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Background: Collagen meniscal implant (CMI) is a biologic scaffold that can be used to replace meniscus host tissue after partial meniscectomy. The short-term results of this procedure have already been described; however, little is known about risk factors for failure. Purpose: To determine the factors that predict failure of meniscal scaffold implantation in a large series of patients treated at a single institution and to better define the indications for surgery. Study Design: Case-control study; Level of evidence, 3. Methods: The analysis included 186 consecutive patients with a minimum 5-year follow-up who underwent CMI scaffold implantation or combined procedures. Patients’ characteristics and details of the surgery were obtained via chart review. Patients with a Lysholm score Results: The final analysis included 156 patients (84%) at a mean follow-up of 10.9 ± 4.3 years. The patients’ mean age at surgery was 42.0 ± 11.1 years, and the survival rate was 87.8%. Subgroup analysis identified Outerbridge grade 3-4 (Hazard ratio [HR], 3.8; P = .004) and a lateral meniscal implant (HR, 3.2; P = .048) as risk factors for failure. The survival rate was 90.4% for medial implants and 77.4% for lateral implants. An Outerbridge grade 3-4 (HR, 2.8; P < .001) and time from meniscectomy to scaffold >10 years (HR, 2.8; P = .020) were predictive of surgical or clinical failure. Conclusion: CMI for partial meniscal deficiency provided good long-term results, with 87.8% of the implants still in situ at a mean 10.9 years of follow-up. Outerbridge grade 3-4, lateral meniscal implants, and longer time from the meniscectomy to implantation of the CMI were identified as risk factors for clinical and surgical failure.

Objective: The purposes of this study were: (1) to compare three different surgical techniques for anterior cruciate ligament (ACL) reconstruction at a minimum 2 years of follow-up in terms of objective laxity and patient-reported outcomes; (2) to inspect the role of meniscal tears and treatment alongside with ACL reconstruction.Methods: 59 patients were randomly assigned to one of the three reconstruction groups according to the ACL reconstruction technique: Double Bundle, Single Bundle, Single Bundle with Lateral Plasty. Autologous hamstring tendons were used in all the ACL reconstruction techniques. Objective laxity tests and KOOS were collected before surgery as a baseline and at a minimum of 2 years of follow-up and compared through a Repeated measure ANOVA. Secondary analysis to evaluate the effect of meniscal treatment on laxity reduction and scores improvement was also conducted using ANOVA. Three laxity evaluations were performed: anterior/posterior displacement at 30 degrees of knee flexion (AP 30), anterior/posterior displacement at 90 degrees of knee flexion (AP 90), and pivot-shift test.Results: Objective laxity and KOOS showed statistically significant improvement at follow-up in all three groups (p < 0.0001) without differences among the techniques. A higher AP 30 (mean difference 2.4 mm, p = 0.0333, ES = 0.66) was found at baseline for the patients with irreparable medial meniscal tear compared to the patients with isolated ACL tear; a statistically significant difference in pain score at two-year follow-up was found between patients who underwent lateral meniscectomy and patients with either meniscal repair (mean difference 6.9 +/- 12.5) or isolated ACL tear (mean difference 6.8 +/- 16.1); patients with reparable meniscal tear had a sta-tistically significant pain score improvement compared to the patients who underwent medial and lateral meniscectomy (mean difference of 9.5 +/- 14.53 and 23.4 +/- 19.2 respectively).Conclusion: Comparable objective laxity and subjective outcomes were found among the three ACL reconstruction techniques at a minimum of 2 years of follow-up. The presence of irreparable medial meniscal tear increased pre-operative laxity (AP 30, mean difference 2.4 +/- 3.6 mm). Patients with meniscal repair presented higher pain relief between baseline and follow-up compared with patients undergoing medial or lateral meniscectomy (mean dif-ference of 9.5 +/- 14.53 and 23.4 +/- 19.2, respectively).

Purpose To retrospectively evaluate a cohort of athletically active patients who underwent surgery for adolescent idiopathic scoliosis (AIS), and to determine which clinical, surgical and anthropometric variables influenced their return to sport after surgery. Methods 112 adolescents who underwent high-density posterior fusion for AIS by a single surgeon were analyzed for clinical, surgical and demographic predictors of return to presurgical physical activity levels. Data were retrospectively collected by charts and X-rays analysis and patients interviews. Results Preoperative main curve Cobb was 64.4 ± 14.12° and obtained correction was 70.0 ± 12.5%. Included patients played many different sports (Table 4), most of all ballet (44/112, 39.2%), swimming (40/112, 35.7%) and gymnastics (32/112, 28.6%). At an average of 50.3 months follow-up, 76 (67.8%) patients returned to sports (RTS) at an equal or higher level than preoperatively. Younger age, lower Lenke curve type and lower main curve Cobb were significantly associated with RTS. As for RTS timing, patients who returned within the first 6 months were younger, with a higher Lenke and a less severe main curve, a more distal UIV and a more proximal LIV. No complications related to RTS were registered. Conclusion In conclusion, patients with adolescent idiopathic scoliosis safely returned to physical activity after surgery. Younger age, higher Lenke type and lower main curve severity predicted a quicker return to sport. However, prospective studies are needed to confirm these findings.

Introduction and hypothesis Few studies in literature have assessed the long-term durability and mesh-related complications of mid-urethral slings (MUSs). The aim of this study is to assess the efficacy and safety of retro-pubic tension-free vaginal tape (TVT) 20 years after implantation for the treatment of female stress urinary incontinence (SUI). Methods A prospective observational study was conducted in two urogynaecologic units in two countries. All the patients involved were consecutive women with urodynamically proven pure SUI treated by TVT. The patients underwent preoperative clinical and urodynamic evaluations. Subjective outcomes, objective outcomes and adverse events were recorded during the follow-up period. Results Fifty-two patients underwent a TVT surgical procedure. Twenty years after surgery, 32 out of 36 patients (88.8%) declared themselves cured (p = 0.98). Similarly, 33 out of these 36 patients (91.7%) were objectively cured (p = 0.98). No significant deterioration of subjective and objective cure rates was observed over time (p for trend 0.50 and 0.48). Fifteen of the 36 patients (41.6%) at the 20-year follow-up reported the onset of de novo overactive bladder (OAB) (p = 0.004). No significant vaginal bladder or urethral erosion or de novo dyspareunia was recorded and no patient required tape release or resection during this period. The cause of death of seven out of ten women who died in the last year of the follow-up period was coronavirus disease 19 (COVID 19). Conclusions The 20-year results of this study showed that TVT is a highly effective and safe option for the treatment of SUI. The impact of COVID 19 on the mortality rate of elderly women has drastically reduced the number of eligible patients for future evaluations in our region.

Background Idiopathic normal pressure hydrocephalus (iNPH) is a chronic neurologic syndrome that affects the elderly population in a context of concomitant medical conditions. The aim of this study was to understand the significance of comorbidities using 4 validated and specific clinical scores: Cumulative Illness Rating Scale (CIRS), American Society of Anesthesiologists (ASA) score, Comorbidity Index (CMI), and Charlson Comorbidity Index (CCI). Methods From 2015 until 2019, the Bologna PRO-Hydro multidisciplinary team selected 63 patients for shunt surgery. All comorbidity scores were collected during preoperative anesthesia evaluation. Positive shunt response was defined as an improvement in overall disability (assessed with modified Rankin Scale [mRS]), in risk of fall (assessed with Tinetti Permormance Orientated Mobility Assessment, Tinetti) and in INPH specific symptoms (assessed with INPH Grading Scale, INPHGS). Results Patients with elevated values of CIRS had worse performance in gait and balance at Tinetti scale, both before (P = 0.039) and after surgery (P = 0.005); patients with high values of CMI had inferior values of Tinetti at baseline (P = 0.027) and higher mRS after surgery (P = 0.009); ASA 2 patients had better postoperative Tinetti scores than ASA 3 patients (P = 0.027). A positive or negative shunt response was not significantly correlated with patients' preoperative comorbidity scores. Conclusions Patients with multiple comorbidities have a worse preoperative condition compared to patients with less concomitant diseases, and the proposed comorbidity scores, CIRS in particular, are useful clinical tools for the anesthesiologist. Comorbidities, though, do not impact overall postoperative outcome.

