Actinium-225 Targeted Agents: Where Are We Now?

α-particle targeted radionuclide therapy has shown promise for optimal cancer management, an exciting new era for brachytherapy. Alpha-emitting nuclides can have significant advantages over gamma- and beta-emitters due to their high linear energy transfer (LET). While their limited path length results in more specific tumor 0kill with less damage to surrounding normal tissues, their high LET can produce substantially more lethal double strand DNA breaks per radiation track than beta particles. Over the last decade, the physical and chemical attributes of Actinium-225 (225Ac) including its half-life, decay schemes, path length, and straightforward chelation ability has peaked interest for brachytherapy agent development. However, this has been met with challenges including source availability, accurate modeling for standardized dosimetry for brachytherapy treatment planning, and laboratory space allocation in the hospital setting for on-demand radiopharmaceuticals production. Current evidence suggests that a simple empirical approach based on 225Ac administered radioactivity may lead to inconsistent outcomes and toxicity. In this review article, we highlight the recent advances in 225Ac source production, dosimetry modeling, and current clinical studies.

Prognostic Implications of Urinary Potassium to Creatinine Ratio in Patients With Predialysis Chronic Kidney Disease: A Cohort Study.

OBJECTIVES: Although a low or high serum potassium level in chronic kidney disease (CKD) is associated with worsening renal function and increased cardiovascular disease (CVD) events, urinary potassium excretion has been found to predict adverse health outcomes with conflicting results. We conducted a cohort study to determine whether urinary potassium to creatinine (K/Cr) ratio is an independent risk for further deterioration in renal function or increased CVD events. METHODS: We identified 650 predialysis patients with CKD hospitalized for an educational program regarding CKD between January 2010 and December 2018. The study outcomes were CKD progression and incident CVD events, with baseline urinary K/Cr ratio categorized into quartiles-Q1, < 19.8; Q2, 19.9-27.7; Q3, 27.8-37.9; and Q4, > 38.0. RESULTS: During follow-up (median, 35 months), 509 CKD progressions and 129 incident CVD events were identified. Sixty two patients died during follow-up. Multivariate Cox proportional hazard model showed that after adjustment for demographic factors and laboratory data, patients in Q1 had a 2.02-fold higher risk of worsening renal function than those in Q4 (95% confidence interval, 1.50-2.71; P < .001), whereas urinary K/Cr ratio had no association with the incidence of CVD events. Similarly, inverse probability weighting analysis showed an increased risk of CKD progression in the lowest quartile. Furthermore, the association between low fractional excretion of potassium and worsening renal function was confirmed. CONCLUSION: A low urinary K/Cr ratio is independently associated with worsening renal function but not with a risk of incident CVD event in predialysis patients with CKD.

The effect of sodium zirconium cyclosilicate on acid-base balance in chronic kidney disease.

Hyperkalemia is a common electrolyte abnormality in chronic kidney disease (CKD). Sodium zirconium cyclosilicate (SZC) is a novel selective cation exchanger that is used to treat hyperkalemia and may also capture ammonium, which is of a similar size to potassium. We investigated the effect of SZC on acid-base balance in CKD patients. This retrospective study surveyed 20 patients with CKD whose serum potassium levels were maintained within the normal range by treatment with polysulfonate resin, which was replaced with SZC during the clinical course. We compared clinical parameters before and after changing medications. Changing the potassium binder from polysulfonate resin to SZC increased serum bicarbonate (p = 0.016) and decreased blood urea nitrogen (p = 0.017). Serum potassium levels were maintained within the normal range. Urine pH, anion gap, and osmolality gap were unchanged during treatment. No gastrointestinal symptoms were noted during the observation period. Our data suggest that SZC may improve not only hyperkalemia but also metabolic acidosis by increasing the excretion of ammonium from the intestinal tract in patients with CKD. SZC could be a more suitable medication for CKD patients with hyperkalemia and metabolic acidosis.

Walking characteristics of runners with a transfemoral or knee-disarticulation prosthesis.

BACKGROUND: Running with prostheses has become a common activity for amputees participating in sports and recreation. However, very few studies have characterized the kinematic and kinetic parameters of walking in individuals with amputation who are runners. Thus, this study attempts to elucidate the kinematics and kinetics of walking in runners with a unilateral transfemoral amputation or knee-disarticulation. METHODS: This study experimentally compares the prosthetic and intact limbs of runners with prostheses as well as compares the findings against the limbs of age-matched able-bodied individuals while walking. Fourteen runners with a unilateral transfemoral amputation or knee-disarticulation were recruited and 14 age-matched able-bodied individuals were prepared using gait database. Spatiotemporal, kinematic, and kinetic parameters of walking were analyzed using a 3-demensional motion capture system. RESULTS: The results showed that the peak ankle positive power at pre-swing and peak hip positive power from loading response to mid stance in the intact limb were significantly larger than that in the prosthetic limb. Moreover, to compensate for missing anatomical functions on the prosthetic limb, it appeared that the intact limb of the runners generated larger peak joint power by producing more ankle plantarflexor and hip extensor moments while walking. INTERPRETATION: This study demonstrated that the runners rely on their intact limb while walking. Training of hip extensor muscles of the intact limb may be beneficial for these individuals.

Effect of step frequency on leg stiffness during running in unilateral transfemoral amputees.

