Characterizing the etiology of recurrent tuberculosis using whole genome sequencing-Alaska, USA, 2008-2020.

BACKGROUND: Understanding the etiology of recurrent tuberculosis (rTB) is important for effective TB control. Prior to the advent of whole genome sequencing (WGS), attributing rTB to relapse or reinfection using genetic information was complicated by the limited resolution of conventional genotyping methods. METHODS: We applied a systematic method of evaluating whole genome single nucleotide polymorphism (wgSNP) distances and results of phylogenetic analyses to characterize the etiology of rTB in American Indian and Alaska Native (AIAN) persons in Alaska during 2008-2020. We contextualized our findings through descriptive analyses of surveillance data and results of a literature search for investigations that characterized rTB etiology using WGS. RESULTS: The percentage of TB cases in AIAN persons in Alaska classified as recurrent episodes (11.8%) was three times the national percentage (3.9%). Of 38 recurrent episodes included in genetic analyses, we attributed 25 (65.8%) to reinfection based on wgSNP distances and phylogenetic analyses; this proportion was the highest among 16 published point estimates identified through the literature search. By comparison, we attributed 11 of 38 (28.9%) and 6 of 38 (15.8%) recurrent episodes to reinfection based on wgSNP distances alone and on conventional genotyping methods, respectively. CONCLUSIONS: WGS and attribution criteria involving genetic distances and patterns of relatedness can provide an effective means of elucidating rTB etiology. Our findings indicate that rTB occurs at high proportions among AIAN persons in Alaska and is frequently attributable to reinfection, reinforcing the importance of active surveillance and control measures to limit the spread of TB disease in Alaskan AIAN communities.

Tuberculosis Outbreaks in State Prisons, United States, 2011-2019.

Objectives. To understand the frequency, magnitude, geography, and characteristics of tuberculosis outbreaks in US state prisons. Methods. Using data from the National Tuberculosis Surveillance System, we identified all cases of tuberculosis during 2011 to 2019 that were reported as occurring among individuals incarcerated in a state prison at the time of diagnosis. We used whole-genome sequencing to define 3 or more cases within 2 single nucleotide polymorphisms within 3 years as clustered; we classified clusters with 6 or more cases during a 3-year period as tuberculosis outbreaks. Results. During 2011 to 2019, 566 tuberculosis cases occurred in 41 state prison systems (a median of 3 cases per state). A total of 19 tuberculosis genotype clusters comprising 134 cases were identified in 6 state prison systems; these clusters included a subset of 5 outbreaks in 2 states. Two Alabama outbreaks during 2011 to 2017 totaled 20 cases; 3 Texas outbreaks during 2014 to 2019 totaled 51 cases. Conclusions. Only Alabama and Texas reported outbreaks during the 9-year period; only Texas state prisons had ongoing transmission in 2019. Effective interventions are needed to stop tuberculosis outbreaks in Texas state prisons. (Am J Public Health. 2022;112(8):1170-1179. https://doi.org/10.2105/AJPH.2022.306864).

The Role of Obesity and Diabetes in Dementia.

Chronic conditions such as obesity, diabetes, and dementia are increasing in the United States (US) population. Knowledge of these chronic conditions, preventative measures, and proper management tactics is important and critical to preventing disease. The overlap between obesity, diabetes, and dementia is becoming further elucidated. These conditions share a similar origin through the components of increasing age, gender, genetic and epigenetic predispositions, depression, and a high-fat Western diet (WD) that all contribute to the inflammatory state associated with the development of obesity, diabetes, and dementia. This inflammatory state leads to the dysregulation of food intake and insulin resistance. Obesity is often the cornerstone that leads to the development of diabetes and, subsequently, in the case of type 2 diabetes mellitus (T2DM), progression to "type 3 diabetes mellitus (T3DM)". Obesity and depression are closely associated with diabetes. However, dementia can be avoided with lifestyle modifications, by switching to a plant-based diet (e.g., a Mediterranean diet (MD)), and increasing physical activity. Diet and exercise are not the only treatment options. There are several surgical and pharmacological interventions available for prevention. Current and future research within each of these fields is warranted and offers the chance for new treatment options and a better understanding of the pathogenesis of each condition.

