Is Blood Flow Restriction Training Superior for the Limitation of Hamstring and Quadriceps Atrophy After Anterior Cruciate Ligament Reconstruction? A Review of Randomized Controlled Trials

Post operative recovery from Anterior Cruciate Ligament Reconstruction (ACLR) includes extensive rehabilitation of 6-9 months with return to sport/activity at 12 months Rehabilitation is initiated shortly following surgery to limit quadriceps and hamstring atrophy, maximizing long term tibiofemoral joint stability and functional outcomes The best way to achieve improved muscle strength and prevent atrophy is progressive overload training, however, these activities cannot be performed post operatively without risk to the reconstructed knee Blood Flow Restriction Training (BFR) involves impairing the blood supply for short periods through the application of an air-filled bladder or cuff to restrict the venous drainage of the region of choice BFR allows the surgically repaired limb to be safely stressed after ACLR without added reinjury potential of progressive overload training BFR achieves this elevated stress via systemic hormone production, cell swelling, production of reactive oxygen species, and increased fast twitch fiber recruitment along with stimulation of anabolic and anti-catabolic cell signaling pathways, particularly the mTOR (mechanistic target of rapamycin) protein kinase pathway There is inconsistency of methods, outcome measures and results in literature comparing the outcomes of BFR vs Traditional Post Operative Rehabilitation (TPR

Does Prehabilitation Prior to Ulnar Collateral Ligament Surgery Affect Return to Sport Rate or Time in Baseball Players with Partial UCL Tears?

Those who suffer a partial thickness ulnar collateral ligament (UCL) tear often undergo a period of nonoperative management including physical therapy rehabilitation. This treatment is aimed at optimizing range of motion (ROM) and strengthening the supporting structures around the elbow to help offload the UCL. Unfortunately, some of these patients fail nonoperative management and require surgical intervention. This creates a unique set of patients who essentially underwent “prehabilitation” prior to their UCL surgery. Prehabilitation is considered a period of structured physical therapy rehabilitation aimed at strengthening structures surrounding an injured tendon or ligament, to allow for dissipation of stress away from the repaired structure after surgery. Prehabilitation has been studied extensively and implemented into the clinical practice of anterior cruciate ligament (ACL) rehabilitation, and is being studied for other injuries as well. However, the efficacy of prehabilitation for UCL surgical patients with partial thickness UCL tears has not been evaluated. This chart review: - determines if baseball players with partial UCL tears who completed at least 4 weeks of prehabilitation prior to surgery (Prehab) had better return to play (RTP) rates and quicker return to sport (RTS) time than players who attempted 0-3 weeks of physical therapy prior to UCL surgery (No Prehab) - compares revision, reoperation, and patient reported outcomes between Prehab and No Prehab player

Latarjet Surgery Leads to Decreased Rates of Subjective Instability Compared to Bankart Repair with Concomitant Remplissage

Background: Predictive factors for performing remplissage concomitantly with arthroscopic Bankart repair include the presence of humeral or glenoid defects \u3e11% and/or revision surgery. International and societal consensus statements support these findings, as surgeons recommend the Latarjet procedure for patients with significant glenoid bone loss (\u3e15-20%) while remplissage is recommended for patients with off-track or engaging Hill-Sachs lesions without significant glenoid bone loss. While several studies have compared outcomes between Latarjet surgery and remplissage, these studies have only evaluated patients with engaging Hill-Sachs lesions, not consecutive patient cohorts indicated for each surgery. Purpose: To compare rates of recurrent instability, re-operation, revision, and return to play (RTP), as well as patient-reported outcomes including the American Shoulder and Elbow Surgeon Score (ASES), Single Assessment Numeric Evaluation (SANE), and Oxford Shoulder Instability Score (OSI) between Latarjet surgery and arthroscopic labral repair plus remplissage surgery (Remplissage) patients

Autophagy gene haploinsufficiency drives chromosome instability, increases migration, and promotes early ovarian tumors.

Autophagy, particularly with BECN1, has paradoxically been highlighted as tumor promoting in Ras-driven cancers, but potentially tumor suppressing in breast and ovarian cancers. However, studying the specific role of BECN1 at the genetic level is complicated due to its genomic proximity to BRCA1 on both human (chromosome 17) and murine (chromosome 11) genomes. In human breast and ovarian cancers, the monoallelic deletion of these genes is often co-occurring. To investigate the potential tumor suppressor roles of two of the most commonly deleted autophagy genes in ovarian cancer, BECN1 and MAP1LC3B were knocked-down in atypical (BECN1+/+ and MAP1LC3B+/+) ovarian cancer cells. Ultra-performance liquid chromatography mass-spectrometry metabolomics revealed reduced levels of acetyl-CoA which corresponded with elevated levels of glycerophospholipids and sphingolipids. Migration rates of ovarian cancer cells were increased upon autophagy gene knockdown. Genomic instability was increased, resulting in copy-number alteration patterns which mimicked high grade serous ovarian cancer. We further investigated the causal role of Becn1 haploinsufficiency for oncogenesis in a MISIIR SV40 large T antigen driven spontaneous ovarian cancer mouse model. Tumors were evident earlier among the Becn1+/- mice, and this correlated with an increase in copy-number alterations per chromosome in the Becn1+/- tumors. The results support monoallelic loss of BECN1 as permissive for tumor initiation and potentiating for genomic instability in ovarian cancer

Does Prehabilitation Before Surgery Affect Return to Sport in Baseball Pitchers With Partial Ulnar Collateral Ligament Tears?