Background Anterior Cruciate Ligament (ACL) injuries have grown in adolescent population in the last decades, and if surgical reconstruction resulted safe in the short term, its impact in the long term is still unclear. The purpose of this study was to assess the long-term risk of failure, the rate of contralateral injury and the clinical reported outcomes in a cohort of high-school athletes after ACL reconstruction. Methods 54 consecutive patients (mean age 16.3 ± 1.4 years) underwent ACL reconstruction with a single-bundle plus lateral plasty hamstring technique between May 2006 and July 2009. The number of subsequent ipsilateral reoperations and contralateral ACL reconstruction, Lhysolm, KOOS, VAS for pain and Tegner Activity Level was determined at a minimum follow-up of 10 years. Results Ipsilateral ACL revision was performed in 8 (3.4%) patients, contralateral ACL reconstruction in 11 (21.1%). The average Lysholm score was 95.1 ± 9.2. The average KOOS was 96.5 ± 6.3 for the Pain subscale, 92.2 ± 9.0 for the Symptom subscale, 99.2 ± 1.8 for the ADL subscale, 94.1 ± 10.1 for the Sport subscale and 91.8 ± 14.5 for the Quality-of-life subscale. The average VAS for pain during activity was 1.7 ± 2.3. 90% returned to sport, 15% decreased the activity level, 61% of patients were still involved in sport, 35% at the same pre-injury level. Conclusion At long-term, single-bundle hamstring ACL-R plus lateral-plasty in a cohort of high school athletes resulted to have a comparable graft failure rate and contralateral ACL injury with other surgical techniques.

A. Kawai43, K. Kopeckova44, D. A. Krakorova45, A. Le Cesne46, F. Le Grange1, E. Legius47, A. Leithner48, A. Lopez Pousa49, J. Martin-Broto36, O. Merimsky50, C. Messiou51, A. B. Miah52, O. Mir53, M. Montemurro54, B. Morland55, C. Morosi56, E. Palmerini57, M. A. Pantaleo58, R. Piana59, S. Piperno-Neumann60, P. Reichardt61, P. Rutkowski62, A. A. Safwat63, C. Sangalli64, M. Sbaraglia19, S. Scheipl48, P. Schoffski65, S. Sleijfer66, D. Strauss67, K. Sundby Hall13, A. Trama68, M. Unk69, M. A. J. van de Sande70, W. T. A. van der Graaf66,71, W. J. van Houdt72, T. Frebourg73x, R. Ladenstein41z, P. G. Casali2,74z &

BACKGROUND & AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) has been shown to predict outcomes of patients with primary biliary cholangitis (PBC) in small-size studies. We aimed to validate the prognostic value of LSM in a large cohort study. METHODS: We performed an international, multicentre, retrospective follow-up study of 3,985 patients with PBC seen at 23 centres in 12 countries. Eligibility criteria included at least 1 reliable LSM by VCTE and a follow-up ≥ 1 year. Independent derivation (n = 2,740) and validation (n = 568) cohorts were built. The primary endpoint was time to poor clinical outcomes defined as liver-related complications, liver transplantation, or death. Hazard ratios (HRs) with CIs were determined using a time-dependent multivariable Cox regression analysis. RESULTS: LSM was independently associated with poor clinical outcomes in the derivation (5,324 LSMs, mean follow-up 5.0 ± 3.1 years) and validation (1,470 LSMs, mean follow-up 5.0 ± 2.8 years) cohorts: adjusted HRs (95% CI) per additional kPa were 1.040 (1.026-1.054) and 1.042 (1.029-1.056), respectively (p

Background and objectives: Stress urinary incontinence (SUI) is the most common type of urinary incontinence, affecting approximately 46% of adult women. After failure of conservative treatment, the mid-urethral sling (MUS) is considered the most effective and safe surgical procedure for SUI. In 2012, Waltregny et al. introduced a new trans-obturator tension-free vaginal tape (TVT) procedure, named TVT-abbrevo (TVT-A). The aim of the present study is to evaluate the efficacy and safety of the TVT-A procedure in women with pure SUI at 5-year follow-up. Materials and Methods: All women who complained of pure SUI symptoms with concomitant urodynamic stress incontinence (USI) were prospectively enrolled and treated with the TVT-A procedure. Postoperative subjective outcome measures included: International Consultation on Incontinence Questionnaire–Short Form (ICI-Q SF), Patient Global Impression of Improvement (PGI-I) scale, and patient degree of satisfaction scale. A PGI-I score ≤ 2 and a patient-satisfaction score ≥8 were used to define subjective success. Objective success was defined as the absence of urine leakage during a cough stress test. Adverse events were collected according to the Clavien–Dindo classification during follow-up. Results: Univariable analysis was used to investigate outcomes. Fifty women who met the inclusion criteria underwent TVT-A implantation. At 5 years after TVT-A implantation, 38 out of 45 (84.4%) patients were subjectively cured (p for trend 0.05), and 40 out of 45 (88.9%) patients were objectively cured (p for trend 0.04). A significant trend of de novo OAB symptoms was reported (22.2% [10/45]) at the 5-year follow-up. No serious early or late complications such as urethral/bladder injury, persistent groin-thigh pain, and sexual dysfunction that required mesh removal were detected. The univariate analysis did not reveal any risk factors (i.e., age, body mass index (BMI), menopause, obstetric factors, and preoperative ICIQ- SF questionnaire) statistically associated with failure of the TVT-A procedure. Conclusions: In conclusion, the 5-year follow-up results of this study demonstrated that TVT-A is a safe and effective option for treatment of SUI with a very low rate of post-operative groin–thigh pain

No abstract available

Nephropathy in Diabetes type 2 (NID-2) study is an open-label cluster randomized clinical trial that demonstrated that multifactorial intensive treatment reduces Major Adverse Cardiac Events (MACEs) and overall mortality versus standard of care in type 2 diabetic subjects with albuminuria and no history of cardiovascular disease. Aim of the present post-hoc analysis of NID- 2 study is to evaluate whether the number of risk factors on target associates with patient outcomes.Intervention phase lasted four years and subsequent follow up for survival lasted 10 years. To the aim of this post-hoc analysis, the whole population has been divided into 3 risk groups: 0-1 risk factor (absent/low); 2-3 risk factors (intermediate); 4 risk factors (high). Primary endpoint was a composite of fatal and non-fatal MACEs, the secondary endpoint was all-cause death at the end of the follow-up phase.Absent/low risk group included 166 patients (52.4%), intermediate risk group 128 (40.4%) and high-risk group 23 (7.3%). Cox model showed a significant higher risk of MACE and death in the high-risk group after adjustment for confounding variables, including treatment arm (HR 1.91, 95% CI 1.04-3.52, P = 0.038 and 1.96, 95%CI 1.02-3.8, P = 0,045, respectively, vs absent/low risk group).This post-hoc analysis of the NID-2 trial indicates that the increase in the number of risk factors at target correlates with better cardiovascular-free survival in patients with type 2 diabetes at high CV risk.ClinicalTrials.gov number, NCT00535925. https://clinicaltrials.gov/ct2/show/NCT00535925.

