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To determine if surgical or nonsurgical treatment of anterior cruciate ligament rupture affects the prevalence of posttraumatic tibiofemoral osteoarthritis (OA).   Studies published between 1983 and April 2012 were identified via EBSCOhost and OVID. Reference lists were then screened in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.   Studies were included if (a) treatment outcomes focused on a direct comparison of surgical versus nonsurgical treatment of anterior cruciate ligament rupture, (b) the prevalence of tibiofemoral OA was reported, and (c) they were written in English. Studies were excluded if (a) the included patients were treated with cast immobilization after surgery, (b) the mean follow-up was less than 10 years, or (c) the patients underwent anterior cruciate ligament revision surgery.   Two independent investigators reviewed the included articles using the Newcastle-Ottawa Scale. Frequency of OA, surgical procedure, nonsurgical treatments, and participant characteristics were extracted and summarized. We calculated prevalence (%) and 95% confidence intervals for treatment groups for each individual study and overall. We developed 2 × 2 contingency tables to assess the association between treatment groups (exposed had surgery, referent was nonsurgical treatment) and the prevalence of OA.   Four retrospective studies were identified (140 surgical patients, 240 nonsurgical patients). The mean Newcastle-Ottawa Scale score was 5 (range = 4-6 [of 10] points). Average length of follow-up was 11.8 years (range = 10-14 years). The prevalence of OA for surgically treated patients ranged from 32.6% to 51.2% (overall = 41.4%, 95% confidence interval = 35.0%, 48.1%) and for nonsurgical patients ranged from 24.5% to 42.3% (overall = 30.9%, 95% confidence interval = 24.4%, 38.3%).   Although OA prevalence was higher in the surgical treatment group at a mean follow-up of 11.8 years, no definitive evidence supports surgical or nonsurgical treatment after anterior cruciate ligament injury to prevent posttraumatic OA. Current studies have been limited by small sample sizes, low methodologic quality, and a lack of data regarding confounding factors.

Information regarding the relative risks of developing knee osteoarthritis (OA) as a result of sport participation is critical for shaping public health messages and for informing knee-OA prevention strategies. The purpose of this systematic review was to investigate the association between participation in specific sports and knee OA.   We completed a systematic literature search in September 2012 using 6 bibliographic databases (PubMed; Ovid MEDLINE; Journals@Ovid; American College of Physicians Journal Club; Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Review, Database of Abstracts of Reviews of Effects; and Ovid HealthStar), manual searches (4 journals), and reference lists (56 articles).   Studies were included if they met the following 4 criteria: (1) an aim was to investigate an association between sport participation and knee OA; (2) the outcome measure was radiographic knee OA, clinical knee OA, total knee replacement, self-reported diagnosis of knee OA, or placement on a waiting list for a total knee replacement; (3) the study design was case control or cohort; and (4) the study was written in English. Articles were excluded if the study population had an underlying condition other than knee OA.   One investigator extracted data (eg, group descriptions, knee OA prevalence, source of nonexposed controls).   The overall knee-OA prevalence in sport participants (n = 3759) was 7.7%, compared with 7.3% among nonexposed controls (referent group n = 4730, odds ratio [OR] = 1.1). Specific sports with a significantly higher prevalence of knee OA were soccer (OR = 3.5), elite-level long-distance running (OR = 3.3), competitive weight lifting (OR = 6.9), and wrestling (OR = 3.8). Elite-sport (soccer or orienteering) and nonelite-sport (soccer or American football) participants without a history of knee injury had a greater prevalence of knee OA than nonexposed participants.   Participants in soccer (elite and nonelite), elite-level long-distance running, competitive weight lifting, and wrestling had an increased prevalence of knee OA and should be targeted for risk-reduction strategies.

Understanding undergraduate student success is central to addressing issues in the current education climate. Many barriers exist for students; however, even more barriers exist for first-generation college students. Especially difficult for first-generation college students is access to social capital with regards to higher education. The current study focused on addressing the following overall research question: does having a sibling who attended college make a difference in the academic outcomes of a student? The sample for the study included all undergraduate students who enrolled as first-semester freshman in a large, Research 1 university in the Northeastern United States from fall 2016 through fall 2021. Transfer students were excluded. The data were provided by the selected institution’s Office of Institutional Research and Assessment (IRA). These data included the primary variables that were used to define academic success-- the student’s first semester GPA, first to second semester retention, first to second year retention, and four-year graduation rate. Additional variables were collected which included student’s SAT scores, high school GPA, gender, and data from a survey that is administered to all incoming freshmen- the New Student Questionnaire (NSQ), which included information about the level of education of each student’s mother, father, and siblings. The analysis of the data revealed that as the number of family members who attended college increased, so did high school GPA, 1st semester GPA, 1st to 2nd semester retention, and 4-year graduation rate. Ultimately, this indicates that as the number of family members who attended higher education increases so does student success. Siblings play a critical role in that they add an additional access point to social capital for the student in question. While siblings are important though, the results suggest that the number of family members who have attended college and not the relationship to the student may be a more important consideration.

