ABSTRACT
BACKGROUND: Cementless femoral fixation in total hip arthroplasty (THA) has increased in prevalence worldwide. However, cementless fixation in elderly patients is controversial due to the risks of periprosthetic fracture and aseptic loosening. This study evaluated outcomes in patients undergoing primary THA utilizing a cementless stem without a collar, comparing those less than 75 years to those older than 75 years. METHODS: Between 2011 and 2021, there were 2,605 cementless THAs performed by 4 surgeons utilizing a highly porous metal fixation surface without a collar and consistent clinical protocols. There were 469 patients who had an age ≥ 75 years. Revision rates, intraoperative fractures, and 90-day mortality were compared between cohorts. In the ≥ 75 year age group, there were more women, more American Society of Anesthesiologists physical status classification III or IV, a lower body mass index, and more kidney disease, osteoporosis, and thyroid disease (P ≤ .002). RESULTS: All-cause revision rates trended lower for the ≥75 year age group compared to < 75 year (1.9 versus 3.5%, P = .082) at 20-months of follow-up. Moreover, there was no difference in all-cause femoral component revisions comparing ≥ 75 to < 75 year age groups (1.5 versus 2.2%, P = .375), with only 3 of 10 femoral revisions due to aseptic loosening being in the ≥ 75 year age group. Intraoperative fracture (0.2 versus 0.5%, P = .701) and 90-day mortality (0.2 versus 0.1%, P = .460) did not differ between ≥ 75 and < 75 year age groups. CONCLUSIONS: Older patients had comparable revision rates compared to younger patients using cementless femoral fixation without a collar. Furthermore, there was no difference in 90-day mortality or intraoperative fracture rates. Study findings provide evidence for the safety and durability of cementless THA using collarless femoral stems in elderly patients ≥ 75 years of age. LEVEL OF EVIDENCE: III.
ABSTRACT
More than 80 loss-of-function (LOF) mutations in the SLC6A8 creatine transporter (hCRT1) are responsible for cerebral creatine deficiency syndrome (CCDS), which gives rise to a spectrum of neurological defects, including intellectual disability, epilepsy, and autism spectrum disorder. To gain insight into the nature of the molecular defects caused by these mutations, we quantitatively profiled the cellular processing, trafficking, expression, and function of eight pathogenic CCDS variants in relation to the wild type (WT) and one neutral isoform. All eight CCDS variants exhibit measurable proteostatic deficiencies that likely contribute to the observed LOF. However, the magnitudes of their specific effects on the expression and trafficking of hCRT1 vary considerably, and we find that the LOF associated with two of these variants primarily arises from the disruption of the substrate-binding pocket. In conjunction with an analysis of structural models of the transporter, we use these data to suggest mechanistic classifications for these variants. To evaluate potential avenues for therapeutic intervention, we assessed the sensitivity of these variants to temperature and measured their response to the proteostasis regulator 4-phenylbutyrate (4-PBA). Only one of the tested variants (G132V) is sensitive to temperature, though its response to 4-PBA is negligible. Nevertheless, 4-PBA significantly enhances the activity of WT hCRT1 in HEK293T cells, which suggests it may be worth evaluating as a therapeutic for female intellectual disability patients carrying a single CCDS mutation. Together, these findings reveal that pathogenic SLC6A8 mutations cause a spectrum of molecular defects that should be taken into consideration in future efforts to develop CCDS therapeutics.
