5. RESULTS: Participants included 99,068,901 vaccinated individuals. In total, 183,559,462 doses of BNT162b2, 36,178,442 doses of mRNA-1273, and 23,093,399 doses of ChAdOx1 were administered across participating sites in the study period. Risk periods following homologous vaccination schedules contributed 23,168,335 person-years of follow-up. OE ratios with LBCI > 1.5 were observed for Guillain-Barré syndrome (2.49, 95 % CI: 2.15, 2.87) and cerebral venous sinus thrombosis (3.23, 95 % CI: 2.51, 4.09) following the first dose of ChAdOx1 vaccine. Acute disseminated encephalomyelitis showed an OE ratio of 3.78 (95 % CI: 1.52, 7.78) following the first dose of mRNA-1273 vaccine. The OE ratios for myocarditis and pericarditis following BNT162b2, mRNA-1273, and ChAdOx1 were significantly increased with LBCIs > 1.5. CONCLUSION: This multi-country analysis confirmed pre-established safety signals for myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis. Other potential safety signals that require further investigation were identified.

Transcriptomic and clinical heterogeneity of metastatic disease timing within metastatic castration-sensitive prostate cancer.

BACKGROUND: Metastatic castration-sensitive prostate cancer (mCSPC) is commonly classified into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes; however, less is known about any underlying biologic differences between these disease states. Herein, we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy. PATIENTS AND METHODS: We performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous versus metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease timing. The median transcriptomic scores between groups were compared with the Mann-Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from the time of metastasis. Survival analysis was carried out with the Kaplan-Meier method and multivariable Cox regression. RESULTS: A total of 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-year OS (39% versus 79%; P < 0.01) and demonstrated lower median androgen receptor (AR) activity (11.78 versus 12.64; P < 0.01) and hallmark androgen response (HAR; 3.15 versus 3.32; P < 0.01). Multivariable Cox regression identified only high-volume disease [hazard ratio (HR) = 4.97, 95% confidence interval (CI) 2.71-9.10; P < 0.01] and HAR score (HR = 0.51, 95% CI 0.28-0.88; P = 0.02) significantly associated with OS. Finally, patients with synchronous (HR = 0.47, 95% CI 0.30-0.72; P < 0.01) but not metachronous (HR = 1.37, 95% CI 0.50-3.92; P = 0.56) disease were found to have better OS with AR and non-AR combination therapy as compared with monotherapy (P value for interaction = 0.05). CONCLUSIONS: We have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low-volume disease, those with metachronous low-volume disease have a more hormone-dependent transcriptional profile and exhibit a better prognosis than synchronous low-volume disease.

Longitudinally extensive transverse myelitis following ChAdOx1 nCoV-19 vaccine.

Transverse myelitis (TM) has been reported in association with various vaccinations. Herein we describe a case of longitudinally extensive transverse myelitis (LETM) associated with vaccination with ChAdOx1 nCoV-19 (COVISHIELD) vaccine. A 59-year-old woman with no prior co-morbidities presented with lower extremity numbness, weakness, acute urinary retention, and constipation. Numbness gradually extended up to the lower costal margin with band like sensation. She had received the vaccine 5 days prior to the onset of the symptoms. Extensive diagnostic evaluation effectively ruled out causes other than vaccination-associated transverse myelitis. Following treatment with intravenous methylprednisolone, the patient made a significant recovery. TM may be associated with vaccination against the novel ChAdOx1 nCoV-19 vaccine and we believe this to be the first report from India of LETM associated with this vaccine.

Association between ambulatory skills and diffusion tensor imaging of corpus callosal white matter in infants with spina bifida.