A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic.

BACKGROUND: Atypical Beijing genotype Mycobacterium tuberculosis strains are widespread in South Africa and have acquired resistance to up to 13 drugs on multiple occasions. It is puzzling that these strains have retained fitness and transmissibility despite the potential fitness cost associated with drug resistance mutations. METHODS: We conducted Illumina sequencing of 211 Beijing genotype M. tuberculosis isolates to facilitate the detection of genomic features that may promote acquisition of drug resistance and restore fitness in highly resistant atypical Beijing forms. Phylogenetic and comparative genomic analysis was done to determine changes that are unique to the resistant strains that also transmit well. Minimum inhibitory concentration (MIC) determination for streptomycin and bedaquiline was done for a limited number of isolates to demonstrate a difference in MIC between isolates with and without certain variants. RESULTS: Phylogenetic analysis confirmed that two clades of atypical Beijing strains have independently developed resistance to virtually all the potent drugs included in standard (pre-bedaquiline) drug-resistant TB treatment regimens. We show that undetected drug resistance in a progenitor strain was likely instrumental in this resistance acquisition. In this cohort, ethionamide (ethA A381P) resistance would be missed in first-line drug-susceptible isolates, and streptomycin (gidB L79S) resistance may be missed due to an MIC close to the critical concentration. Subsequent inadequate treatment historically led to amplification of resistance and facilitated spread of the strains. Bedaquiline resistance was found in a small number of isolates, despite lack of exposure to the drug. The highly resistant clades also carry inhA promoter mutations, which arose after ethA and katG mutations. In these isolates, inhA promoter mutations do not alter drug resistance, suggesting a possible alternative role. CONCLUSION: The presence of the ethA mutation in otherwise susceptible isolates from ethionamide-naïve patients demonstrates that known exposure is not an adequate indicator of drug susceptibility. Similarly, it is demonstrated that bedaquiline resistance can occur without exposure to the drug. Inappropriate treatment regimens, due to missed resistance, leads to amplification of resistance, and transmission. We put these results into the context of current WHO treatment regimens, underscoring the risks of treatment without knowledge of the full drug resistance profile.

Injection laser system for Advanced Radiographic Capability using chirped pulse amplification on the National Ignition Facility.

We report on the design, performance, and qualification of the injection laser system designed to deliver joule-level chirped pulse beamlets arranged in dual rectangular beam formats into two main laser amplifier beamlines of the National Ignition Facility. The system is designed to meet the requirements of the Advanced Radiographic Capability upgrade with features that deliver performance, adjustability, and long-term reliability.

Validation of Novel Mycobacterium tuberculosis Isoniazid Resistance Mutations Not Detectable by Common Molecular Tests.

Resistance to the first-line antituberculosis (TB) drug isoniazid (INH) is widespread, and the mechanism of resistance is unknown in approximately 15% of INH-resistant (INH-R) strains. To improve molecular detection of INH-R TB, we used whole-genome sequencing (WGS) to analyze 52 phenotypically INH-R Mycobacterium tuberculosis complex (MTBC) clinical isolates that lacked the common katG S315T or inhA promoter mutations. Approximately 94% (49/52) of strains had mutations at known INH-associated loci that were likely to confer INH resistance. All such mutations would be detectable by sequencing more DNA adjacent to existing target regions. Use of WGS minimized the chances of missing infrequent INH resistance mutations outside commonly targeted hotspots. We used recombineering to generate 12 observed clinical katG mutations in the pansusceptible H37Rv reference strain and determined their impact on INH resistance. Our functional genetic experiments have confirmed the role of seven suspected INH resistance mutations and discovered five novel INH resistance mutations. All recombineered katG mutations conferred resistance to INH at a MIC of ≥0.25 µg/ml and should be added to the list of INH resistance determinants targeted by molecular diagnostic assays. We conclude that WGS is a useful tool for detecting uncommon INH resistance mutations that would otherwise be missed by current targeted molecular testing methods and suggest that its use (or use of expanded conventional or next-generation-based targeted sequencing) may provide earlier diagnosis of INH-R TB.

