Mental health disorder,pain, and pain treatment among long-term care residents: Evidence from the Minimum Data Set 3.0

Objective: This study evaluated: (a) associations between long-term care residents’ mental health disorder diagnoses and their pain self-reports and pain treatments, and (b) the extent to which communication, cognitive, and physical functioning problems help explain disparities in the pain and pain treatments of long-term care residents with and without mental health disorders.

Method: Minimum Data Set 3.0 records of 8,300 residents of Department of Veterans Affairs Community Living Centers were used to determine statistically unadjusted and adjusted cross-sectional associations between residents' mental health diagnoses and their pain and pain treatments.

Results: Residents diagnosed with dementia and serious mental illness (SMI) were less likely, and those diagnosed with depressive disorder, post-traumatic stress disorder (PTSD), and substance use disorder (SUD) were more likely, to report recent, severe, and debilitating pain. Among residents affirming recent pain, those with dementia or SMI diagnoses were twice as likely to obtain no treatment for their pain and significantly less likely to receive as-needed pain medication and non-pharmacological pain treatments than were other residents. Those with either depressive disorder or PTSD were more likely, and those with SUD less likely, to obtain scheduled pain medication. In general, these associations remained even after statistically adjusting for residents' demographic characteristics, other mental health disorder diagnoses, and functioning.

Conclusion: Long-term care residents with mental health disorders experience disparities in pain and pain treatment that are not well-explained by their functioning deficits. They may benefit from more frequent, thorough pain assessments and from more varied and closely tailored pain treatment approaches.     

Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition

Human leukocyte antigen (HLA) gene polymorphism plays a critical role in protective immunity, disease susceptibility, autoimmunity, and drug hypersensitivity, yet the basis of how HLA polymorphism influences T cell receptor (TCR) recognition is unclear. We examined how a natural micropolymorphism in HLA-B44, an important and large HLA allelic family, affected antigen recognition. T cell–mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid. The micropolymorphism in these HLA-B44 allotypes altered the mode of binding and dynamics of the bound viral epitope. The structure of the TCR–HLA-B*4405^EENLLDFVRF complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03. Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes.     

Nonselective Filters Offer Important Dose-Reducing Potential in Radiological Examination of the Paediatric Pelvis

Rationale and Objectives: Children are more vulnerable to the harmful effects of radiation than adults; therefore, every effort should be made to keep radiation doses as low as reasonably achievable. One effective dose-reducing tool for pediatrics is additional filtration. This anthropomorphic phantom-based study explores use of additional filters for the radiographic anteroposterior pelvis examination.Materials and Methods: Image quality, entrance surface, and effective doses were monitored with the existing inherent level of filtration for 0-, 5-, and 15-year-old pediatric phantoms. A range of filter types and thicknesses were added, including aluminium, copper, and compound (aluminium and copper), and changes were noted.Results: Compared with the current level of filtration, results showed a decrease in entrance surface dose by up to 62.9%, 56.4%, and 55.0%, and effective dose by up to 46.4%, 36.1%, and 28.7% for the 0-, 5-, and 15-year-olds, respectively. No significant degradation in image quality was noted.Conclusion: Despite compound filters offering marginal benefits over copper, 0.3 mm copper filtration is recommended for clinical trials because of reduced physical thickness. Results demonstrated that additional filtration in excess of current recommendations may offer important benefits for children undergoing this radiographic examination.     

Early intervention: Which patients and how early?

Despite advances in preventive therapy, acute coronary syndromes (ACS) remain a significant cause of morbidity and mortality. Patient risk varies widely along a spectrum from unstable angina to ST-segment elevation myocardial infarctions (STEMIs) and can be estimated using risk prediction algorithms. Estimated risk is useful to select therapeutic options ranging from aggressive medical therapy for patients at low risk to revascularization for high-risk patients in whom bypass or percutaneous coronary intervention (PCI) is feasible. Appropriate timing of an invasive strategy is crucial, with early intervention maximally benefiting the highest-risk patients. Facilitated PCI’s role in patients who present with STEMI and the most appropriate timing of interventional therapy in patients at moderate risk after a non-ST-elevation ACS remain the subject of ongoing debate.     