OBJECTIVES: To assess brain white matter using diffusion tensor imaging (DTI) at 1 year of age in infants diagnosed with open neural tube defect (ONTD) and explore the association of DTI parameters with ambulatory skills at 30 months of age. METHODS: Magnetic resonance imaging (MRI) was performed at an average of 12 months of age and included an echo planar axial DTI sequence with diffusion gradients along 20 non-collinear directions. TORTOISE software was used to correct DTI raw data for motion artifacts, and DtiStudio, DiffeoMap and RoiEditor were used for further postprocessing. DTI data were analyzed in terms of fractional anisotropy (FA), trace, radial diffusivity and axial diffusivity. These parameters reflect the integrity and maturation of white-matter motor pathways. At 30 months of age, ambulation status was evaluated by a developmental pediatrician, and infants were classified as ambulatory if they were able to walk independently with or without orthoses or as non-ambulatory if they could not. Linear mixed-effects method was used to examine the association between study outcomes and study group. Possible confounders were sought, and analyses were adjusted for age at MRI scan and ventricular size by including them in the regression model as covariates. RESULTS: Twenty patients with ONTD were included in this study, including three cases that underwent postnatal repair and 17 cases that underwent prenatal repair. There were five ambulatory and 15 non-ambulatory infants evaluated at a mean age of 31.5 ± 5.7 months. MRI was performed at 50.3 (2-132.4) weeks postpartum. When DTI analysis results were compared between ambulatory and non-ambulatory infants, significant differences were observed in the corpus callosum (CC). Compared with non-ambulatory infants, ambulatory infants had increased FA in the splenium (0.62 (0.48-0.75) vs 0.41 (0.34-0.49); P = 0.01, adjusted P = 0.02), genu (0.64 (0.47-0.80) vs 0.47 (0.35-0.61); P = 0.03, adjusted P = 0.004) and body (0.55 (0.45-0.65) vs 0.40 (0.35-0.46), P = 0.01, adjusted P = 0.01). Reduced trace was observed in the CC of ambulatory children at the level of the splenium (0.0027 (0.0018-0.0037) vs 0.0039 (0.0034-0.0044) mm2 /s; P = 0.04, adjusted P = 0.03) and genu (0.0029 (0.0020-0.0038) vs 0.0039 (0.0033-0.0045) mm2 /s; P = 0.04, adjusted P = 0.01). In addition, radial diffusivity was reduced in the CC of the ambulatory children at the level of the splenium (0.00057 (0.00025-0.00089) vs 0.0010 (0.00084-0.00120) mm2 /s; P = 0.02, adjusted P = 0.02) and the genu (0.00058 (0.00028-0.00088) vs 0.0010 (0.00085-0.00118) mm2 /s; P = 0.02, adjusted P = 0.02). There were no differences in axial diffusivity between ambulatory and non-ambulatory children. CONCLUSION: This study demonstrates a significant association between white matter integrity of connecting fibers of the corpus callosum, as assessed by DTI, and ambulatory skills at 30 months of age in infants with ONTD. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Virtual and experimental high throughput screening of substituted hydrazones on ß-Tubulin polymerization.

Microtubule targeting agents that disrupt the dynamic functioning of the mitotic spindle are some of the best chemotherapeutic agents. Interruption of microtubule dynamics through polymerization or depolymerization causes cell arrest leading to apoptosis. We report a novel class of aroylhydrazones with anticancer properties. Tubulin inhibition studies were performed using both computational and biological methods. Docking and pharmacophore mapping showed efficient binding between the ligands and the protein. Tubulin inhibition assay showed the aroylhydrazones to be inhibitors of tubulin polymerization. DFT studies explains the geometrical and electronic properties of the compounds. Furthermore, anticancer studies using lung and liver cancer cell lines gave low IC50 values with the methyl substituted hydrazone MH-2 being the most potent. (IC50 of 0.0896 and 0.1040 µM respectively). The methyl group is responsible for the effective binding to the protein. Thus, a new class of tubulin binding agents have been identified as potential agents in cancer therapy.

A histological study on the tendons at chiasma plantare in pes cavus.

INTRODUCTION: In the dysfunction of large muscles of the leg, tendon transfer surgery is found to be very helpful in restoring the normal function of these muscles. The tendons involved in the chiasma plantare play a major role in this regard. OBJECTIVE: The present cadaveric study has been carried out in cadavers presenting pes cavus. MATERIAL AND METHODS: Cadaveric feet presenting pes cavus were identified based on their foot prints. All these tendons and their interconnections were subjected to histological procedures. The sections of the tendons were stained with hematoxylin and eosin in order to identify the underlying pathologies in the tendons. RESULTS: Various types of tendinous interconnections between the tendons of flexor digitorum longus and flexor hallucis longus were noted. The histological findings showed infiltration of lymphocytes in the tendon sheath indicating tenosynovitis and tendinitis. This could be attributed to the compression of the tendons. A few tendons were also stretched due to the skeletal framework of the foot in pes cavus. The bones along the medial longitudinal arch in pes cavus feet could tend to develop spurs or elongated tuberosity that could impinge on the tendons causing the tendons to stretch and elongate. CONCLUSION: In harvesting the tendons for grafting, the surgeons must be aware about the pathologies involved, such as tendinitis or tenosynovitis, in order to reduce the time taken for the healing of the graft post-surgery. These variations and histological findings can sub-serve as an efficient guide for the restoration of non-functioning muscles of the lower limb.