Variables Describing Individuals With Improved Pain and Function With a Primary Complaint of Low Back Pain: A Secondary Analysis.

OBJECTIVES: The purpose of this study was to identify descriptive factors in individuals with a primary complaint of low back pain (LBP) associated with improved pain and function after receiving physical therapy for LBP with or without manual therapy and exercise directed at the femoroacetabular joints. METHODS: Participants were enrolled in a randomized clinical trial investigating physical therapy interventions for their LBP, with or without interventions directed at the femoroacetabular joints (hips). A participant was deemed recovered if all of the following were met: Numeric Pain Rating Scale (NPRS) score of ≤2 points, ≤10% on the modified Oswestry Disability Index at discharge, and a global rating of change score of +4 at both 2 weeks and discharge. Logistic regression modelling determined descriptor variables that best predicted treatment recovery. RESULTS: Data from 90 participants were included in the analysis, with 44% (n = 40) achieving recovery by discharge from physical therapy (average 7.95 [±4.68]) visits. The variables of concurrent hip problems, lower body mass index ≤25.4, an irritable condition, and a baseline NPRS score of 4 points or less were retained in the final model (R2 = .384). Having a concurrent hip problem had the highest odds of achieving recovery in the model (odds ratio: 5.34, 95 % confidence interval: 1.31-21.8). CONCLUSIONS: The findings for the patients in this study suggest that those with a concurrent hip problem, a lower body mass index, irritable symptoms, and a baseline NPRS score of 4 points or less were associated with greater odds of achieving recovery with multimodal physical therapy interventions. Further research should continue to investigate the interplay between the lumbar spine and hip joints.

Experimental study of the installation acetabular component with uncoverage in arthroplasty patients with severe developmental hip dysplasia.

PURPOSE: The purpose of this study was stimation of optimal percentage of lateral uncoverage of the acetabular component during total hip arthroplasty for patients with severe developmental hip dysplasia. METHODS: Mathematical computer modeling based on the finite element technique and the mechanical experiment were performed. Critical values of uncoverage enabling safe primary fixation of acetabular component were estimated in designed models. RESULTS: Using the finite element technique and the mechanical experiment on pelvis models, a possibility of mounting an acetabular component with moderate uncoverage within 25% without screws and with significant uncoverage to 35% with an additional two-screw fixation was demonstrated. CONCLUSIONS: This study provides additional guidance on optimal acetabular uncoverage assessment and fixation methods of surgeons performing THA on patients with DDH.

Combining forces to manage the continuum of care.

Many healthcare organizations are pursuing affiliation strategies to effectively manage population health. Healthcare organizations should take the following key steps in setting such a strategy: Ensuring the strategy aligns with the organization's mission Identifying potential partners. Outlining expectations for the affiliation. Assessing affiliation structure options.

Athletic Trainers' Beliefs Regarding Professionalism.

CONTEXT: Limited research exists regarding athletic trainers' (ATs') perceptions of professionalism. OBJECTIVE: To explore the lived experiences of ATs and their perceptions of professionalism. DESIGN: Qualitative study. SETTING: Participants were ATs who completed a semistructured interview protocol via audio-only recording conferencing. PATIENTS OR OTHER PARTICIPANTS: Seventeen participants (age = 33 ± 8 years; range = 25-56 years) who were certified ATs with an average of 10 years of experience (SD = ±8; range = 1-33 years) were interviewed. DATA COLLECTION AND ANALYSIS: Individuals self-identified their interest in participating in a follow-up interview recruitment located within a survey. Interviews occurred until saturation was met and included a variety of participants. Demographic information was gathered from the survey for each person. All transcripts were audio recorded, transcribed verbatim, and coded using a 3-person coding team following the consensual qualitative research protocol. Member checking, auditing, and triangulation established trustworthiness and credibility in the data-analysis process. RESULTS: A total of 4 domains with supporting categories were identified. Athletic trainers spoke of the employee environment that affected perceptions of what was determined to be professional, specifically in various settings or situations. They shared their personal determination of outward appearance and expression when differentiating what was deemed professional, including references to cleanliness, judgment of self-expression, and implicit bias. Whether intentional or unintentional, participants made comments that demonstrated a bias toward sex or race and ethnicity when determining outward appearance appropriateness. They noted various cultural awareness situations, including progression of perceptions over time, external pressure, and internal dialog. Respondents shared discourse regarding an internal struggle of what was right and wrong in their responses. They discussed professionalism based on the provider's conduct, mainly in terms of communication and patient care. Participants shared that communication occurring through both verbal and nonverbal means is vital to the perceptions of professionalism for ATs. CONCLUSIONS: Current views of professionalism in athletic training were shaped by various lived experiences. With the movement toward athletic training becoming more diverse, equitable, and inclusive, antiquated professionalism ideals need to shift to provide a better work environment for all.