Previously published guidelines have provided comprehensive recommendations for detecting and preventing healthcare-associated infections (HAIs). The intent of this document is to highlight practical recommendations in a concise format designed to assist acute-care hospitals in implementing and prioritizing efforts to prevent methicillin-resistant Staphylococcus aureus (MRSA) transmission and infection. This document updates the “Strategies to Prevent Methicillin-Resistant Staphylococcus aureus Transmission and Infection in Acute Care Hospitals” published in 2014.1 This expert guidance document is sponsored by the Society for Healthcare Epidemiology of America (SHEA). It is the product of a collaborative effort led by SHEA, the Infectious Diseases Society of America (IDSA), the Association for Professionals in Infection Control and Epidemiology (APIC), the American Hospital Association (AHA), and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise.

Insomnia is prevalent and distressing but access to the first-line treatment, cognitive behavioural therapy (CBT), is extremely limited. We aimed to assess the clinical and cost-effectiveness of sleep restriction therapy, a key component of CBT, which has the potential to be widely implemented. We did a pragmatic, superiority, open-label, randomised controlled trial of sleep restriction therapy versus sleep hygiene. Adults with insomnia disorder were recruited from 35 general practices across England and randomly assigned (1:1) using a web-based randomisation programme to either four sessions of nurse-delivered sleep restriction therapy plus a sleep hygiene booklet or a sleep hygiene booklet only. There was no restriction on usual care for either group. Outcomes were assessed at 3 months, 6 months, and 12 months. The primary endpoint was self-reported insomnia severity at 6 months measured with the insomnia severity index (ISI). The primary analysis included participants according to their allocated group and who contributed at least one outcome measurement. Cost-effectiveness was evaluated from the UK National Health Service and personal social services perspective and expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. The trial was prospectively registered (ISRCTN42499563). Between Aug 29, 2018, and March 23, 2020 we randomly assigned 642 participants to sleep restriction therapy (n=321) or sleep hygiene (n=321). Mean age was 55·4 years (range 19–88), with 489 (76·2%) participants being female and 153 (23·8%) being male. 580 (90·3%) participants provided data for at least one outcome measurement. At 6 months, mean ISI score was 10·9 (SD 5·5) for sleep restriction therapy and 13·9 (5·2) for sleep hygiene (adjusted mean difference –3·05, 95% CI –3·83 to –2·28; p<0·0001; Cohen's d –0·74), indicating that participants in the sleep restriction therapy group reported lower insomnia severity than the sleep hygiene group. The incremental cost per QALY gained was £2076, giving a 95·3% probability that treatment was cost-effective at a cost-effectiveness threshold of £20 000. Eight participants in each group had serious adverse events, none of which were judged to be related to intervention. Brief nurse-delivered sleep restriction therapy in primary care reduces insomnia symptoms, is likely to be cost-effective, and has the potential to be widely implemented as a first-line treatment for insomnia disorder. The National Institute for Health and Care Research Health Technology Assessment Programme.

Immunity to one of the four dengue virus (DV) serotypes can increase disease severity in humans upon subsequent infection with another DV serotype. Serotype cross-reactive antibodies facilitate DV infection of myeloid cells in vitro by promoting virus entry via Fcgamma receptors (FcgammaR), a process known as antibody-dependent enhancement (ADE). However, despite decades of investigation, no in vivo model for antibody enhancement of dengue disease severity has been described. Analogous to human infants who receive anti-DV antibodies by transplacental transfer and develop severe dengue disease during primary infection, we show here that passive administration of anti-DV antibodies is sufficient to enhance DV infection and disease in mice using both mouse-adapted and clinical DV isolates. Antibody-enhanced lethal disease featured many of the hallmarks of severe dengue disease in humans, including thrombocytopenia, vascular leakage, elevated serum cytokine levels, and increased systemic viral burden in serum and tissue phagocytes. Passive transfer of a high dose of serotype-specific antibodies eliminated viremia, but lower doses of these antibodies or cross-reactive polyclonal or monoclonal antibodies all enhanced disease in vivo even when antibody levels were neutralizing in vitro. In contrast, a genetically engineered antibody variant (E60-N297Q) that cannot bind FcgammaR exhibited prophylactic and therapeutic efficacy against ADE-induced lethal challenge. These observations provide insight into the pathogenesis of antibody-enhanced dengue disease and identify a novel strategy for the design of therapeutic antibodies against dengue.