Clinical utility of skin cancer and melanoma risk scores for population screening: TRoPICS study.

BACKGROUND: Screening for skin cancer can be cost-effective if focused on high-risk groups. Risk prediction tools have been developed for keratinocyte cancers and melanoma to optimize advice and management. However, few have been validated in a clinical setting over the past few years. OBJECTIVES: To assess the clinical utility of risk assessment tools to identify individuals with prevalent skin cancers in a volunteer-based screening clinic. METHODS: Participants were adults presenting for a skin check at a volunteer-based skin cancer screening facility. We used previously published tools, based on questionnaire responses, to predict melanoma and keratinocyte cancers [KCs; basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] and classified each participant into one of five risk categories. Participants subsequently underwent a full skin examination by a dermatologist. All suspicious lesions were biopsied, and all cancers were histopathologically confirmed. RESULTS: Of 789 people who presented to the clinic, 507 (64%) consented to the study. Twenty-two BCCs, 19 SCCs and eight melanomas were diagnosed. The proportion of keratinocyte cancers diagnosed increased according to risk category from <1% in the lowest to 24% in the highest risk category (P < 0.001). Subtype analysis revealed similar proportionate increases in BCC or SCC prevalence according to risk category. However, a similar proportion of melanoma cases were detected in the low-risk and high-risk groups. CONCLUSION: The risk prediction model for keratinocyte cancers can reliably identify individuals with a significant skin cancer burden prior to a skin examination in the community setting. The prediction tool for melanoma needs to be tested in a larger sample exposed to a wider range of environmental risk factors.

Comparison of brain microstructure after prenatal spina bifida repair by either laparotomy-assisted fetoscopic or open approach.

OBJECTIVE: To compare prenatal and postnatal brain microstructure between infants that underwent fetoscopic myelomeningocele (MMC) repair and those that had open-hysterotomy repair. METHODS: This was a longitudinal retrospective cohort study of 57 fetuses that met the Management of Myelomeningocele Study (MOMS) trial criteria and underwent prenatal MMC repair, by a fetoscopic (n = 27) or open-hysterotomy (n = 30) approach, at 21.4-25.9 weeks' gestation. Fetoscopic repair was performed under CO2 insufflation, according to our protocol. Diffusion-weighted magnetic resonance imaging (MRI) was performed before surgery in 30 cases (14 fetoscopic and 16 open), at 6 weeks postsurgery in 48 cases (24 fetoscopic and 24 open) and within the first year after birth in 23 infants (five fetoscopic and 18 open). Apparent diffusion coefficient (ADC) values from the basal ganglia, frontal, occipital and parietal lobes, mesencephalon and genu as well as splenium of the corpus callosum were calculated. ADC values at each of the three timepoints (presurgery, 6 weeks postsurgery and postnatally) and the percentage change in the ADC values between the timepoints were compared between the fetoscopic-repair and open-repair groups. ADC values at 6 weeks after surgery in the two prenatally repaired groups were compared with those in a control group of eight healthy fetuses that underwent MRI at a similar gestational age (GA). Comparison of ADC values was performed using the Student's t-test for independent samples (or Mann-Whitney U-test if non-normally distributed) and multivariate general linear model analysis, adjusting for GA or age at MRI and mean ventricular width. RESULTS: There were no differences in GA at surgery or GA/postnatal age at MRI between the groups. No significant differences were observed in ADC values in any of the brain areas assessed between the open-repair and fetoscopic-repair groups at 6 weeks after surgery and in the first year after birth. No differences were detected in the ADC values of the studied areas between the control and prenatally repaired groups, except for significantly increased ADC values in the genu of the corpus callosum in the open-hysterotomy and fetoscopic-repair groups. Additionally, there were no differences between the two prenatally repaired groups in the percentage change in ADC values at any of the time intervals analyzed. CONCLUSIONS: Fetoscopic MMC repair has no detectable effect on brain microstructure when compared to babies repaired using an open-hysterotomy technique. CO2 insufflation of the uterine cavity during fetoscopy does not seem to have any isolated deleterious effects on fetal brain microstructure. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

A comparative study evaluating the role of adductor canal block catheter versus intraarticular analgesic infusion on knee pain and range of motion in the immediate postoperative period: a prospective multicenter trial.