Background Leber Hereditary Optic Neuropathy (LHON) is a rare, maternally-inherited mitochondrial disease that primarily affects retinal ganglion cells (RGCs) and their axons in the optic nerve, leading to irreversible, bilateral severe vision loss. Lenadogene nolparvovec gene therapy was developed as a treatment for patients with vision loss from LHON caused by the most prevalent m.11778G > A mitochondrial DNA point mutation in the MT-ND4 gene. Lenadogene nolparvovec is a replication-defective recombinant adeno-associated virus vector 2 serotype 2 (AAV2/2), encoding the human wild-type MT-ND4 protein. Lenadogene nolparvovec was administered by intravitreal injection (IVT) in LHON patients harboring the m.11778G > A ND4 mutation in a clinical development program including one phase 1/2 study (REVEAL), three phase 3 pivotal studies (REVERSE, RESCUE, REFLECT), and one long-term follow-up study (RESTORE, the follow-up of REVERSE and RESCUE patients). Case presentation A 67-year-old woman with MT-ND4 LHON, included in the REVERSE clinical study, received a unilateral IVT of lenadogene nolparvovec in the right eye and a sham injection in the left eye in May 2016, 11.4 months and 8.8 months after vision loss in her right and left eyes, respectively. The patient had a normal brain magnetic resonance imaging with contrast at the time of diagnosis of LHON. Two years after treatment administration, BCVA had improved in both eyes. The product was well tolerated with mild and resolutive anterior chamber inflammation in the treated eye. In May 2019, the patient was diagnosed with a right temporal lobe glioblastoma, IDH-wildtype, World Health Organization grade 4, based on histological analysis of a tumor excision. The brain tumor was assessed for the presence of vector DNA by using a sensitive validated qPCR assay targeting the ND4 sequence of the vector. Conclusion ND4 DNA was not detected (below 15.625 copies/μg of genomic DNA) in DNA extracted from the brain tumor, while a housekeeping gene DNA was detected at high levels. Taken together, this data shows the absence of detection of lenadogene nolparvovec in a brain tumor (glioblastoma) of a treated patient in the REVERSE clinical trial 3 years after gene therapy administration, supporting the long-term favorable safety of lenadogene nolparvovec.

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Objective/methods Phosphorylated alpha-synuclein (p-syn) in dermal nerves of patients with isolated REM sleep behavior disorder (iRBD) is detectable by immunofluorescence-labeling. Skin-biopsy-p-syn-positivity was recently postulated to be a prodromal marker of Parkinson's disease (PD) or related synucleinopathies. Here, we provide two-to four-year clinical and skin biopsy follow-up data of 33 iRBD patients, whose skin biopsy findings at baseline were reported in 2017. Results Follow-up biopsies were available from 25 patients (18 positive at baseline) and showed consistent findings over time in 24 patients. One patient converted from skin-biopsy-negativity to -positivity. P-syn-positivity was observed in iRBD patients who still had a normal FP-CIT-SPECT two years later. Clinically, five of the 23 at baseline skin-biopsy-positive patients (21.7%) had converted to PD or dementia with Lewy bodies at follow-up, but none of the skin-biopsy-negative patients. Conclusions Dermal p-syn in iRBD is most probably an early consistent marker of synucleinopathy and may support other indicators of conversion to manifest disease state.

Data on the long-term neurodevelopmental outcomes of children exposed to hematological maternal cancer with or without treatment during pregnancy are lacking. A total of 57 children, of whom 33 males and 24 females, prenatally exposed to hematological malignancies and its treatment, were invited for neuropsychological and physical examinations at 18 months, 36 months, 6, 9, 12, 15 and 18 years of age. Oncological, obstetrical, neonatal and follow-up data of these children were collected. Parents were asked to complete questionnaires on their child's general health, school performances, social situation, behavioral development, executive functioning, and if their child receives supportive care. Non-Hodgkin lymphoma was diagnosed in 35.1%, Hodgkin lymphoma in 28.1%, acute myeloid leukemia in 15.8%, chronic myeloid leukemia in 12.3%, and acute lymphoblastic leukemia in 8.8%. Cognitive development at a median age of 10.7 years was within the normal range. In subgroup analyses of children in early childhood, the gestational age at birth was correlated with the cognitive outcome at a median age of 1.7 years. Scores for language development, intelligence, attention, memory and behavior, as well as clinical neurological and general pediatric examinations were within normal ranges. In subgroup analyses, the need for supportive care in the child was associated with the loss of the mother. Prenatal exposure to hematological maternal malignancies with or without treatment did not affect the neurodevelopment of the child in the long term. Yet, caution is indicated and surveillance of the emotional development of the child is needed, especially when the mother is deceased to cancer. ispartof: CHILD NEUROPSYCHOLOGY vol:27 issue:6 pages:822-833 ispartof: location:England status: published

Periods of absence from supervised group exercise while maintaining physical activity might be a frequent pattern in adults' exercise habits. The aim of the present study was to determine detraining effects on musculoskeletal outcomes after a 3-month detraining period in early post-menopausal, osteopenic women. Due to the COVID-19 pandemic, we terminated the 18-month randomized controlled ACTLIFE exercise intervention immediately after the 13-month follow-up assessment. This put an abrupt stop to the high-intensity aerobic and resistance group exercise sessions undertaken three times per week by the exercise group (EG: n = 27) and the gentle exercise program performed once per week for the attention control group (CG: n = 27); but both groups were permitted to conduct individual outdoor activity for the 3-month lock-down period. Study endpoints were lean body mass (LBM), bone mineral density (BMD) at the lumbar spine (LS), maximum hip-/leg extension strength and power. Detraining-induced reductions of LBM, hip/leg strength and power (but not BMD-LS) were significantly greater (p p = 0.044) compared with the CG. Significant exercise effects, i.e. differences between EG and CG, present after 13 months of exercise, were lost after 3 months of detraining for LBM (p = 0.157) and BMD-LS (p = 0.065), but not for strength (p p Trial registration number: ClinicalTrials.gov: NCT04420806, 06.05.2020.

In 816 patients with 2016 World Health Organization-defined polycythemia vera (PV) enrolled in a multicenter retrospective study, we investigated the predictive value of Charlson comorbidity index (CCI) and body mass index (BMI) on thrombosis, progression to post-PV myelofibrosis (PPV-MF) and survival. Patients were subgrouped according to CCI=0 (58.1%, no comorbidities) or CCI≥1 (41.9%) and according to normal/underweight (BMI&nbsp

Purpose Approximately 1–2% of chronic myeloid leukemia (CML) patients harbor atypical BCR-ABL1 transcripts that cannot be monitored by real-time quantitative PCR (RT-qPCR) using standard methodologies. Within the European Treatment and Outcome Study (EUTOS) for CML we established and validated robust RT-qPCR methods for these patients. Methods BCR-ABL1 transcripts were amplified and sequenced to characterize the underlying fusion. Residual disease monitoring was carried out by RT-qPCR with specific primers and probes using serial dilutions of appropriate BCR-ABL1 and GUSB plasmid DNA calibrators. Results were expressed as log reduction of the BCR-ABL1/GUSB ratio relative to the patient-specific baseline value and evaluated as an individual molecular response (IMR). Results In total, 330 blood samples (2–34 per patient, median 8) from 33 CML patients (19 male, median age 62 years) were analyzed. Patients expressed seven different atypical BCR-ABL1 transcripts (e1a2, n = 6; e6a2, n = 1; e8a2, n = 2; e13a3, n = 4; e14a3, n = 6; e13a3/e14a3, n = 2; e19a2, n = 12). Most patients (61%) responded well to TKI therapy and achieved an IMR of at least one log reduction 3 months after diagnosis. Four patients relapsed with a significant increase of BCR-ABL1/GUSB ratios. Conclusions Characterization of atypical BCR-ABL1 transcripts is essential for adequate patient monitoring and to avoid false-negative results. The results cannot be expressed on the International Scale (IS) and thus the common molecular milestones and guidelines for treatment are difficult to apply. We, therefore, suggest reporting IMR levels in these cases as a time-dependent log reduction of BCR-ABL1 transcript levels compared to baseline prior to therapy.