The potent and partial agonist sunobinop activates the nociceptin/orphanin-FQ peptide receptor and promotes non-REM sleep in rodents and patients with insomnia.The potent and partial agonist sunobinop activates the nociceptin/orphanin-FQ peptide receptor and promotes non-REM sleep in rodents and patients with insomnia.

A small-molecule activator specific for PKM2 binds to a site distinct from the endogenous activator fructose-1,6-bisphosphate, promoting tetramerization and constitutive activation of PKM2, to inhibit xenograft tumor growth in mice. Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.

PrPC, the cellular isoform of the prion protein, serves to transduce the neurotoxic effects of PrPSc, the infectious isoform, but how this occurs is mysterious. Here, using a combination of electrophysiological, cellular, and biophysical techniques, we show that the flexible, N-terminal domain of PrPC functions as a powerful toxicity-transducing effector whose activity is tightly regulated in cis by the globular C-terminal domain. Ligands binding to the N-terminal domain abolish the spontaneous ionic currents associated with neurotoxic mutants of PrP, and the isolated N-terminal domain induces currents when expressed in the absence of the C-terminal domain. Anti-PrP antibodies targeting epitopes in the C-terminal domain induce currents, and cause degeneration of dendrites on murine hippocampal neurons, effects that entirely dependent on the effector function of the N-terminus. NMR experiments demonstrate intramolecular docking between N- and C-terminal domains of PrPC, revealing a novel auto-inhibitory mechanism that regulates the functional activity of PrPC. Prion diseases are a group of degenerative illnesses of the brain caused when a molecule called the prion protein (PrP for short) adopts the wrong shape. These diseases include the human form of mad cow disease, and are often fatal with no effective treatments or cures. Though the normal activity of PrP is not certain, abnormal PrP can affect the healthy PrP on the surface of brain cells and lead to disease. Similar mechanisms may also contribute to other life-threatening brain disorders, including Alzheimer’s disease and Parkinson’s disease. It had been shown that certain altered PrP proteins caused the death of brain cells by allowing excessive electrical charges to cross the membranes of the cell. These changes led to symptoms in animal models of the diseases. Experiments showed that adding a large amount of normal PrP to the cells could prevent these effects. These studies, however, had not yet resolved how PrP behaves inside cells and how this contributes to disease. Using genetically modified mice and cells grown in the laboratory, Wu et al. investigated the role of different parts of PrP in causing brain cells to degenerate. The experiments showed that one end of the protein, called the N-terminus, is involved in the movement of electrical charges across the cell membrane and is able to cause cell degeneration. By contrast, the other end of the protein, the C-terminus, acts as a regulator for the N-terminus and can prevent cell degeneration. Further investigation revealed that the C-terminus regulates the N-terminus through direct contact. A better understanding of the role of PrP in prion diseases may help to reveal new treatments for these and other degenerative brain disorders. In particular, the new findings highlight that treatments should target the toxic N-terminus of altered PrP and not the regulatory C-terminus. Further study will examine how different molecules in the brain control the interaction between the two ends of PrP in healthy brain cells and how this is altered in diseased cells.

Background Neovascular age-related macular degeneration causes vision loss from destructive angiogenesis, termed choroidal neovascularization (CNV). Cx3cr1 −/− mice display alterations in non-classical monocytes and microglia with increased CNV size, suggesting that non-classical monocytes may inhibit CNV formation. NR4A1 is a transcription factor that is necessary for maturation of non-classical monocytes from classical monocytes. While Nr4a1 −/− mice are deficient in non-classical monocytes, results are confounded by macrophage hyper-activation. Nr4a1 se2/se2 mice lack a transcriptional activator, resulting in non-classical monocyte loss without macrophage hyper-activation. Main body We subjected Nr4a1 −/− and Nr4a1 se2/se2 mice to the laser-induced CNV model and performed multi-parameter flow cytometry. We found that both models lack non-classical monocytes, but only Nr4a1 −/− mice displayed increased CNV area. Additionally, CD11c + macrophages were increased in Nr4a1 −/− mice. Single-cell transcriptomic analysis uncovered that CD11c + macrophages were enriched from Nr4a1 −/− mice and expressed a pro-angiogenic transcriptomic profile that was disparate from prior reports of macrophage hyper-activation. Conclusions These results suggest that non-classical monocytes are dispensable during CNV, and NR4A1 deficiency results in increased recruitment of pro-angiogenic macrophages.