Postoperative pain after total knee arthroplasty (TKA) is an important determinant of hospital stay and rehabilitation and thereby functional outcome. Adductor canal block (ACB) and intraarticular analgesic infiltration through catheters (IAC) are techniques of multimodal analgesia which have shown to control postoperative pain satisfactorily. The aim of this study is to evaluate the efficacy of ACB versus IAC in reducing immediate postoperative pain and thereby allow early rehabilitation. A multicenter quasi-experimental study was conducted on 511 patients undergoing unilateral primary TKA from March 2016 to April 2017 who either received ACB with catheter (Group I, n = 350 patients) or IAC (Group II, n = 172 patients) for postoperative pain control. All the patients were assessed for severity of pain by Visual Analogue Scale at 8, 24, 48, 72 h postoperatively and knee range of motion (ROM) on the day of discharge. There was no significant difference in pain scores on postoperative day (POD) 0 (1.09 ± 0.30 vs. 0.98 ± 0.46, p = 0.45) and POD 1 (1.21 ± 0.45 vs. 1.00 ± 0.00, p = 0.11) and in mean ROM on the day of discharge between ACB and IAC (88.40° ± 7.96° vs. 88.34° ± 5.74°; p = 0.93) groups. This study shows that both ACB and IAC provide satisfactory postoperative analgesia with sparing of quadriceps function and good knee ROM leading to early rehabilitation and reduced hospital with no advantage of one technique over another.

Prenatal brain imaging for predicting need for postnatal hydrocephalus treatment in fetuses that had neural tube defect repair in utero.