ispartof: HEMASPHERE vol:5 issue:2 ispartof: location:United States status: published

Exposure to antibiotics in the first days of life is thought to affect various physiological aspects of neonatal development. Here, we investigate the long-term impact of antibiotic treatment in the neonatal period and early childhood on child growth in an unselected birth cohort of 12,422 children born at full term. We find significant attenuation of weight and height gain during the first 6 years of life after neonatal antibiotic exposure in boys, but not in girls, after adjusting for potential confounders. In contrast, antibiotic use after the neonatal period but during the first 6 years of life is associated with significantly higher body mass index throughout the study period in both boys and girls. Neonatal antibiotic exposure is associated with significant differences in the gut microbiome, particularly in decreased abundance and diversity of fecal Bifidobacteria until 2 years of age. Finally, we demonstrate that fecal microbiota transplant from antibiotic-exposed children to germ-free male, but not female, mice results in significant growth impairment. Thus, we conclude that neonatal antibiotic exposure is associated with a long-term gut microbiome perturbation and may result in reduced growth in boys during the first six years of life while antibiotic use later in childhood is associated with increased body mass index., In this study, Omry Koren, Samuli Rautava and colleagues report a sex-specific association between neonatal antibiotic exposure and weight and height gain during the first six years of life and showing that boys but not girls exposed to neonatal antibiotics exhibit impaired weight and height development.

With the goal to restore ankle and foot function also in the long term, custom-made prostheses are becoming more frequently possible solutions for severe bone loss and avascular necrosis of the talus. A young professional rock climber was implanted with a custom-made talonavicular prosthesis, and short-term (30 months) assessment has been published. A thorough assessment at the intermediate term (60 months), with state-of-the-art gait and medical imaging analyses, is reported here. Level walking and more demanding motor tasks were analyzed with both a full-body and a multisegment foot protocol on the operated and contralateral limbs. Cone-beam computer-tomography was also used to obtain 3-dimensional (3D) position and orientation of bone models on the operated ankle. These models were also used for a 3D video fluoroscopy analysis, with the ankle in 3 joint positions at the extremes of motion. Distance map analysis was performed to check for possible changes over time of bone morphology and joint contact areas, in all 3 joint positions. Very satisfactory functional results were observed, with large and symmetric joint motion and physiological muscular recruitment even in demanding motor tasks. Distance map analyses revealed that very small morphologic and contact patterns changes occurred in the replaced ankle between 30 and 60 months. Concerns about possible wear of the cartilage in the tibial mortise are not yet supported by experimental evidence.

Supplemental Digital Content is Available in the Text., Background: RESCUE and REVERSE were 2 Phase 3 clinical trials that assessed the efficacy and safety of intravitreal gene therapy with lenadogene nolparvovec (rAAV2/2-ND4) for the treatment of Leber hereditary optic neuropathy (LHON). RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials. Methods: In RESCUE and REVERSE, 76 subjects with LHON because of the m.11778 G>A mutation in the mitochondrial gene ND4 received a single unilateral intravitreal injection of lenadogene nolparvovec. After 96 weeks, 61 subjects were enrolled in the long-term follow-up study RESTORE. The best-corrected visual acuity (BCVA) was assessed over a period of up to 52 months after onset of vision loss. A locally estimated scatterplot smoothing regression model was used to analyze changes in BCVA over time. Vision-related quality of life was reported using the visual function questionnaire-25 (VFQ-25). Results: The population of MT-ND4 subjects enrolled in RESTORE was representative of the combined cohorts of RESCUE and REVERSE for mean age (35.1 years) and gender distribution (79% males). There was a progressive and sustained improvement of BCVA up to 52 months after the onset of vision loss. The final mean BCVA was 1.26 logarithm of the minimal angle of resolution 48 months after the onset of vision loss. The mean VFQ-25 composite score increased by 7 points compared with baseline. Conclusion: The treatment effect of lenadogene nolparvovec on BCVA and vision-related quality of life observed 96 weeks (2 years) after treatment in RESCUE and REVERSE was sustained at 3 years in RESTORE, with a maximum follow-up of 52 months (4.3 years) after the onset of vision loss.

Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14−CD15+CD33+HLADR− cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC–related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.

Background:Arthroscopic debridement with graft preservation has been advocated as the treatment of choice for septic arthritis after anterior cruciate ligament (ACL) reconstruction, but no previous studies have investigated if hardware removal, while retaining the graft in situ, improves the success rate. Moreover, it is unclear whether the premature removal of fixation devices may affect graft integration and knee stability.Purpose/Hypothesis:The purpose was to assess the clinical and functional outcomes of patients with septic arthritis after ACL reconstruction who underwent arthroscopic debridement, while retaining the graft in situ but removing fixation devices, and to determine if premature hardware removal affects graft integrity and function. The hypothesis was that arthroscopic debridement with hardware removal would be effective in eradicating infections while not compromising graft integration and function.Study Design:Case series; Level of evidence, 4.Methods:From a cohort of 2384 cases of arthroscopic ACL reconstruction, 24 patients with postoperative septic arthritis were included for the analysis; 18 patients were available for a clinical evaluation using the International Knee Documentation Committee (IKDC) form, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lysholm score, and Tegner score at a minimum 12-month follow-up. Knee laxity was assessed clinically with standardized manual laxity tests and instrumentally using an arthrometer and a triaxial accelerometer. Additionally, 3-T magnetic resonance imaging (MRI) at final follow-up was performed, focusing on the graft signal, the cartilage status, and the occurrence of arthrofibrosis.Results:Eradication of the infection was achieved in all cases, and only 1 graft removal was performed because of insufficient tension. Among the remaining 23 patients, a single arthroscopic debridement procedure with hardware removal while preserving the graft was effective in 21 cases (91%) at a mean of 30 ± 37 days from ACL reconstruction to debridement. At last follow-up, 2 patients required a further ACL revision procedure. The mean IKDC, WOMAC, Lysholm, and Tegner scores of the patients available for the clinical evaluation were 75 ± 19, 90 ± 8, 79 ± 21, and 6 ± 2, respectively. No abnormal laxity was reported on manual testing, and arthrometric and accelerometer tests also demonstrated good knee stability (mean KT-1000 arthrometer side-to-side difference was 1.6 ± 1.2 mm at manual maximum force). On MRI, a good graft signal was found in 50% of cases, while concomitant signs of arthrofibrosis were detected in 81% of patients. Severe cartilage defects (International Cartilage Repair Society grade ≥3) were reported in 63% of cases.Conclusion:Arthroscopic debridement with hardware removal was effective in the eradication of infections after ACL reconstruction with extra-articular fixation while preserving graft integrity without compromising knee stability. Patients and surgeons should be aware of complications that might affect the outcome, particularly arthrofibrosis and chondrolysis.