Rehabilitative Health Care Professionals' Perceptions of Appearance-Based Professionalism.

CONTEXT: Professionalism has been discussed and defined in a variety of ways, including attire and other forms of self-expression. OBJECTIVES: To determine athletic trainer (AT), physical therapist (PT), and athletic training or PT students' perceptions of appearance-based professionalism in the workplace and, secondly, to ascertain how perceptions differed across professions. DESIGN: Cross-sectional study. SETTING: Web-based survey. PATIENTS OR OTHER PARTICIPANTS: Athletic trainers, PTs, and athletic training and PT students who were predominantly White, non-Hispanic, female, aged 30 ± 9 years, and recruited via listservs and social media. DATA COLLECTION AND ANALYSIS: The independent variables were participant demographics. The dependent variables were self-reported perceptions of professionalism for each photo. The survey consisted of 3 sections: demographics, 8 photos of ATs or PTs with depictions of patient-provider interactions, and open-ended responses. For each photo, participants selected yes, no, or unsure regarding the photo. An open-ended response was prompted with a no or unsure selection. The participant further described the reason for that choice. RESULTS: Most participants determined the health care provider depicted in 7 photos appeared professional. Only 1 photo was deemed unprofessional by the professional majority. Significant differences existed between students and professionals for 5 photos. The proportion of participants who reported the photos were unprofessional differed among professions for 2 photos. From our qualitative analysis, we found 6 domains: (1) unprofessional attire and hair, (2) situation-dependent attire, (3) role confusion and health care employer or employee identification, (4) nonappearance related, (5) tattoo-related bias, and (6) rethinking after question is displayed. CONCLUSION: What is considered appropriate and professional is not concrete. Differing concepts of professionalism generated biased judgments and criticisms. CLINICAL RELEVANCE: Our findings should lead providers to reexamine the definition of professionalism. The past should not dictate the future, and today's social mores can help shape the definition as it should be considered in today's settings.

Therapeutics of Alzheimer's Disease: Recent Developments.

With increasing aging, dementia is a growing public health concern globally. Patients with dementia have multiple psychological and behavioral changes, including depression, anxiety, inappropriate behavior, paranoia, agitation, and hallucinations. The major types of dementia are Alzheimer's disease (AD), vascular dementia (VCID), Lewy body dementia (LBD), frontotemporal dementia (FTD), and mixed dementia (MiAD). Among these, AD is the most common form of dementia in the elderly population. In the last three decades, tremendous progress has been made in understanding AD's biology and disease progression, particularly its molecular basis, biomarker development, and drug discovery. Multiple cellular changes have been implicated in the progression of AD, including amyloid beta, phosphorylated tau, synaptic damage, mitochondrial dysfunction, deregulated microRNAs, inflammatory changes, hormonal deregulation, and others; based on these changes, therapeutic strategies have been developed, which are currently being tested in animal models and human clinical trials. The purpose of our article is to highlight recent therapeutic strategies' developments, critically discuss current strategies' failures, and propose new strategies to combat this devasting mental illness.

When Treating Coexisting Low Back Pain and Hip Impairments, Focus on the Back: Adding Specific Hip Treatment Does Not Yield Additional Benefits-A Randomized Controlled Trial.