OBJECTIVE: To determine if brain imaging in fetuses that underwent prenatal repair of neural tube defect (NTD) can predict the need for postnatal hydrocephalus treatment (HT) in the first year postpartum. METHODS: This was a retrospective study of fetuses diagnosed with open NTD that had in-utero myelomeningocele repair between April 2014 and April 2016. Independent variables were collected from four chronological sets of fetal images: presurgery ultrasound, presurgery magnetic resonance imaging (MRI), 6-week postsurgery MRI and predelivery ultrasound. The following independent variables were collected from all image sets unless otherwise noted: gestational age, head circumference, mean ventricular width, ventricular volume (MRI only), hindbrain herniation (HBH) score (MRI only), and level of lesion (LOL), defined as the upper bony spinal defect (presurgery ultrasound only). Based on these measurements, additional variables were defined and calculated including change in degree of HBH, ventricular width growth (mm/week) and ventricular volume growth (mL/week). The need for HT (by either ventriculoperitoneal shunt or endoscopic third ventriculostomy with choroid plexus cauterization) was determined by a pediatric neurosurgeon using clinical and radiographic criteria; a secondary analysis was performed using the MOMS trial criteria for hydrocephalus. The predictive value of each parameter was assessed by receiver-operating characteristics curve and logistic regression analyses. RESULTS: Fifty affected fetuses were included in the study, of which 32 underwent open hysterotomy and 18 fetoscopic repair. Two neonates from the open hysterotomy group died and were excluded from the analysis. The mean gestational ages for the presurgery ultrasound, presurgery MRI, postsurgery MRI and predelivery ultrasound were 21.8 ± 2.1, 22.0 ± 1.8, 30.4 ± 1.6 and 31.0 ± 4.9 weeks, respectively. A total of 16 subjects required HT. The area under the curve (AUC) of predictive accuracy for HT showed that HBH grading on postsurgery MRI had the strongest predictive value (0.86; P < 0.01), outperforming other predictors such as postsurgery MRI ventricular volume (0.73; P = 0.03), MRI ventricular volume growth (0.79; P = 0.01), change in HBH (0.82; P = 0.01), and mean ventricular width on predelivery ultrasound (0.73; P = 0.01). Other variables, such as LOL, mean ventricular width on presurgery ultrasound, mean ventricular width on presurgery and postsurgery MRI, and ventricular growth assessment by MRI or ultrasound, had AUCs < 0.7. Optimal cut-offs of the variables with the highest AUC were evaluated to improve prediction. A combination of ventricular volume growth ≥ 2.02 mL/week and/or HBH of 3 on postsurgery MRI were the optimal cut-offs for the best prediction (odds ratio (OR), 42 (95% CI, 4-431); accuracy, 84%). Logistic regression analyses showed that persistence of severe HBH 6 weeks after surgery by MRI is one of the best predictors for HT (OR, 39 (95% CI, 4-369); accuracy, 84%). There was no significant change in the results when the MOMS trial criteria for hydrocephalus were used as the dependent variable. CONCLUSIONS: Persistence of HBH on MRI 6 weeks after prenatal NTD repair independently predicted the need for postnatal HT better than any ultrasound- or other MRI-derived measurements of ventricular characteristics. These results should aid in prenatal counseling and add support to the hypothesis that HBH is a significant driver of hydrocephalus in myelomeningocele patients. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Imágenes cerebrales prenatales para predecir el tratamiento postnatal de la hidrocefalia en fetos con reparación de defectos del tubo neural OBJETIVOS: Determinar si las imágenes cerebrales en fetos que se sometieron a reparación prenatal de defectos del tubo neural (DTN) pueden predecir la necesidad de tratamiento postnatal de la hidrocefalia (TH) en el primer año después del parto. MÉTODOS: Este fue un estudio retrospectivo de fetos diagnosticados con DTN aun abierto cuyo mielomeningocele fue reparado en el útero, entre abril de 2014 y abril de 2016. Se recolectaron variables independientes de cuatro conjuntos cronológicos de imágenes fetales: ecografía prequirúrgica, imágenes por resonancia magnética (IRM) prequirúrgica, imágenes por resonancia magnética (IRM) posquirúrgica a las seis semanas y ecografía previa al parto. Las siguientes variables independientes se recolectaron de todos los conjuntos de imágenes, a menos que se indique lo contrario: edad gestacional, perímetro cefálico, ancho ventricular medio, volumen ventricular (IRM solamente), puntaje de hernia del rombencéfalo (HR) (IRM solamente) y nivel de lesión (NDL), definido como el defecto espinal óseo superior (ecografía prequirúrgica solamente). A partir de estas mediciones se definieron y calcularon variables adicionales, como el cambio en el grado de HR, el aumento del ancho ventricular (mm/semana) y el aumento del volumen ventricular (mL/semana). La necesidad de TH (ya sea por derivación ventriculoperitoneal o por ventriculostomía endoscópica del tercer ventrículo y cauterización del plexo coroideo) fue determinada por un neurocirujano pediátrico utilizando criterios clínicos y radiográficos; se realizó un análisis secundario utilizando los criterios del estudio MOMS para la hidrocefalia. El valor predictivo de cada parámetro se evaluó mediante un análisis de la curva de la característica operativa del receptor y de la regresión logística. RESULTADOS: Se incluyeron en el estudio 50 fetos afectados, de los cuales 32 se sometieron a histerotomía abierta y 18 a reparación fetoscópica. Dos de los recién nacidos del grupo de histerotomía abierta murieron y fueron excluidos del análisis. Las edades gestacionales medias para la ecografía prequirúrgica, la IRM prequirúrgica, la IRM postoperatoria y la ecografía previa al parto fueron 21,8 ±2,1; 22,0 ±1,8; 30,4 ±1,6 y 31,0 ±4,9 semanas, respectivamente. Un total de 16 sujetos requirieron TH. El área bajo la curva (ABC) de precisión predictiva para la TH mostró que la clasificación de la HR en la IRM postoperatoria tuvo el valor predictivo más fuerte (0,86; P<0.01), por encima de otros valores predictivos como el volumen ventricular en la IRM posquirúrgica (0,73; P=0,03), el crecimiento del volumen ventricular en la IRM (0,79; P=0,01), cambios en la HR (0,82; P=0,01), y el ancho ventricular medio en la ecografía previa al parto (0,73; P=0,01). Otras variables, como el NDL, la anchura ventricular media en la ecografía prequirúrgica, la anchura ventricular media en la IRM prequirúrgica y posquirúrgica, y la evaluación del crecimiento ventricular mediante ecografía o IRM, tuvieron AUC <0,7. Para mejorar la predicción se evaluaron los límites óptimos de las variables con las AUC más altas. Los límites óptimos para la mejor predicción (razones de momios [RM], 42 [IC 95%: 4-431]; precisión, 84%) fueron una combinación de crecimiento del volumen ventricular ≥2,02 mL/semana y/o HR de 3 en la IRM postoperatoria. Los análisis de regresión logística mostraron que la persistencia de la HR grave a las 6 semanas después de la cirugía en IRM es uno de los mejores predictores de la TH (RM, 39 (IC 95%: 4-369); precisión, 84%). Los resultados no cambiaron de forma significativa cuando se utilizaron los criterios del estudio MOMS para la hidrocefalia como variable dependiente. CONCLUSIONES: La persistencia de la HR en la IRM 6 semanas después de la reparación prenatal de DTN predijo independientemente la necesidad de la TH postnatal mejor que cualquier ecografía o que otras mediciones de las características ventriculares a partir de IRM. Estos resultados deberían ayudar en el asesoramiento previo al parto y a apoyar la hipótesis de que la HR es un impulsor significativo de la hidrocefalia en pacientes con mielomeningocele.