BACKGROUND: Purposeful rehabilitation before surgery (prehabilitation) has been researched and implemented in the treatment of anterior cruciate ligament tears. However, it is unclear whether prehabilitation would affect outcomes for baseball pitchers with partial ulnar collateral ligament (UCL) tears. PURPOSE/HYPOTHESIS: The purpose of this study was to determine whether baseball pitchers with partial UCL tears who completed ≥4 weeks of prehabilitation (prehab group) have different return to play (RTP) outcomes than pitchers with 0 to 3 weeks of preoperative physical therapy (no prehab group). We hypothesized that pitchers in the prehab group would have similar RTP rates compared with pitchers in the no prehab group. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Baseball pitchers of all competitive levels who underwent primary UCL reconstruction (UCLR) or UCL repair between 2010 and 2019 were included. Physician chart notes, magnetic resonance images, and operative notes were screened to confirm primary UCLR or UCL repair of a partial UCL tear and to identify whether the nonoperative treatment had been attempted. Patients were contacted via RedCap for postoperative complications, reoperations, RTP, and patient-reported outcomes (Kerlan-Jobe Orthopaedic Clinic score, Andrews-Timmerman score, Conway-Jobe score, and satisfaction). RESULTS: Overall, 105 baseball pitchers (n = 55 prehab group; n = 50 no prehab group) were included and evaluated at 3.4 ± 2.5 years postoperatively. Six pitchers underwent UCL repair, and 99 pitchers underwent UCLR. All demographic characteristics were similar between groups except the prehab group received a gracilis graft more frequently (76.5% vs 51.2%; CONCLUSION: Postoperative and patient-reported outcomes did not differ significantly between pitchers with partial UCL tears who performed rehabilitation before UCL surgery and pitchers who did not attempt a significant period of rehabilitation before UCL surgery. Clinicians should feel comfortable recommending rehabilitation for patients with partial UCL tears who wish to attempt a period of nonoperative treatment, as postoperative outcomes are not affected if UCL surgery is later needed

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Vehicles for Drug Delivery and Cosmetic Moisturizers: Review and Comparison

Many dermatological conditions, such as eczema and psoriasis, are treated with topical therapeutic products. Instead of applying the active drug directly onto the skin, it is combined with a vehicle to aid in its delivery across the stratum corneum (SC) and into deeper regions of the skin, namely the epidermis and dermis. Absorption into the systemic circulation is minimized. Topical vehicles are also used as cosmetic moisturizers (often termed emollient therapy) to ameliorate dry skin, which is a cornerstone of the management of various dermatological conditions, including xerosis, eczema, psoriasis, and aging. The most common topical vehicles include ointments, creams, gels, and lotions, among others. It is crucial that topical vehicles are chosen based upon the size and properties (wet/dry, mucous/non-mucous, healthy/diseased) of the skin to be treated in order to optimize application and contact of the product with the skin, as this can have profound impacts on potency, efficacy, and patient compliance. This review examines common topical vehicles used for drug delivery and cosmetic moisturizers, including their formulation, advantages and disadvantages, and effects on the skin. The unique rules imposed by governing regulatory bodies in Australia and around the world, in terms of topical product claims, are also briefly examined

Autophagy gene haploinsufficiency drives chromosome instability, increases migration, and promotes early ovarian tumors.

Autophagy, particularly with BECN1, has paradoxically been highlighted as tumor promoting in Ras-driven cancers, but potentially tumor suppressing in breast and ovarian cancers. However, studying the specific role of BECN1 at the genetic level is complicated due to its genomic proximity to BRCA1 on both human (chromosome 17) and murine (chromosome 11) genomes. In human breast and ovarian cancers, the monoallelic deletion of these genes is often co-occurring. To investigate the potential tumor suppressor roles of two of the most commonly deleted autophagy genes in ovarian cancer, BECN1 and MAP1LC3B were knocked-down in atypical (BECN1+/+ and MAP1LC3B+/+) ovarian cancer cells. Ultra-performance liquid chromatography mass-spectrometry metabolomics revealed reduced levels of acetyl-CoA which corresponded with elevated levels of glycerophospholipids and sphingolipids. Migration rates of ovarian cancer cells were increased upon autophagy gene knockdown. Genomic instability was increased, resulting in copy-number alteration patterns which mimicked high grade serous ovarian cancer. We further investigated the causal role of Becn1 haploinsufficiency for oncogenesis in a MISIIR SV40 large T antigen driven spontaneous ovarian cancer mouse model. Tumors were evident earlier among the Becn1+/- mice, and this correlated with an increase in copy-number alterations per chromosome in the Becn1+/- tumors. The results support monoallelic loss of BECN1 as permissive for tumor initiation and potentiating for genomic instability in ovarian cancer