Diverse high-torque bacterial flagellar motors assemble wider stator rings using a conserved protein scaffold

Although it is known that diverse bacterial flagellar motors produce different torques, the mechanism underlying torque variation is unknown. To understand this difference better, we combined genetic analyses with electron cryo-tomography subtomogram averaging to determine in situ structures of flagellar motors that produce different torques, from Campylobacter and Vibrio species. For the first time, to our knowledge, our results unambiguously locate the torque-generating stator complexes and show that diverse high-torque motors use variants of an ancestrally related family of structures to scaffold incorporation of additional stator complexes at wider radii from the axial driveshaft than in the model enteric motor. We identify the protein components of these additional scaffold structures and elucidate their sequential assembly, demonstrating that they are required for stator-complex incorporation. These proteins are widespread, suggesting that different bacteria have tailored torques to specific environments by scaffolding alternative stator placement and number. Our results quantitatively account for different motor torques, complete the assignment of the locations of the major flagellar components, and provide crucial constraints for understanding mechanisms of torque generation and the evolution of multiprotein complexes.Flagellated bacteria have tailored their motility to diverse habitats. For example, the enteric model organisms Salmonella enterica serovar Typhimurium and Escherichia coli colonize animal digestive tracts and can reside outside a host, assembling flagella over their cell body to swim. However, a diverse spectrum of flagellar swimming ability is seen across the bacterial kingdom. Caulobacter crescentus inhabits low-nutrient freshwater environments where it swims using a high-efficiency flagellar motor (1, 2), whereas Vibrio species produce high-speed, sodium-driven polar flagella to capitalize on the high sodium gradient of their marine habitat (3). On the other hand, the ε-proteobacteria and spirochetes, many of which thrive exclusively in association with a host, have evolved characteristically rapid and powerful swimming capabilities that enable them to bore through mucous layers coating epithelial cells or between tissues. Indeed, the ε-proteobacteria Campylobacter jejuni and Helicobacter pylori are capable of continued swimming in high-viscosity media that immobilize E. coli or Vibrio cells (4–6), and similar behavior is observed for spirochetes (7, 8).Despite differences in the organisms’ swimming ability, the flagellar motor is composed of a conserved core of ∼20 structural proteins (9). The mechanism of flagellar motility is conserved (10), with torque generated by rotor and stator components (9). Stator complexes, heterooligomers of four motility A (MotA) and two motility B (MotB) proteins, are thought to form a ring that surrounds the axial driveshaft. Transmembrane helices of MotA and MotB form an ion channel, and MotB features a large periplasmic domain that binds peptidoglycan (11, 12) and the flagellar structural component, the P-ring (13). The stator complex couples ion flux to exertion of force on the cytoplasmic rotor ring (the C-ring), which transmits torque to the axial driveshaft (the rod), universal joint (the hook), and helical propeller (the filament), culminating in propulsion of the bacterium. Biophysical (14) and freeze-fracture (15) studies together with modeling (16) have proposed that a tight ring of ∼11 stator complexes dynamically assembles around the rod above the outer lobe of the C-ring in closely related Salmonella and E. coli motors (which we collectively refer to as the “enteric motor”). However, despite these conclusions, and although the structures observed in subtomogram averages have been proposed to be the stator complexes (17–19), the locations and stoichiometries of the stator complexes remain to be confirmed.How can we explain the wide diversity in flagellar swimming abilities in the context of a conserved core flagellar motor? Biophysical studies suggest that the source of the difference lies, at least in part, in variations in the mechanical output of the motors themselves. Torques of motors from different bacteria have been shown to range over an order of magnitude, and torque correlates with swimming speed and the ability of bacteria to propel themselves through different viscosities, indicating that adaptations are likely to be at the level of the motor itself. [Torque also varies within a single species, up to a maximum value, as a function of the number of stator complexes incorporated into the motor (14)]. For example, C. crescentus motors have been measured to produce torques of 350 pN⋅nm (2). Estimates for the torque of the enteric motor ranges from ∼1,300 to ∼2,000 pN⋅nm (20, 21). The ε-proteobacterium H. pylori has been estimated to swim with torque of 3,600 pN⋅nm (22), and spirochetes are capable of swimming with 4,000 pN⋅nm of torque (21, 23). Sodium-driven motor torques in Vibrio spp. have been measured between ∼2,000 and 4,000 pN⋅nm (24), depending on the magnitude of the sodium gradient. It is noteworthy, however, that an estimated sodium motive force in Vibrio spp. that is lower than the standard E. coli proton motive force nevertheless drives the Vibrio motor with higher torque than the E. coli motor (24, 25), further suggesting that torque differences likely exist at the level of the motor. However, the molecular mechanism by which different motors might produce different torques has not been investigated.The simplest scenario for tuning motor torque would be evolved adaptation of motor architecture. In support of this scenario, we recently showed that many motors have evolved additional structures not found in the well-studied enteric motors (18), and we observed that the C-ring radius varies among species (17, 18). One of the most widespread novel structures is a periplasmic basal disk directly beneath the outer membrane, often co-occurring with varied uncharacterized additional structures, which we collectively term “disk complexes.” Consistently, disk complexes have been seen only in motors that produce torque higher than that in E. coli or Salmonella. For example, the sodium-driven ∼2,000+ pN⋅nm torque motors of Vibrio species assemble a disk complex featuring a basal disk beneath the outer membrane (18) in addition to smaller H- and T-rings composed of FlgOT (flagella O, T) and MotXY (motility X, Y), respectively (26, 27). It has been shown that the T-ring interacts with stator complexes in Vibrio spp. (28), although the exact location and number of stator complexes in Vibrio spp. remains unclear. ε-Proteobacteria such as Helicobacter species, C. jejuni, and Wolinella succinogenes also assemble disk complexes composed of large basal disks beneath the outer membrane together with additional smaller disks (18, 29). Although these and other cases of additional disks have been reported (18, 30), their relation to flagellar function remains enigmatic, and it is unclear if these widespread disk complexes are homologous or analogous.In this study, we hypothesized that bacteria have tuned their swimming abilities by evolving structural adaptations to their flagellar motors that would result in altered torque generation. Using electron cryo-tomography and subtomogram averaging, we found that Vibrio polar γ-proteobacterial and Campylobacter ε-proteobacterial flagellar motors incorporate 13 and 17 stator complexes, respectively, compared with the ∼11 in enteric bacteria. In both cases, these stator complexes are scaffolded into wider stator rings relative to the enteric motor by components of their respective disk complexes. The wider C. jejuni stator ring is further reflected in a considerably wider rotor C-ring. Further analysis of the components of the Vibrio and C. jejuni disk complexes reveals that they share a core protein, FlgP, but each has acquired diverse additional components to form divergent disk-complex architectures. We conclude by showing that our structural data of wider stator rings featuring additional stator complexes can quantitatively account for the differences in torque between different flagellar motors.     