A cost-effective cell- and matrix-based minimally invasive single-stage chondroregenerative technique developed with validated vertical translation methodology.

Introduction The morbidity and significant health economic impact associated with the chondral lesion has led to a large number of strategies for therapeutic neochondrogenesis. The challenge has been to develop techniques that are cost effective single-stage procedures with minimal surgical trauma that have undergone rigorous preclinical scrutiny and robust reproducible assessment of effectiveness. A biological repair requires the generation of a cellular and matrix composite with appropriate signalling for chondrogenic differentiation. Methods and results A technique was developed that allowed chondrogenic primary (uncultured) cells from bone marrow aspirate concentrate, combined with a composite hydrophilic and fibrillar matrix to be applied arthroscopically to a site of a chondral lesion. The construct was tested in vitro and in animal experiments before clinical trials. Clinical trials involved 60 patients in a prospective study. Symptomatic International Cartilage Repair Society grade 3 and 4a lesions were mapped and treated. Pre- and postoperative clinical assessments showed statistically significant improved outcomes; Lysholm Knee Scoring Scale (mean 52.8 to > 76.4; P < 0.05) International Knee Documentation Committee (mean 39 to > 79 P < 0.05) and Knee injury and Osteoarthritis Outcome Score (64.5 to >89.2 P < 0.05). Postoperative magnetic resonance imaging was evaluated morphologically (magnetic resonance observation of cartilage repair tissue, average MOCART score 72) and qualitatively; the regenerate was comparable to native cartilage. Conclusions This technique is effective, affordable, requires no complex tools and delivers a single-stage treatment that is potentially accessible to any centre capable of performing arthroscopic surgery. Good clinical results were found to be sustained at five years of follow-up with a regenerate that appears hyaline like using multiple magnetic resonance measures.

Evaluation of Mycotube, a modified version of Lowenstein-Jensen (LJ) medium, for efficient recovery of Mycobacterium tuberculosis (MTB).

Timely diagnosis of tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is only achieved for ~58% cases. An improved, accurate, time- and cost-effective method for bacteriological confirmation of MTB is necessary. We evaluated Mycotube, a new variant of Lowenstein-Jensen (LJ) culture medium, by comparing it with Mycobacterium Growth Indicator Tube (MGIT) 960 (gold standard), local LJ, and bioMérieux LJ-T in terms of isolation rate and time-to-growth. Pulmonary and extra-pulmonary samples from treatment-naïve suspects (n = 207) were decontaminated by the N-acetyl-L-cysteine-sodium hydroxide method and used to inoculate the four media. Subjective and objective parameters were used for evaluation. Mycotube yielded 140 positive results, compared to 162, 69, and 141 from MGIT, local LJ, and LJ-T, respectively. Of these, 139 (67%) were true-positive results and 1 (0.5%) was false-positive. The mean time-to-growth detection was 17.4 days for Mycotube, compared to 14.5, 28.1, and 16.5 days for MGIT, local LJ, and LJ-T, respectively. The mean time-to-growth for local LJ significantly differed from that for MGIT, but not those for LJ-T and Mycotube. No contamination was observed. Mycotube had a sensitivity of 85.8% and a specificity of 97.8% as compared to MGIT. Mycotube offers good results, comparable with those observed for conventional LJ. It requires only basic laboratory infrastructure. The overall cost of the test should be nearly three times lower than that of MGIT. Mycotube helps with TB diagnosis and generates pure isolates for drug susceptibility testing.