Spring-like leg behavior is a general feature of mammalian bouncing gaits, such as running and hopping. Although increases in step frequency at a given running speed are known to increase the stiffness of the leg spring (kleg) in non-amputees, little is known about stiffness regulation in unilateral transfemoral amputees. In this study, we investigated stiffness regulation at different step frequencies at a given running speed in unilateral transfemoral amputees. We recruited nine unilateral transfemoral amputees wearing running-specific prostheses. They were asked to perform the action of running across a range of step frequencies (±20, ±15, ±10, ±5, and 0% of their preferred step frequency) at a given speed on an instrumented treadmill. The kleg values were calculated using ground reaction force data in both the affected and unaffected limbs. It was found that kleg increased with increasing step frequency for the unaffected limb, but not for the affected limb. Consequently, the unilateral transfemoral amputees attained the desired step frequency in the unaffected limb, but were unable to match the three highest step frequencies using their affected limbs. These results suggest that the stiffness regulation strategy during running differs between the affected and unaffected limbs.

Joint moments during sprinting in unilateral transfemoral amputees wearing running-specific prostheses.

Knowledge of joint moments will provide greater insight into the manner in which lower-extremity amputees wearing running-specific prostheses regain running capacity and compensate for replacement of an active leg with a passive prosthetic implement. Thus, the purpose of this study was to investigate three-dimensional joint moments during sprinting for unilateral transfemoral amputees wearing running-specific prostheses. Ten sprinters with unilateral transfemoral amputation performed maximal sprinting at the 22 m mark while wearing running-specific prostheses. Joint moments were calculated through an inverse dynamics approach. All peak flexion and extension moments in the prosthetic leg were found to be lower than those of the intact leg, except for the peak plantar flexion moment. In the frontal plane, the peak adduction and abduction moments in the prosthetic leg were generally lower than those of the intact leg. The peak internal rotation moments differed significantly between the legs, but the peak external rotation moments did not. The results of the present study suggest that asymmetric joint moment adaptations occur for unilateral transfemoral amputees to compensate for replacement of the biological leg with a passive prosthetic knee joint and running-specific prosthesis.

Spatiotemporal parameters in sprinters with unilateral and bilateral transfemoral amputations and functional impairments.

PURPOSE: Although sprinters with unilateral (UTF) and bilateral transfemoral (BTF) amputations and functional impairments (FIs) without amputation were allocated into different classifications because of the recent revision of the International Paralympic Committee Athletics Rules and Regulations, it is unclear whether running mechanics differ among the three groups. The aim of this study was to investigate the differences in the spatiotemporal parameters of the three groups during 100-m sprint in official competitions. METHODS: Using publicly available Internet broadcasts, we analyzed 11 elite-level sprinters with UTF amputation, 4 sprinters with BTF amputation, and 5 sprinters with FI without amputation. The best personal times for nearly all individuals were included. For each sprinter's race, the average speed, step frequency, and step length were calculated using the number of steps in conjunction with the official race time. RESULTS: Although there were no significant differences in the average speed among the UTF, BTF, and FI groups (7.95 ± 0.22, 7.90 ± 0.42, and 7.93 ± 0.14 m/s, respectively, p = 0.87), those with BTF amputation showed significantly lower step frequency (UTF: 4.20 ± 0.20 Hz, BTF: 3.71 ± 0.32 Hz, FI: 4.20 ± 0.10 Hz, p < 0.05) and longer step length (UTF: 1.90 ± 0.08 m, BTF: 2.14 ± 0.02 m, FI: 1.89 ± 0.06 m, p < 0.05) than the other two groups. CONCLUSION: These results suggest that the step characteristics during sprinting are not the same among sprinters with UTF amputation, BTF amputations, or FI without amputations.

Differences in spatiotemporal parameters during 200-m sprint between bilateral and unilateral transfemoral amputees.

BACKGROUND AND AIM:: Although Paralympic T42 class Men's 200 m sprints are currently competed by athletes with bilateral and unilateral transfemoral amputations, there may be performance differences between the groups. This study aimed to compare the spatiotemporal parameters of a 200-m sprint between bilateral and unilateral transfemoral amputees wearing running-specific prostheses. TECHNIQUE:: We analyzed 29 races (nine sprinters) with bilateral or unilateral transfemoral amputations from publicly available Internet broadcasts. For each sprinter's race, the average speed, step frequency, and step length were calculated using the number of steps in conjunction with the official race time. DISCUSSION:: Average speed of bilateral transfemoral amputees was 5.7% greater than in unilateral transfemoral amputees. Bilateral transfemoral amputees exhibited lower step frequency (-8.9%) but longer step length (16.3%) than unilateral transfemoral amputees. Therefore, even in the same Paralympic classification (T42), different spatiotemporal strategies exist between bilateral and unilateral transfemoral amputees wearing running-specific prostheses during 200-m sprints. CLINICAL RELEVANCE: Since different spatiotemporal strategies exist between bilateral and unilateral transfemoral amputees during 200-m sprints, our data supports recent revisions of classification rules (1st January, 2018), which each population was allocated into the different classification (T61 and T63, respectively).

Susceptibility and resistance genes to fluoroquinolones in methicillin-resistant Staphylococcus aureus isolated in 2002.

The activity of six fluoroquinolones (FQs) was determined against 100 methicillin-resistant Staphylococcus aureus (MRSA) isolated in 2002 along with mutations in the grlA and gyrA genes and in the norA promoter of these isolates. Of the isolates tested, 97% had mutations in grlA and gyrA. A single mutation in grlA and gyrA resulted in a decrease of susceptibility to old generation FQs (norfloxacin, enoxacin, ciprofloxacin, fleroxacin, sparfloxacin and levofloxacin) but not to new generation FQs (gatifloxacin and moxifloxacin). Double mutations of both grlA and gyrA resulted in high-level resistance to all FQs tested. All norA mutants (15%) contained double mutations in grlA and gyrA and showed no decrease of MIC in the presence of reserpine, which is known to inhibit the drug-efflux pump. Our results showed that double mutations in grlA and gyrA were necessary for the expression of high-level resistance to new generation FQs. As different FQ-resistant mutants occur in the same PFGE type, FQ-resistant MRSA may well develop individually.