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Shoulder pain is a common musculoskeletal condition in the general population. Passive physical modalities are commonly used to treat shoulder pain. However, previous systematic reviews reported conflicting results. The aim of this study was to evaluate the effectiveness of passive physical modalities for the management of soft tissue injuries of the shoulder. MEDLINE, EMBASE, CINAHL, PsycINFO, and the Cochrane Central Register of Controlled Trials were searched from January 1, 1990, to April 18, 2013. Randomized controlled trials (RCTs) and cohort and case-control studies were eligible. Random pairs of independent reviewers screened 1,470 of 1,760 retrieved articles after removing 290 duplicates. Twenty-two articles were eligible for critical appraisal. Eligible studies were critically appraised using the Scottish Intercollegiate Guidelines Network criteria. Of those, 11 studies had a low risk of bias. The lead author extracted data from low risk of bias studies and built evidence tables. A second reviewer independently checked the extracted data. The findings of studies with a low risk of bias were synthesized according to principles of best evidence synthesis. Pretensioned tape, ultrasound, and interferential current were found to be noneffective for managing shoulder pain. However, diathermy and corticosteroid injections led to similar outcomes. Low-level laser therapy provided short-term pain reduction for subacromial impingement syndrome. Extracorporeal shock-wave therapy was not effective for subacromial impingement syndrome but provided benefits for persistent shoulder calcific tendinitis. Non-English studies were excluded. Most passive physical modalities do not benefit patients with subacromial impingement syndrome. However, low-level laser therapy is more effective than placebo or ultrasound for subacromial impingement syndrome. Similarly, shock-wave therapy is more effective than sham therapy for persistent shoulder calcific tendinitis.

Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein–kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly subcutaneous administrations of garadacimab as prophylaxis for hereditary angioedema. VANGUARD was a pivotal, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial that recruited patients (aged ≥12 years) with type I or type II hereditary angioedema across seven countries (Canada, Germany, Hungary, Israel, Japan, the Netherlands, and the USA). Eligible patients were randomly assigned (3:2) to receive garadacimab or placebo for 6 months (182 days) by an interactive response technology (IRT) system. Randomisation was stratified by age (≤17 years vs >17 years) and baseline attack rate (1 to <3 attacks per month vs ≥3 attacks per month) for the adult group. The randomisation list and code were kept by the IRT provider during the study, with no access by site staff and funding representatives. All patients and investigational site staff, and representatives from the funder (or their delegates) with direct interaction with the study sites or patients, were masked to treatment assignment in a double-blind fashion. Randomly assigned patients received a 400-mg loading dose of subcutaneous garadacimab as two 200-mg injections or volume-matched placebo on day 1 of the treatment period, followed by five additional self-administered (or caregiver-administered) monthly doses of 200-mg subcutaneous garadacimab or volume-matched placebo. The primary endpoint was the investigator-assessed time-normalised number of hereditary angioedema attacks (number of hereditary angioedema attacks per month) during the 6-month treatment period (day 1 to day 182). Safety was evaluated in patients who received at least one dose of garadacimab or placebo. The study is registered with the EU Clinical Trials Register, 2020-000570-25 and ClinicalTrials.gov, NCT04656418. Between Jan 27, 2021, and June 7, 2022, we screened 80 patients, 76 of whom were eligible to enter the run-in period of the study. Of 65 eligible patients with type I or type II hereditary angioedema, 39 were randomly assigned to garadacimab and 26 to placebo. One patient was randomly assigned in error and did not enter the treatment period (no dose of study drug received), resulting in 39 patients assigned to garadacimab and 25 patients assigned to placebo being included. 38 (59%) of 64 participants were female and 26 (41%) were male. 55 (86%) of 64 participants were White, six (9%) were Asian (Japanese), one (2%) was Black or African American, one (2%) was Native Hawaiian or Other Pacific Islander, and one (2%) was listed as other. During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group (0·27, 95% CI 0·05 to 0·49) than in the placebo group (2·01, 1·44 to 2·57; p<0·0001), corresponding to a percentage difference in means of –87% (95% CI –96 to –58; p<0·0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0·00–0·31) for garadacimab and 1·35 (1·00–3·20) for placebo. The most common treatment-emergent adverse events were upper-respiratory tract infections, nasopharyngitis, and headaches. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events. Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favourable safety profile. Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults. CSL Behring.

Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression. In this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25. A total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P = 0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity. Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.).

Infections caused by drug-resistant bacteria are a major problem worldwide. Carbapenem-resistant Klebsiella pneumoniae , most notably isolates classified as multilocus sequence type (ST) 258, have emerged as an important cause of hospital deaths. ST258 isolates are predominantly multidrug resistant, and therefore infections caused by them are difficult to treat. It is not known why the ST258 lineage is the most prevalent cause of multidrug-resistant K. pneumoniae infections in the United States and other countries. Here we tested the hypothesis that carbapenem-resistant ST258 K. pneumoniae is a single genetic clone that has disseminated worldwide. We sequenced to closure the genomes of two ST258 clinical isolates and used these genomes as references for comparative genome sequencing of 83 additional clinical isolates recovered from patients at diverse geographic locations worldwide. Phylogenetic analysis of the SNPs in the core genome of these isolates revealed that ST258 K. pneumoniae organisms are two distinct genetic clades. This unexpected finding disproves the single-clone hypothesis. Notably, genetic differentiation between the two clades results from an ∼215-kb region of divergence that includes genes involved in capsule polysaccharide biosynthesis. The region of divergence appears to be a hotspot for DNA recombination events, and we suggest that this region has contributed to the success of ST258 K. pneumoniae . Our findings will accelerate research on novel diagnostic, therapeutic, and vaccine strategies designed to prevent and/or treat infections caused by multidrug resistant K. pneumoniae .

Bacteriophages are the most abundant forms of life in the biosphere and carry genomes characterized by high genetic diversity and mosaic architectures. The complete sequences of 30 mycobacteriophage genomes show them collectively to encode 101 tRNAs, three tmRNAs, and 3,357 proteins belonging to 1,536 \"phamilies\" of related sequences, and a statistical analysis predicts that these represent approximately 50% of the total number of phamilies in the mycobacteriophage population. These phamilies contain 2.19 proteins on average; more than half (774) of them contain just a single protein sequence. Only six phamilies have representatives in more than half of the 30 genomes, and only three-encoding tape-measure proteins, lysins, and minor tail proteins-are present in all 30 phages, although these phamilies are themselves highly modular, such that no single amino acid sequence element is present in all 30 mycobacteriophage genomes. Of the 1,536 phamilies, only 230 (15%) have amino acid sequence similarity to previously reported proteins, reflecting the enormous genetic diversity of the entire phage population. The abundance and diversity of phages, the simplicity of phage isolation, and the relatively small size of phage genomes support bacteriophage isolation and comparative genomic analysis as a highly suitable platform for discovery-based education.

Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin's lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin's lymphoma, including in preliminary studies involving previously untreated patients. We conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin's lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause. Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P = 0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation. N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin's lymphoma and had a better side-effect profile. (Funded by the National Cancer Institute of the National Institutes of Health and others; S1826 ClinicalTrials.gov number, NCT03907488.).