Objective: To test the safety of a new volume-stable collagen matrix (VCMX) in combination with coronally advanced flap (CAF) for the treatment of single gingival recession. Material and methods: Ten patients were treated for single RT1 gingival recession. Complete and mean root coverage, gingival thickness and keratinized tissue height, patient-reported outcome measures (PROMs), and safety were assessed up to 180days. Descriptive statistics were used to analyze the clinical parameters. Results: VCMX resulted to be safe with no serious adverse events in all patients. At 6months, root coverage was 96.7% with 90% of defects exhibiting complete coverage. There was an increase in mean width of keratinized tissue (KT) (0.4 ± 0.8mm) and in gingival thickness (GT) (0.4 ± 0.34mm); however, the difference was not statistically significant compared to baseline parameters. Pain perception and pain-killer consumption were low and decreasing further at 7days. Esthetic satisfaction for both patients and experts revealed excellent scores. Conclusions: VCMX is a safe and well-tolerated device for the treatment of single gingival recessions. In combination with CAF, it resulted in a high performance in terms of mean and complete root coverage, KT width, and GT increase. VCMX may reduce patient discomfort and post-operative morbidity. Clinical relevance: VCMX is a safe and stable substitute for the treatment of gingival recession in conjunction with coronally advanced technique.

Introduction: We used data from MOBI-Kids, a 14-country international collaborative case-control study of brain tumors (BTs), to study clinical characteristics of the tumors in older children (10 years or older), adolescents and young adults (up to the age of 24). Methods: Information from clinical records was obtained for 899 BT cases, including signs and symptoms, symptom onset, diagnosis date, tumor type and location. Results: Overall, 64% of all tumors were low-grade, 76% were neuroepithelial tumors and 62% gliomas. There were more males than females among neuroepithelial and embryonal tumor cases, but more females with meningeal tumors. The most frequent locations were cerebellum (22%) and frontal (16%) lobe. The most frequent symptom was headaches (60%), overall, as well as for gliomas, embryonal and 'non-neuroepithelial' tumors; it was convulsions/seizures for neuroepithelial tumors other than glioma, and visual signs and symptoms for meningiomas. A cluster analysis showed that headaches and nausea/vomiting was the only combination of symptoms that exceeded a cutoff of 50%, with a joint occurrence of 67%. Overall, the median time from first symptom to diagnosis was 1.42 months (IQR 0.53-4.80); it exceeded 1 year in 12% of cases, though no particular symptom was associated with exceptionally long or short delays.Conclusions: This is the largest clinical epidemiology study of BT in young people conducted so far. Many signs and symptoms were identified, dominated by headaches and nausea/vomiting. Diagnosis was generally rapid but in 12% diagnostic delay exceeded 1 year with none of the symptoms been associated with a distinctly long time until diagnosis. This work was supported by the MOBI-Kids study and the work in this study was obtained from the European Community's Seventh Framework Programme under Grant Agreements Number 226873—the MOBI-Kids Project—and 603794—the GERoNiMO project. Additional funds for the coordination of MOBI-Kids were obtained from the Spanish Ministry of Science and Innovation (MINECO), while complementary funds for the conduct of MOBI-Kids in Spain were obtained from the Spanish Health Research Fund (FIS) of the National Institute for Health Carlos III. Italian participation is partially supported by a Ministry of Health grant (RF-2009-1546284). In Canada, funding was provided by a grant from the Canadian Institutes for Health Research under a peer-reviewed university-industry partnership program that involved the Canadian Wireless Telecommunications Association, who provided technical data on wireless telecommunications practices in Canada. The German study centre received additional support by the Federal Office for Radiation Protection (BfS). Japanese participation in MOBI-Kids was supported by the Ministry of Internal Affairs and Communications. New Zealand participation was supported by Health Research Council and Cure Kids. In France, this study received funds from the French National Agency for Sanitary Safety of Food, Environment and Labour (ANSES, contract FSRF2008-3), French National Cancer Institute (INCa), Pfizer Foundation and League against cancer. India received funding from Board of Research in Nuclear Sciences (BRNS). The funding sources had no role in: the study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the article for publication.

Background: Early pathogenesis of diabetic cardiomyopathy (DMCM) may involve lipotoxicity of cardiomyocytes in the context of hyperglycemia. There are many preclinical studies of DMCM pathogenesis, but the human evidence is still poorly understood. Objectives: By using a nondiabetic mellitus (non-DM) heart transplanted (HTX) in diabetes mellitus (DM) recipients, this study conducted a serial study of human heart transplant recipients evaluating cardiac effects of diabetic milieu (hyperglycemia and insulin resistance) on lipotoxic-mediated injury. We evaluated cardiomyocyte morpho-pathology by seriated biopsies of healthy implanted hearts in DM recipients during 12-month follow-up from HTX. Because metformin reduces ectopic lipid accumulation, we evaluated the effects of the drug in a nonrandomized subgroup. Methods: The DMCM-AHEAD (Diabetes and Lipid Accumulation and Heart Transplant) prospective ongoing study (NCT03546062) evaluated 158 first HTX recipients (82 non-DM, 76 DM of whom 35 [46%] were receiving metformin). HTX recipients were undergoing clinical standard evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsies). Biopsies evaluated immune response, Oil Red-O staining, ceramide, and triacylglycerol levels. Lipotoxic factors and insulin resistance were evaluated by reverse transcriptase–polymerase chain reaction. Results: There was a significant early and progressive cardiomyocyte lipid accumulation in DM but not in non-DM recipients (p = 0.019). In the subgroup receiving metformin, independently from immunosuppressive therapy that was similar among groups, lipid accumulation was reduced in comparison with DM recipients not receiving the drug (hazard ratio: 6.597; 95% confidence interval: 2.516 to 17.296; p < 0.001). Accordingly, lipotoxic factors were increased in DM versus non-DM recipients, and, relevantly, metformin use was associated with fewer lipotoxic factors. Conclusions: Early pathogenesis of human DMCM started with cardiomyocyte lipid accumulation following HTX in DM recipients. Metformin use was associated with reduced lipid accumulation independently of immunosuppressive therapy. This may constitute a novel target for therapy of DMCM.

Summary Background Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. Methods We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov , NCT01243944 . Findings We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9–12·3) in the ruxolitinib group and 9·3 years (4·9–13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51–88). The probability of maintaining complete haematological remission was 55% (95% CI 32–73) and the probability of maintaining overall clinicohaematological responses was 67% (54–77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4–95·9) with ruxolitinib therapy and 91·0% (82·8–95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment. Interpretation We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population. Funding Novartis Pharmaceuticals Corporation.

Study Objective: The effect of the different types of vaginal cuff closures on posthysterectomy sexual function has not been investigated in depth. We evaluated if there is a difference between transvaginal versus a laparoscopic closure after total laparoscopic hysterectomy (TLH) on female sexual function, using a validated questionnaire. Design: Secondary analysis of a prospective randomized controlled trial. Setting: Three academic research centers. Patients: Women consenting to telephone interviews on their sexual life before and after undergoing TLH were included. Interventions: Patients were randomly assigned to a laparoscopic or transvaginal approach for vaginal cuff closure at the end of TLH for benign indications. Measurements and Main Results: A validated questionnaire (the Female Sexual Function Index [FSFI]) was used to explore sexuality before and after the operation. Of the 1408 patients enrolled in the primary study, 400 patients were asked to complete the questionnaire. Of them, 182 (41.4%) were eligible and accepted enrollment in the present analysis. No difference was found in terms of pre- and postoperative FSFI scores between groups. Patients with a low preoperative FSFI score (

Soft tissue augmentation procedures are crucial to obtain a successful outcome in implant therapy. The aim of this case series was to describe the 1-year clinical outcomes of a porcine-derived acellular dermal matrix for buccal mucosal thickness augmentation at osseointegrated single implants with facial peri-implant soft tissue deficiencies. Ten patients were included and treated with a prosthetic and surgical approach that combined a coronally advanced flap and a dermal matrix. Results showed the possibility to obtain an increase in buccal soft tissue thickness of 1.2 ± 0.18 mm at single implant sites in the esthetic area.