OBJECTIVE: To determine whether adding hip treatment to usual care for low back pain (LBP) improved disability and pain in individuals with LBP and a concurrent hip impairment. DESIGN: Randomized controlled trial. METHODS: Seventy-six participants (age, 18 years or older; Oswestry Disability Index, 20% or greater; numeric pain-rating scale, 2 or more points) with LBP and a concurrent hip impairment were randomly assigned to a group that received treatment to the lumbar spine only (LBO group) (n = 39) or to one that received both lumbar spine and hip treatments (LBH group) (n = 37). The individual treating clinicians decided which specific low back treatments to administer to the LBO group. Treatments aimed at the hip (LBH group) included manual therapy, exercise, and education, selected by the therapist from a predetermined set of treatments. Primary outcomes were disability and pain, measured by the Oswestry Disability Index and the numeric pain-rating scale, respectively, at baseline, 2 weeks, discharge, 6 months, and 12 months. The secondary outcomes were fear-avoidance beliefs (work and physical activity subscales of the Fear-Avoidance Beliefs Questionnaire), global rating of change, the Patient Acceptable Symptom State, and physical activity level. We used mixed-model 2-by-3 analyses of variance to examine group-by-time interaction effects (intention-to-treat analysis). RESULTS: Data were available for 68 patients at discharge (LBH group, n = 33; LBO group, n = 35) and 48 at 12 months (n = 24 for both groups). There were no between-group differences in disability at discharge (-5.0; 95% confidence interval [CI]: -10.9, 0.89; P = .09), 12 months (-1.0; 95% CI: -4.44, 2.35; P = .54), and all other time points. There were no between-group differences in pain at discharge (-0.2; 95% CI: -1.03, 0.53; P = .53), 12 months (0.1; 95% CI: -0.53, 0.72; P = .76), and all other time points. There were no between-group differences in secondary outcomes, except for higher Fear-Avoidance Beliefs Questionnaire (work subscale) scores in the LBH group at 2 weeks (-3.35; 95% CI: -6.58, -0.11; P = .04) and discharge (-3.45; 95% CI: - 6.30, -0.61; P = .02). CONCLUSION: Adding treatments aimed at the hip to usual low back physical therapy did not provide additional short- or long-term benefits in reducing disability and pain in individuals with LBP and a concurrent hip impairment. Clinicians may not need to include hip treatments to achieve reductions in low back disability and pain in individuals with LBP and a concurrent hip impairment. J Orthop Sports Phys Ther 2021;51(12):581-601. Epub 16 Nov 2021. 2021. doi:10.2519/jospt.2021.10593.

Molecular evolution, functional variation, and proposed nomenclature of the gene family that includes sphingomyelinase D in sicariid spider venoms.

The venom enzyme sphingomyelinase D (SMase D) in the spider family Sicariidae (brown or fiddleback spiders [Loxosceles] and six-eyed sand spiders [Sicarius]) causes dermonecrosis in mammals. SMase D is in a gene family with multiple venom-expressed members that vary in functional specificity. We analyze molecular evolution of this family and variation in SMase D activity among crude venoms using a data set that represents the phylogenetic breadth of Loxosceles and Sicarius. We isolated a total of 190 nonredundant nucleotide sequences encoding 168 nonredundant amino acid sequences of SMase D homologs from 21 species. Bayesian phylogenies support two major clades that we name alpha and beta, within which we define seven and three subclades, respectively. Sequences in the alpha clade are exclusively from New World Loxosceles and Loxosceles rufescens and include published genes for which expression products have SMase D and dermonecrotic activity. The beta clade includes paralogs from New World Loxosceles that have no, or reduced, SMase D and no dermonecrotic activity and also paralogs from Sicarius and African Loxosceles of unknown activity. Gene duplications are frequent, consistent with a birth-and-death model, and there is evidence of purifying selection with episodic positive directional selection. Despite having venom-expressed SMase D homologs, venoms from New World Sicarius have reduced, or no, detectable SMase D activity, and Loxosceles in the Southern African spinulosa group have low SMase D activity. Sequence conservation mapping shows >98% conservation of proposed catalytic residues of the active site and around a plug motif at the opposite end of the TIM barrel, but alpha and beta clades differ in conservation of key residues surrounding the apparent substrate binding pocket. Based on these combined results, we propose an inclusive nomenclature for the gene family, renaming it SicTox, and discuss emerging patterns of functional diversification.