This study examined fiber type-dependent differences in the regulation of protein synthesis in individual muscle fibers found within the same whole muscle. Specifically, the in vivo SUrface SEnsing of Translation (SUnSET) methodology was used to measure protein synthesis in type 1, 2A, 2X and 2B fibers of the mouse plantaris muscle, in response to food deprivation (FD), and mechanical overload induced by synergist ablation (SA). The results show that 48 h of FD induced a greater decrease in protein synthesis in type 2X and 2B fibers compared to type 1 and 2A fibers. Type 2X and 2B fibers also had the largest FD-induced decrease in total S6 protein and Ser(240/244) S6 phosphorylation, respectively. Moreover, only type 2X and 2B fibers displayed a FD-induced decrease in cross-sectional area (CSA). Ten days of SA also induced fiber type-dependent responses, with type 2B fibers having the smallest SA-induced increases in protein synthesis, CSA and Ser(240/244) S6 phosphorylation, but the largest increase in total S6 protein. Embryonic myosin heavy chain (MHC(Emb)) positive fibers were also found in SA muscles and the protein synthesis rates, levels of S6 Ser(240/244) phosphorylation, and total S6 protein content, were 3.6-, 6.1- and 2.9-fold greater than that found in fibers from control muscles, respectively. Overall, these results reveal differential responses in the regulation of protein synthesis and fiber size between fiber types found within the same whole muscle. Moreover, these findings demonstrate that changes found at the whole muscle level do not necessarily reflect changes in individual fiber types.

A risk haplotype for type 2 diabetes is identified with four amino acid substitutions in SLC16A11, which is present at ∼50% frequency in Native American samples and ∼10% in east Asian samples, but is rare in European and African samples; SLC16A11 may alter hepatic lipid metabolism, causing an increase in triacylglycerol levels. Diabetes risk factors in Central America Genome-wide association studies (GWASs) have discovered thousands of genetic variants associated with common disease. This study demonstrates the potential of a comparative approach, whereby analysis of genetic variation in diverse populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. The SIGMA Type 2 Diabetes Genetics Consortium undertook a GWAS for propensity to type 2 diabetes in more than 8,000 samples in a Latin American population. They identified a risk haplotype, SLC16A11 , with four amino acid substitutions in the solute carrier SLC16A11, which is present at about 50% frequency in Native American samples and 10% in East Asian, but rare in European and African samples. SLC16A11 appears to alter lipid metabolism, causing an increase in intracellular triacylglycerol levels. Intriguingly, the haplotype was introduced into the modern human population via admixture with Neanderthals. Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others 1 , with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings 2 , 3 , 4 , we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 ( P = 3.9 × 10 −13 ; odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples ( P = 1.1 × 10 −4 ; OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ∼50% frequency in Native American samples and ∼10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.

In this placebo-controlled trial, CSL830, a subcutaneous C1 inhibitor, significantly reduced the rate of hereditary angioedema attacks; local site reactions were the dominant side effect. Of the patients who received 60 IU per kilogram twice weekly, 40% had no attacks for 16 weeks. Hereditary angioedema is a disabling and potentially fatal condition characterized by recurrent episodes of swelling without urticaria or pruritus. The condition is caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. 1 Patients have insufficient C1 inhibitor function to prevent bradykinin production by the contact system, leading to episodes of increased capillary hyperpermeability and swelling. These episodes manifest clinically as angioedema attacks. 2 , 3 Low levels of C1 inhibitor protein antigen or low functional levels of C1 inhibitor activity, as well as low levels of complement C4, are diagnostic for hereditary angioedema, and baseline C1 inhibitor function . . .

A recently developed preparation of C1 inhibitor concentrate was evaluated in patients with hereditary angioedema in two trials. In the acute-attack treatment trial, the time to relief of an acute attack of angioedema was significantly shorter with the C1 inhibitor than with placebo. In the prophylaxis trial, the attack rate over a 12-week period was significantly lower with the C1 inhibitor than with placebo. Hereditary angioedema due to C1 inhibitor deficiency is an autosomal dominant disorder characterized by recurrent episodes of angioedema that typically involve the extremities, abdomen, external genitalia, face, or oropharynx. 1 Abdominal attacks of angioedema, which are caused by local mucosal swelling, are often associated with severe abdominal pain, nausea, and vomiting. Such attacks frequently lead to hospitalization and occasionally to unnecessary exploratory surgery. 2 Laryngeal attacks are associated with a substantial risk of death. 2 Two forms of hereditary angioedema have been defined: type I (accounting for 85% of cases) is characterized by low antigenic and functional levels of C1 inhibitor, whereas type . . .