Contains fulltext : 220431.pdf (Publisher’s version ) (Closed access) BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1.5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score

Background: Celiac disease (CD) follow-up is a relatively underevaluated topic. However, correct adherence to follow-up procedures is central to the early recognition of complicated CD and other conditions typically associated with CD. Establishing whether patients at increased risk of complications follow clinicians’ recommendations has multiple repercussions. Methods: We retrospectively analyzed the records of patients consecutively diagnosed with CD in our outpatient clinic between January 2004 and October 2017 to investigate the factors associated with drop-out from follow-up procedures. Results: Among the 578 patients analyzed, 40 (6.9%) dropped out during the first six months and 272 (50.6%) during the observation period. The median time to drop-out was 7.4 years (95% confidence interval: 6.8–8.0). No factors were associated with early drop-out. Instead, age at diagnosis >40 years (40–59 years, p < 0.001; ≥60 years, p = 0.048) and classical clinical presentation (p = 0.016) were significantly associated with a lower risk of later drop-out. Conclusions: Patients at increased risk of complicated CD are more compliant with follow-up procedures than patients at lower risk, despite being prescribed the same controls. These results indirectly support the hypothesis of tailored follow-up strategies, differentiated according to the risk of complications.

Stridor treatment in multiple system atrophy (MSA) mainly comprises tracheostomy or continuous positive airway pressure (CPAP), but guidelines for the use of these treatments are lacking. The aim of the study was to evaluate the predictive value of stridor treatment in an MSA cohort.This is a retrospective and prospective monocentric cohort study including MSA patients evaluated at least once a year during the disease course. Stridor was video-polysomnography confirmed. The time of stridor treatment (CPAP or tracheostomy) and latency from stridor onset were collected. Survival and predictors of survival were calculated.A total of 182 (107 males, mean age at disease onset 57.3 ± 8.4 years) MSA patients were included in the study; 141 were deceased at the time of study. Of the total sample, 75 patients were diagnosed with stridor: 22 patients were treated with tracheostomy and 29 with CPAP, whilst 24 patients did not receive treatment. Treatment with tracheostomy showed longer survival compared with both treatment with CPAP or no treatment (incidence rate of death 12 vs. 21 vs. 23 per 100 person-years, respectively). Tracheostomy remained an independent factor associated with longer survival (hazard ratio 0.38, p = 0.029), also after adjustment for other confounders and latency for stridor treatment.This is the largest monocentric and long-term follow-up study comparing survival between tracheostomy and CPAP in MSA patients with stridor. Treatment with tracheostomy showed longer survival compared with both treatment with CPAP or no treatment. A careful multidisciplinary approach is required for the management of MSA patients with stridor.

BACKGROUND: Darvadstrocel is an expanded allogeneic adipose-derived mesenchymal stem cell therapy for the treatment of complex perianal fistulas in patients with Crohn’s disease. Safety and efficacy outcomes from the clinical trial known as “Adipose derived mesenchymal stem cells for induction of remission in perianal fistulizing Crohn’s disease,” or ADMIRE-CD (NCT01541579), from up to 52 weeks posttreatment were previously reported. Here, the outcomes from an extended 104-week follow-up are reported. OBJECTIVE: The goal of this study was to assess the long-term safety and efficacy of darvadstrocel at 2 years post-treatment in patients with Crohn’s disease and complex perianal fistulas. DESIGN: This was a phase 3 double-blind randomized controlled study (ADMIRE-CD) in patients with perianal fistulizing Crohn’s disease. SETTINGS: This study extension was conducted in multiple hospitals across 7 European countries and Israel. PATIENTS: Forty patients entered the extended follow-up period: 25 patients in the darvadstrocel treatment group and 15 in the control group. INTERVENTIONS: Darvadstrocel or saline solution (control group) was administered once, locally, after fistula tract curettage and internal opening closure (with previous seton placement). All patients were permitted to continue ongoing medical treatments for fistulas. MAIN OUTCOME MEASURES: Treatment-emergent serious adverse events were recorded through week 104. Clinical remission, defined as closure of all treated external openings that were draining at baseline despite gentle finger compression, was assessed at week 104. RESULTS: Of 40 patients, 37 completed the extended follow-up. Through week 104, 7 treatment-emergent serious adverse events were reported, of which 4 occurred between weeks 52 and 104. At week 104, clinical remission was reported in 14/25 (56%) patients in the darvadstrocel group and 6/15 (40%) patients in the control group. LIMITATIONS: Limitations include the small number of patients who entered the extended follow-up period, and no imaging examinations were performed at the 104-week time point. CONCLUSIONS: Darvadstrocel was well tolerated and clinical remission after treatment with darvadstrocel may be sustained for up to 104 weeks in patients with perianal fistulizing Crohn’s disease, This study was sponsored by Takeda Pharmaceuticals International Co. Medical writing support was provided by Sally McTaggart, PhD, of Oxford PharmaGenesis, Oxford, UK, and was funded by Takeda Pharmaceuticals International Co

Objectives To assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM). Methods Twelve months follow-up data of 117 patients with PMM were collected. We analysed the 6-min walk test (6MWT), timed up-and-go test (× 3) (3TUG), five-times sit-to-stand test (5XSST), timed water swallow test (TWST), and test of masticating and swallowing solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional pain inventory as patient-reported outcome measures. PMM patients were divided into three phenotypic categories: mitochondrial myopathy (MiMy) without extraocular muscles involvement, pure chronic progressive external ophthalmoplegia (PEO) and PEO&MiMy. As 6MWT is recognized to have significant test–retest variability, we calculated MCID (minimal clinically important difference) as one third of baseline 6 min walking distance (6MWD) standard deviation. Results At 12-month follow-up, 3TUG, 5XSST and FSS were stable, while TWST and the perceived pain severity (WHYMPI) worsened. 6MWD significantly increased in the entire cohort, especially in the higher percentiles and in PEO patients, while was substantially stable in the lower percentile ( Conclusions PMM patients showed a slow global decline valued by NMDAS at 12 months; 6MWT was a more reliable measurement below 408 m, substantially stable at 12 months. PEO patients had better motor performance and lower NMDAS than PEO&MiMy and MiMy also at 12 months of follow-up.

Purpose The impact of anastomotic leaks (AL) on oncological outcomes after low anterior resection for mid-low rectal cancer is still debated. The aim of this study was to evaluate overall survival (OS), disease-free survival (DFS), and local and distant recurrence in patients with AL following low anterior resection. Methods This is an extension of a multicentre RCT (NCT01110798). Kaplan–Meier method and the log-rank test were used to estimate and compare the 3-, 5-, and 10-year OS and DFS, and local and distant recurrence in patients with and without AL. Predictors of OS and DFS were evaluated using the Cox regression analysis as secondary aim. Results Follow-up was available for 311 patients. Of them, 252 (81.0%) underwent neoadjuvant chemoradiotherapy and 138 (44.3%) adjuvant therapy. AL occurred in 63 (20.3%) patients. At a mean follow-up of 69.5 ± 31.9 months, 23 (7.4%) patients experienced local recurrence and 49 (15.8%) distant recurrence. The 3-, 5-, and 10-year OS and DFS were 89.2%, 85.3%, and 70.2%; and 80.7%, 75.1%, and 63.5% in patients with AL, and 88.9%, 79.8% and 72.3%; and 83.7, 74.2 and 62.8%, respectively in patients without (p = 0.89 and p = 0.84, respectively). At multivariable analysis, AL was not an independent predictor of OS (HR 0.65, 95%CI 0.34–1.28) and DFS (HR 0.70, 95%CI 0.39–1.25), whereas positive circumferential resection margins and pathological stage impaired both. Conclusions In the context of modern multimodal rectal cancer treatment, AL does not affect long-term OS, DFS, and local and distant recurrence in patients with mid-low rectal cancer.