Effectiveness of Long Term Supervised and Assisted Physiotherapy in Postsurgery Oral Submucous Fibrosis Patients.

Oral submucous fibrosis is one of the leading potentially malignant disorders prevailing in India. A number of conservative and surgical treatment options have been suggested for this potentially malignant disorder (Arakeri and Brennan, 2013). While the role of physiotherapy has been highlighted in the conservative management, its importance in postsurgical cases to avoid scar contracture and subsequent relapse has not been given due importance in the literature. The following is a case report of a male patient surgically treated for OSMF (oral submucous fibrosis) and meticulously followed up for recalls and physiotherapy. The constant supervision and motivation for physiotherapy along with the constant assistance helped achieve satisfying results.

Extramedullary haematopoiesis: radiological imaging features.

Extramedullary haematopoiesis (EMH) is defined as the production of blood cells outside of the bone marrow, which occurs when there is inadequate production of blood cells. The most common causes of EMH are myelofibrosis, diffuse osseous metastatic disease replacing the bone marrow, leukaemia, sickle cell disease, and thalassemia. The purpose of this article is to review the common and uncommon imaging appearances of EMH by anatomical compartment. In the thorax, EMH most commonly presents as paravertebral fat-containing masses, and typically does not present a diagnostic dilemma; however, EMH in the abdomen most commonly manifests as hepatosplenomegaly with or without focal soft-tissue masses in the liver, spleen, perirenal space, and in the peritoneum. Hepatosplenomegaly, a non-specific feature, most often occurs without an associated focal mass, which makes suggestion of EMH difficult. EMH manifesting as visceral soft-tissue masses often requires biopsy as the differential diagnosis can include lymphoma, metastatic disease, and sarcoma. Many of these soft-tissue masses do not contain adipose elements, making the diagnosis of EMH difficult. Clinical history is crucial, as EMH would likely not otherwise be in the differential in patients with non-specific abdominal masses. Careful biopsy planning is necessary when EMH is a diagnostic consideration, given the propensity for haemorrhage. Understanding the typical imaging appearances of EMH based on its site of manifestation can help the radiologist when encountered with a finding that is diagnostic for EMH, and can help the radiologist suggest the need and plan appropriately for image-guided biopsy.

History of spine surgery for tuberculous spondylodiscitis.

For those stricken with tuberculosis, a disease that was present in ancient times, treatment was originally limited to conservative treatment including high altitude, fresh air, rest, and immobilization, manual reduction devices, and surgical procedures. Mortality and morbidity were high until the advent of antitubercular chemotherapy in the 1940s. Today multidrug regimen enable good disease clearance and also make direct surgical debridement without complications possible. Antitubercular drugs have reduced mortality by 72.5%. Surgical intervention is reserved for selected situations.

Expanding the Clinical Spectrum Associated With GLIS3 Mutations.

CONTEXT: GLIS3 (GLI-similar 3) is a member of the GLI-similar zinc finger protein family encoding for a nuclear protein with 5 C2H2-type zinc finger domains. The protein is expressed early in embryogenesis and plays a critical role as both a repressor and activator of transcription. Human GLIS3 mutations are extremely rare. OBJECTIVE: The purpose of this article was determine the phenotypic presentation of 12 patients with a variety of GLIS3 mutations. METHODS: GLIS3 gene mutations were sought by PCR amplification and sequence analysis of exons 1 to 11. Clinical information was provided by the referring clinicians and subsequently using a questionnaire circulated to gain further information. RESULTS: We report the first case of a patient with a compound heterozygous mutation in GLIS3 who did not present with congenital hypothyroidism. All patients presented with neonatal diabetes with a range of insulin sensitivities. Thyroid disease varied among patients. Hepatic and renal disease was common with liver dysfunction ranging from hepatitis to cirrhosis; cystic dysplasia was the most common renal manifestation. We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia and confirm further cases with sensorineural deafness and exocrine pancreatic insufficiency. CONCLUSION: We report new findings within the GLIS3 phenotype, further extending the spectrum of abnormalities associated with GLIS3 mutations and providing novel insights into the role of GLIS3 in human physiological development. All but 2 of the patients within our cohort are still alive, and we describe the first patient to live to adulthood with a GLIS3 mutation, suggesting that even patients with a severe GLIS3 phenotype may have a longer life expectancy than originally described.