Population pharmacokinetic analysis of oseltamivir and oseltamivir carboxylate following intravenous and oral administration to patients with and without renal impairment

This work characterizes the pharmacokinetics (PK) of oseltamivir phosphate (OP) and its active metabolite, oseltamivir carboxylate (OC), and investigates oseltamivir i.v. dosing regimens for treatment of influenza in patients with normal renal function and with various degrees of renal impairment. Initially, data collected from 149 subjects with normal renal function and mild to severe renal impairment who were administered 40–200 mg oseltamivir i.v. were described by a four-compartment model. Two compartments described OP, one compartment described OC and one compartment described OP to OC metabolism. Then, data of 128 subjects administered 20–1,000 mg oseltamivir orally were added. The absorption model included three first-order processes with direct (via first-pass) input in the OC compartment and two (direct and delayed) inputs in the OP compartment. Simulations and PK bridging were used to recommend i.v. dosing regimens. The analysis demonstrated that renal function had a major effect on OC clearance (CL _M ) and exposure. CL _M for subjects with mild, moderate and severe renal impairment was 18, 50, and 84 % lower than for subjects with normal renal function. Simulations were used to select i.v. dosing regimens that provide OC C_min coverage and exposures comparable to those achieved in subjects with normal renal function administered 75 mg b.i.d. orally. The oseltamivir dose depended on the degree of renal impairment and was independent of route of administration. Specifically, 75 mg b.i.d. is recommended for subjects with normal renal function or mild renal impairment, 30 mg b.i.d. for subjects with moderate renal impairment, and 30 mg q.d. for subjects with severe renal impairment. Recommended i.v. doses were the same as those recommended for oral administration in corresponding renal impairment groups.