Background: Cerebral arteriovenous malformations (AVMs) are challenging lesions, often requiring multimodal interventions; however, data on the efficacy of stereotactic radiosurgery for cerebral AVMs are limited. This study aimed to evaluate the clinical and radiographic results following robotic radiosurgery, alone or in combination with endovascular treatment, and to investigate factors associated with obliteration and complications in patients with AVM. Methods: We retrospectively analyzed the clinical and imaging characteristics of 123 patients with AVMs of all Spetzler-Martin grades treated at two institutions by robotic radiosurgery in single-fraction doses (CyberKnife). Embolization was performed before radiosurgery in a subset of patients to attempt to downgrade the lesions. Factors associated with AVM obliteration and complications (toxicity) were identified via univariate and multivariate analyses. Results: The median follow-up time was 48.1 months (range, 3.6–123 months). Five patients were lost to follow-up. The obliteration rate in the 59 patients with a follow-up period exceeding four years was 72.8%. Complete obliteration and partial remission were achieved in 67 (56.8%) and 31 (26.3%) cases, respectively, whereas no change was observed in 20 cases (17.8%). Embolization was performed in 54/123 cases (43.9%). Complete and partial obliteration were achieved in 29 (55.7%) and 14 (26.9%) embolized patients, respectively. In the multivariate analysis, the factors associated with obliteration were age (p = .018) and the Spetzler-Martin grade (p = .041). Treatment-induced toxicity (radiation necrosis and/or edema) was observed in 15 cases (12.7%), rebleeding occurred in three cases (2.5%), and the rate of mortality associated with rebleeding was 1.7%. Conclusions: CyberKnife radiosurgery is a valid approach for treating AVMs of all Spetzler-Martin-grades, with satisfactory obliteration rates, low toxicity, and a relatively rare incidence of rebleeding.

Journal: INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Invest Ophthalmol Vis Sci. 2022 Jan 3;63(1):43. doi: 10.1167/iovs.63.1.43. PMID: 35098304; PMCID: PMC8802032 Abstract Purpose:The purpose of this study was to evaluate optic disk perfusion and neural retinal structure in patients with subacute Leber's hereditary optic neuropathy (LHON) and LHON carriers, as compared with healthy controls. Methods:This study included 8 patients with LHON in the subacute stage, 10 asymptomatic carriers of a LHON-associated mitochondrial DNA mutation, and 40 controls. All subjects underwent measurement of the retinal nerve fiber layer (RNFL) thickness, the ganglion cell-inner plexiform layer (GCIPL) thickness using optical coherence tomography and optic disk microvascular perfusion (Mean Tissue [MT]) using laser speckle flowgraphy (LSFG). Patients were re-examined after a median interval of 3 months from the baseline visit. Results:LHON carriers had higher values of RNFL thickness, GCIPL thickness, and disk area than controls (P < 0.05), whereas MT was not different between the two groups (P = 0.936). Median MT and RNFL thickness were 32% and 15% higher in the early subacute stage of the disease than in controls (P < 0.001 and P = 0.001). MT declined below the values of controls during the late subacute stage (P = 0.024), whereas RNFL thickness declined later during the dynamic stage (P < 0.001). GCIPL thickness was lower in patients with LHON than in controls independently of the stage of the disease (P < 0.001). Conclusions:The high blood flow at the optic disk during the early subacute stage may be the consequence of vasodilation due to nitric oxide release as compensation to mitochondrial impairment. Optic disk perfusion as measured by LSFG is a promising biomarker for LHON diagnosis and monitoring as well as an objective outcome measure for assessing response to therapies.

Background Pyrocardan® (Wright Medical-Tornier) is a pyrocarbon implant proposed in the treatment of trapeziometacarpal joint (TMCJ) osteoarthritis. Our aim was to assess the clinical and radiographic results after Pyrocardan® arthroplasty at midterm follow-up. Methods In this prospective monocentric study, we enrolled 119 patients treated with Pyrocardan® for TMCJ osteoarthritis and followed up at a minimum of four years. The clinical outcome was assessed through the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, the Visual Analog Score (VAS) for pain and the Kapandji score collected pre-operatively, at three, six and 12 months, then yearly. Hand radiographs were taken before surgery, at three months and every year. Complications and re-operations were also recorded. Results The mean follow-up was 5.2 years (range, 4–9). DASH, VAS and Kapandji scores significantly improved at three (p p p = 0.01 and p Conclusion Pyrocardan® arthroplasty provides a satisfactory clinical and radiographic outcome for treating TMCJ osteoarthritis, with a 97% survival rate at four years. We advocate comparative studies with more common techniques (i.e., trapeziectomy) to verify its cost-effectiveness.

Neonatal nutritional supplements may improve early growth for infants born small, but effects on long-term growth are unclear and may differ by sex. We assessed the effects of early macronutrient supplements on later growth. We searched databases and clinical trials registers from inception to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter BMI in childhood (kg/m2: adjusted mean difference (aMD) −0.11[95% CI −0.47, 0.25], p = 0.54; 3 trials, n = 333). Supplementation increased length (cm: aMD 0.37[0.01, 0.72], p = 0.04; 18 trials, n = 2008) and bone mineral content (g: aMD 10.22[0.52, 19.92], p = 0.04; 6 trials, n = 313) in infancy, but not at older ages. There were no differences between supplemented and unsupplemented groups for other outcomes. In subgroup analysis, supplementation increased the height z-score in male toddlers (aMD 0.20[0.02, 0.37], p = 0.03; 10 trials, n = 595) but not in females, and no significant sex interaction was observed (p = 0.21). Macronutrient supplementation for infants born small may not alter BMI in childhood. Supplementation increased growth in infancy, but these effects did not persist in later life. The effects did not differ between boys and girls.

Background: Ultrasound is a reliable tool for airway assessment and management. We evaluated the accuracy of ultrasound in the preprocedure planning and follow-up evaluation of patients undergoing airway stenting for benign upper airway stenosis.Methods: This was a retrospective single center study on patients with benign upper airway stenosis treated with airway stenting. Ultrasound evaluated the characteristics of the stenosis (distance from vocal folds, diameter, and length) before treatment and any complications after treatment; these results were then statistically compared with those obtained by computed tomography, taking the endoscopy as the reference method.Results: Twenty-seven patients were evaluated. Ultrasound was significantly correlated with endoscopy and computed tomography scan measurements as distance of stenosis from vocal folds (r = 0.88; P < .001 and r = 0.87; P < .001, respectively), diameter of the stenosis (r = 0.97; P < .001 and r = 0.97; P < .001, respectively), and length of the stenosis (r = 0.97; P < .001 and r = 0.97; P < .001, respectively). Four out of 27 (15%) patients presented complications after treatment as stent migration (n = 2; 7%); stent obstruction (n = 1; 4%), and granulation of vocal fold (n = 1; 4%). All complications but granulation of vocal fold were correctly depicted by ultrasound and computed tomography without significant difference in comparison to endoscopy (P = .87)CONCLUSIONS: Ultrasound is a promising tool in assessment of airway stenosis and follow-up of patients after stenting; it may be routinely used in adjunction to computed tomography and/or endoscopy in this setting, if our results are corroborated by a future larger study. (C) 2022 by The Society of Thoracic Surgeons