Maternal and perinatal consequences of antepartum haemorrhage of unknown origin.

OBJECTIVE: To explore the risk of adverse maternal and perinatal outcomes in women with antepartum bleeding of unknown origin (ABUO). DESIGN: Cohort study based on data extracted from the Aberdeen Maternity and Neonatal Databank. Exposure was antepartum haemorrhage occurring after the first trimester not attributable to placenta praevia or placental abruption. SETTING: Aberdeen Maternity Hospital, Aberdeen, Scotland, UK. POPULATION: All primigravidae delivering between 1976 and 2010. METHODS: Data were analysed using univariate and multivariate statistical methods. MAIN OUTCOME MEASURES: Pre-eclampsia, induced labour, mode of delivery, preterm delivery, postpartum haemorrhage, admission to neonatal unit, perinatal death. RESULTS: Between 1976 and 2010, there were 7517 women with ABUO and 68,423 women without ABUO in the cohort. Women with ABUO were more likely to be non-smokers, belong to a lower social class, and have a higher body mass index. ABUO was a significant risk factor for induced labour (adjusted odds ratio, aOR, 1.23; 95% CI 1.16-1.31), preterm delivery at <37 weeks of gestation (aOR 2.30; 95% CI 2.11-2.50), and postpartum haemorrhage (aOR 1.15; 95% CI 1.06-1.25). There was no significant association detected with pre-eclampsia (aOR 0.93; 95% CI 0.83-1.05). Whereas there was an increased risk of low birthweight (aOR 0.90; 95% CI 0.79-1.03) and stillbirth (aOR 0.92; 95% CI 0.66-1.30) with ABUO on univariate analysis, once adjusted for confounding factors this risk was non-significant. CONCLUSION: Pregnancies complicated by ABUO are at a greater risk of preterm delivery and induced labour. There was no increase seen in perinatal mortality after adjusting for preterm birth.

Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with pazopanib after disease progression with other targeted therapies.

AIM: The multi-tyrosine kinase inhibitor pazopanib prolongs progression-free survival (PFS) versus placebo in treatment-naive and cytokine-refractory metastatic clear-cell renal cell carcinoma (ccRCC). Outcomes and safety data with pazopanib after targeted therapy (TT) are limited. METHODS: We retrospectively evaluated records of consecutive patients with metastatic ccRCC who had progressive disease (PD) after TT and received pazopanib from November 2009 through November 2011. Tumour response was assessed by a blinded radiologist using Response Evaluation Criteria In Solid Tumours (RECIST). PFS and overall survival (OS) were estimated by Kaplan-Meier methods. RESULTS: Ninety-three patients were identified. Median number of prior TTs was 2 (range, 1-5). There were 68 events (PD or death). Among 85 evaluable patients, 13 (15%) had a partial response. Median PFS was 6.5 months (95% CI: 4.5-9.7); median OS was 18.1 months (95% CI: 10.26-NA). Common adverse events (AEs) included fatigue (44%), elevated transaminases (35%), diarrhoea (30%), hypothyroidism (18%), nausea/vomiting (17%), anorexia (14%) and hypertension exacerbation (14%); 91% of AEs were grade 1/2. Eleven patients (12%) discontinued therapy due to AEs. There were no treatment-related deaths. CONCLUDING STATEMENT: Pazopanib demonstrated efficacy in patients with metastatic ccRCC after PD with other TTs. Toxicity overall was mild/moderate and manageable.

Beware of delayed severe brain swelling after intracerebral haematoma in HELLP syndrome.

Haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is a condition associated with increased risk of adverse outcomes during pregnancy and peripartum, including neurological complications. We report the third case in the world literature of delayed brain swelling following cerebral haemorrhage as a complication of HELLP syndrome. A 36-year-old woman in labour developed HELLP, which was complicated with intracerebral haematoma. This was evacuated, but motor impairment persisted after surgery and unfortunately the patient died unexpectedly during the 11th postoperative day. Computer tomographic brain scans documented diffuse cerebral swelling, which we think may have been caused by cerebral vasospasm. Cerebral vasospasm should always be considered when managing patients who suffered from stroke complicating HELLP syndrome. Close monitoring is advised even in later stages of recovery.