Sign of the buttock following total hip arthroplasty.

The patient was a 68-year-old man who had undergone a right total hip arthroplasty 3 years prior. He complained of progressively worsening right hip pain. Physical examination findings were consistent with a positive sign of the buttock. A triple-bone scan showed increased radio-pharmaceutical activity, which is consistent with infection. Subsequent aspiration of the right hip revealed infection, which was treated with antibiotics before the patient underwent a revision total hip arthroplasty. J Orthop Sports Phys Ther 2010;40(6):377. doi:10.2519/jospt.2010.0410.

Examination procedures and interventions for the hip in the management of low back pain: a survey of physical therapists.

OBJECTIVES: The main research aims were to investigate whether physical therapists are examining the hip(s) in individuals with a primary complaint of low back pain (LBP) and if so, the interventions being provided that target the hip(s). METHODS: An anonymous electronic survey was distributed to the membership of the American Physical Therapy Association Orthopaedic and Sports Sections, as well as that of the American Academy of Orthopaedic Manual Physical Therapists. Participant demographics and survey responses were analyzed using descriptive statistics. Associations between variables were examined using chi-square analysis. RESULTS: The estimated response rate was 18.4% (n=1163, mean age 40.5±11.4 years). The majority of respondents (91%, n=1059) reported they always or most of the time examined the hip(s) in individuals with LBP. The most common examination items utilized were hip strength testing (94%, n=948), passive range of motion (91%, n=921) and muscle flexibility testing (90%, n=906). The most common interventions included hip strengthening (94%, n=866) and hip flexibility exercises (90%, n=814). Respondents enrolled in or having completed a post-professional fellowship were more likely to utilize hip joint manual therapy techniques (x2=25.3, p=<0.001) and less likely to prescribe hip flexibility exercises (x2=7.9, p=0.005) or use electrophysical modalities (x2=4.3, p=0.039). CONCLUSIONS: Physical therapists commonly examine and provide interventions directed at the hip(s) for individuals with LBP. Post-professional fellowship training appears to influence the intervention selection of the physical therapist, with an increase in usage of hip joint manual therapy and a decrease in hip muscle flexibility and modality usage.

Effectiveness of physical therapy interventions for low back pain targeting the low back only or low back plus hips: a randomized controlled trial protocol.

BACKGROUND: Recent evidence suggests that physical therapy interventions targeting the hips may improve outcomes, including pain and disability, for patients with low back pain (LBP). Currently, there is conflicting data in regard to whether an individual with LBP needs to have a concurrent hip impairment in order to respond to this approach. The purpose of this clinical trial will be to determine the short and long-term effectiveness of physical therapy interventions directed at the lumbar spine only, versus lumbar spine and hip(s), in individuals with a primary complaint of LBP with a concurrent hip impairment. METHODS: A multi-center, randomized controlled trial of 76 adult individuals with a primary complaint of LBP, who also have at least one concurrent hip impairment. Participants will be randomized into the 'LBP only' or 'LBP+Hip' group. Treatment to the low back in both groups will be a pragmatic approach consisting of interventions targeting the low back without targeting the hip(s). Participants randomized to the LBP+Hip group will also receive a semi-prescriptive set of manual therapy and exercise techniques that target the hips. The primary outcome measures will be the modified Oswestry Disability Index and the Numeric Pain Rating Scale at discharge. DISCUSSION: These two treatment strategies are commonly utilized in physical therapy practice, but there is uncertainty which is superior. This trial will also help to provide a better understanding of the role of concurrent hip impairments in LBP. TRIAL REGISTRATION: This trial has been prospectively registered at clinicaltrials.gov (ID# NCT03550014, https://clinicaltrials.gov/ct2/show/NCT03550014) on June 7, 2018.