Objective: Although the two-stage technique is a validated strategy in periprosthetic joint infections, there is a lack of data on the patients' clinical outcomes after the spacer placement. This study aims at evaluating the quality of life, joint function, and pain in patients over 70 years affected by periprosthetic joint infection treated with a two-stage exchange using metal on polyethylene spacers. Patients and methods: We conducted a follow-up study to evaluate the quality of life and functionality of consecutive patients over 70 years treated for PJI at our institution using a validated assessment set including the Western Ontario and Mac Master University (WOMAC) score, Knee Society Score (KSS), numerical rating scale (NRS). Knee Range of Movement (ROM) before and after the surgery was also analyzed. Results: Forty-five patients with a mean age of 76 ± 5.3 years were included. Coagulase-negative staphylococci were the most isolated microorganisms. In the preoperative study group, the WOMAC score was 48.4 ± 18.9, and the KSS objective and functional scores were 37.6 ± 17.3 and 27.6 ± 22.3, respectively. NRS was 7.3 ± 1.8. After three months of follow-up, we found better results than preoperative clinical evaluation. We retrieved similar results comparing our post-operative PROMS (WOMAC and KSS scores) with published thresholds for treatment success two months after primary total knee arthroplasty. The infection eradication rate was 87%. Conclusions: The two-stage technique confirmed its efficacy in the treatment of PJI. Patients over 70 years who had undergone the first stage of the two-stage technique for PJI showed a good quality of life and knee function.

Objectives: The improvements in survival with expansion of the survivors’ population, along with evolution of endoscopically-based treatment modalities, have contributed to emphasize the clinical relevance of recurrences in sinonasal cancers. However, at present, literature is scant regarding the pattern of recurrences and the therapeutic strategies available to manage long survivors who experienced single or multiple failures. The aim of the present study was to analyze sinonasal cancers recurrences to provide data regarding rates and patterns of relapse, predictors of failure and prognostic impact of the recurrence. Materials and Methods: All patients receiving multimodal treatments including endoscopic surgery between 1995 and 2021 in three European referral centers were included. Statistical analysis of survival was performed through univariable, multivariable and unidirectional multistate models. Survival after recurrence analysis was implemented for patients experiencing at least one recurrence. Results: The 5- and 10-year recurrence free survival rates were 34.1% and 38.4% for the whole population. With a mean follow-up time of 60 months, a global recurrence rate of 32.9% was observed. The 5- and 10-year survival after recurrence rates were 27.2% and 21.7%, respectively. Incidence and rates of recurrences were significantly associated with histology subtypes. Conclusion: This study provides valuable oncologic outcomes regarding a large homogenous cohort of patients affected by sinonasal malignances treated within a multimodal framework, emphasizing the strong correlation of histologic type with prognosis, as well as with pattern of recurrences.

Objective To update the analysis of mortality of a cohort of talc miners and millers in Northern Italy. Methods We analyzed overall mortality and mortality from specific causes of death during 1946–2020 of 1749 male workers in a talc mine where asbestos was not detected (1184 miners and 565 millers) employed during 1946–1995. Results The overall standardized mortality ratio (SMR) was 1.21 (95 % confidence interval [CI] 1.14–1.28); no deaths were observed from pleural cancer. Mortality from lung cancer was not increased (SMR = 1.02 95 % CI 0.82–1.27), while mortality from pneumoconiosis was (SMR 9.55; 95 % CI 7.43–12.08), especially among miners (SMR 12.74; 95 % CI 9.79–16.31). There was a trend in risk of pneumoconiosis with increasing duration of employment in the overall cohort, and the SMR for 25+ years of employment was 15.12 (95 % CI 10.89–20.43). Conclusions This uniquely long-term follow up confirms the results of previous analyses, namely the lack of association between exposure to talc with no detectable level of asbestos and lung cancer and mesothelioma. Increased mortality from pneumoconiosis among miners is related to past exposure to silica.

As of November 17, 2021, SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus 2), the causative agent of COVID-19 (COronaVIrus Disease 19), has infected ~250 million people worldwide, causing around five million deaths. Titers of anti-SARS-CoV-2 neutralizing antibodies were relatively stable for at least 9 months in a population-based study conducted in Wuhan, China, both in symptomatic and in asymptomatic individuals. In the mass screening campaign conducted in the town of Ariano Irpino (Avellino, Italy) in May, 2020, 5.7% (95% CI: 5.3-6-1) of the 13,444 asymptomatic citizens screened were positive for anti-nucleocapsid antibodies against SARS-CoV-2. Among these, 422 citizens were re-tested for anti SARS-CoV-2 antibodies in January, 2021 and/or in April, 2021 and enrolled in this longitudinal observational study. Median (interquartile range) age of the study cohort was 46 years (29–59), with 47 (11.1%) participants of minor age, while 217 (51.4%) participants were females. There was no evidence of re-infection in any of the subjects included. Presence of anti-nuclear antibodies antibodies (Elecysis, Roche) was reported in 95.7 and 93.7% of evaluable participants in January and April, 2021. Multiple logistic regression analysis used to explore associations between age, sex and seroprevalence showed that adults vs. minors had significantly lower odds of having anti-S1 antibodies (Biorad) both in January, 2021 and in April, 2021. Our findings showed that antibodies remained detectable at least 11.5 months after infection in >90% of never symptomatic cases. Further investigation is required to establish duration of immunity against SARS-CoV-2.

Background: Bortezomib-based induction followed by high-dose melphalan (200 mg/m2) and autologous stem-cell transplantation (MEL200-ASCT) and maintenance treatment with lenalidomide alone is the current standard of care for young and fit patients with newly diagnosed multiple myeloma. We aimed to evaluate the efficacy and safety of different carfilzomib-based induction and consolidation approaches with or without transplantation and of maintenance treatment with carfilzomib plus lenalidomide versus lenalidomide alone in newly diagnosed multiple myeloma. Methods: UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done in 42 Italian academic and community practice centres. We enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 65 years or younger with a Karnofsky Performance Status of 60% or higher. Patients were stratified according to International Staging System stage (I vs II/III) and age (

ispartof: ANNALS OF ONCOLOGY vol:32 issue:11 pages:1348-1365 ispartof: location:England status: published

Overweight and obesity are growing worldwide and strongly associated with hypertension. The Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE) index is proposed as an optimal indicator of body fatness. We aimed to investigate the association of body fat as captured by the CUN-BAE index with incident hypertension in a Mediterranean population. We assessed 15,950 participants of the SUN (Seguimiento Universidad de Navarra) prospective cohort (63.7% women) initially free of hypertension. Participants completed follow-up questionnaires biennially. A validated 136-item food-frequency questionnaire was administered at baseline. We used Cox models adjusted for multiple confounders. Among 12.3 years of median follow-up (interquartile range: 8.3, 15.0 years), 2160 participants reported having received a diagnosis of hypertension. We observed a strong direct association between progressively higher the CUN-BAE index at baseline and incident hypertension during follow-up in multivariable-adjusted models for men and women, even after further adjustment for BMI ≥ 30 kg/m2, showing a significant association also in non-obese participants. For each 2-unit increase in the CUN-BAE index, hypertension risk increased by 27% and 29% in men and women, respectively. The results remained significant when considering longitudinal repeated measures of changes in body fat assessed with the CUN-BAE index among the different biennial follow-up questionnaires. Our results emphasize the importance of reducing and maintaining a low body fat to prevent hypertension.