Search for gamma-ray emission from DES dwarf spheroidal galaxy candidates with Fermi-LAT data

Due to their proximity, high dark-matter (DM) content, and apparent absence of non-thermal processes, Milky Way dwarf spheroidal satellite galaxies (dSphs) are excellent targets for the indirect detection of DM. Recently, eight new dSph candidates were discovered using the first year of data from the Dark Energy Survey (DES). We searched for gamma-ray emission coincident with the positions of these new objects in six years of Fermi Large Area Telescope data. We found no significant excesses of gamma-ray emission. Under the assumption that the DES candidates are dSphs with DM halo properties similar to the known dSphs, we computed individual and combined limits on the velocity-averaged DM annihilation cross section for these new targets. If the estimated DM content of these dSph candidates is confirmed, they will constrain the annihilation cross section to lie below the thermal relic cross section for DM particles with masses 20 GeV annihilating via the bb¯ or τ+τ− channels

Factors associated with early outcomes following standardised therapy in children with ulcerative colitis (PROTECT): a multicentre inception cohort study

BackgroundPrevious retrospective studies of paediatric ulcerative colitis have had limited ability to describe disease progression and identify predictors of treatment response. In this study, we aimed to identify characteristics associated with outcomes following standardised therapy after initial diagnosis.MethodsThe PROTECT multicentre inception cohort study was based at 29 centres in the USA and Canada and included paediatric patients aged 4-17 years who were newly diagnosed with ulcerative colitis. Guided by the Pediatric Ulcerative Colitis Activity Index (PUCAI), patients received initial standardised treatment with mesalazine (PUCAI 10-30) oral corticosteroids (PUCAI 35-60), or intravenous corticosteroids (PUCAI ≥65). The key outcomes for this analysis were week 12 corticosteroid-free remission, defined as PUCAI less than 10 and taking only mesalazine, and treatment escalation during the 12 study weeks to anti-tumour necrosis factor α (TNFα) agents, immunomodulators, or colectomy among those initially treated with intravenous corticosteroids. We identified independent predictors of outcome through multivariable logistic regression using a per-protocol approach. This study is registered with ClinicalTrials.gov, number NCT01536535.FindingsPatients were recruited between July 10, 2012, and April 21, 2015. 428 children initiated mesalazine (n=136), oral corticosteroids (n=144), or intravenous corticosteroids (n=148). Initial mean PUCAI was 31·1 (SD 13·3) in children initiating with mesalazine, 50·4 (13·8) in those initiating oral corticosteroids, and 66·9 (13·7) in those initiating intravenous corticosteroids (p&lt;0·0001 for between-group comparison). Week 12 outcome data were available for 132 patients who initiated with mesalazine, 141 with oral corticosteroids, and 143 with intravenous corticosteroids. Corticosteroid-free remission with the patient receiving mesalazine treatment only at 12 weeks was achieved by 64 (48%) patients in the mesalazine group, 47 (33%) in the oral corticosteroid group, and 30 (21%) in the intravenous corticosteroid group (p&lt;0·0001). Treatment escalation was required by nine (7%) patients in the mesalazine group, 21 (15%) in the oral corticosteroid group, and 52 (36%) in the intravenous corticosteroid group (p&lt;0·0001). Eight patients, all of whom were initially treated with intravenous corticosteroids, underwent colectomy. Predictors of week 12 corticosteroid-free remission were baseline PUCAI less than 35 (odds ratio 2·44, 95% CI 1·41-4·22; p=0·0015), higher baseline albumin by 1 g/dL increments among children younger than 12 years (4·05, 1·90-8·64; p=0·00030), and week 4 remission (6·26, 3·79-10·35; p&lt;0·0001). Predictors of treatment escalation by week 12 in patients initially treated with intravenous corticosteroids included baseline total Mayo score of 11 or higher (2·59, 0·93-7·21; p=0·068 [retained in model due to clinical relevance]), rectal biopsy eosinophil count less than or equal to 32 cells per high power field (4·55, 1·62-12·78; p=0·0040), rectal biopsy surface villiform changes (3·05, 1·09-8·56; p=0·034), and not achieving week 4 remission (30·28, 6·36-144·20; p&lt;0·0001).InterpretationOur findings provide guidelines to assess the response of children newly diagnosed with ulcerative colitis to standardised initial therapy and identify predictors of treatment response and failure. These data suggest that additional therapeutic interventions might be warranted to improve early outcomes, especially in patients presenting with severe disease and requiring intravenous corticosteroids.FundingNational Institutes of Health