Outcomes in 14 live births resulting from Pegvaliase-treated pregnancies in PKU-affected females.

BACKGROUND: Adults with PKU have difficulty maintaining plasma phenylalanine (Phe) in the range that is safe for neurologic function. Elevated plasma Phe is a risk factor for congenital anomalies and developmental delay in offspring resulting from pregnancies with poor Phe control in women with PKU. Enzyme supplementation with pegvaliase allows adults with PKU to eat an unrestricted diet and have plasma Phe levels in a safe range for pregnancy but pegvaliase has not been approved for use in pregnant females with PKU. We report the results of chart review of 14 living offspring of females affected with PKU who were responsive to pegvaliase and chose to remain on pegvaliase throughout their pregnancy. METHODS: Fourteen pregnancies (one triplet pregnancy) and their offspring were identified at eight PKU treatment centers and medical records from pregnancy and birth were submitted for this study. Institutional Review Board approval was obtained. Responses to a dataset were provided to a single center and analyzed. RESULTS: Six females and eight males were born without congenital anomalies and all offspring had normal growth parameters. While mothers had preexisting comorbidities, no additional comorbidities were reported in the offspring. Four of eleven infants (excluding triplet pregnancies) were delivered preterm (36%), a higher rate than the general population (12%). A single first trimester (eight weeks) miscarriage in a 40y was not counted in this cohort of 14 live born infants. CONCLUSION: This retrospective study suggests that pegvaliase is effective at maintaining safe maternal blood Phe levels during pregnancy without deleterious effects on mother or child. A tendency toward premature birth (4/11; 36%) is higher than expected.

Utilization of Total Joint Arthroplasty by Rural-Urban Designation in Patients With Osteoarthritis in a Universal Coverage System.

BACKGROUND: Utilization of total joint arthroplasty (TJA) is affected by differences linked to sex, race, and socioeconomic status; there is little information about how geographic variation contributes to these differences. We sought to determine whether discrepancies in TJA utilization exist in patients diagnosed with osteoarthritis (OA) based upon urban-rural designation in a universal coverage system. METHODS: We conducted a cohort study using data from a US-integrated healthcare system (2015 to 2019). Patients aged ≥50 years who had a diagnosis of hip or knee OA were included. Total hip arthroplasty and total knee arthroplasty utilization (in respective OA cohorts) was evaluated by urban-rural designation (urban, mid, and rural). Incidence rate ratios (IRRs) for urban-rural regions were modeled using multivariable Poisson regressions. RESULTS: The study cohort included 93,642 patients who have hip OA and 275,967 patients who had knee OA. In adjusted analysis, utilization of primary total hip arthroplasty was lower in patients living in urban areas (IRR = 0.87, 95% confidence interval = 0.81 to 0.94) compared to patients in rural regions. Similarly, total knee arthroplasty was used at a lower rate in urban areas (IRR = 0.88, 95% confidence interval = 0.82 to 0.95) compared with rural regions. We found no differences in the hip and knee groups within the mid-region. CONCLUSIONS: In hip and knee OA patients enrolled in a universal coverage system, we found patients living in urban areas had lower TJA utilization compared to patients living in rural areas. Further research is needed to determine how patient location contributes to differences in elective TJA utilization. LEVEL OF EVIDENCE: III.

Association Between Graft Type and Risk of Repeat Revision Anterior Cruciate Ligament Reconstruction: A Cohort Study of 1747 Patients.

BACKGROUND: With an increasing number of primary anterior cruciate ligament reconstructions (ACLRs), the burden of revision ACLR (rACLR) has also increased. Graft choice for rACLR is complicated by patient factors and the remaining available graft options. PURPOSE: To examine the association between graft type at the time of rACLR and the risk of repeat rACLR (rrACLR) in a large US integrated health care system registry while accounting for patient and surgical factors at the time of revision surgery. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data from the Kaiser Permanente ACLR registry were used to identify patients who underwent a primary isolated ACLR between 2005 and 2020 and then went on to have rACLR. Graft type used at rACLR, classified as autograft versus allograft, was the exposure of interest. Multivariable Cox proportional hazard regression was used to evaluate the risk of rrACLR, with ipsilateral and contralateral reoperation as secondary outcomes. Models included factors at the time of the rACLR (age, sex, body mass index, smoking status, staged revision, femoral fixation, tibial fixation, femoral tunnel method, lateral meniscal injury, medial meniscal injury, and cartilage injury) and a factor from the primary ACLR (activity at injury) as covariates. RESULTS: A total of 1747 rACLR procedures were included. The crude cumulative rrACLR incidence at 8-year follow-up was 13.9% for allograft and 6.0% for autograft. Cumulative ipsilateral reoperation incidence at 8-year follow-up was 18.3% for allograft and 18.9% for autograft; contralateral reoperation cumulative incidence was 4.3% for allograft and 6.8% for autograft. With adjustment for covariates, a 70% lower risk for rrACLR was observed for autograft compared with allograft (hazard ratio [HR], 0.30; 95% CI, 0.18-0.50; P < .0001). No differences were observed for ipsilateral reoperation (HR, 1.05; 95% CI, 0.73-1.51; P = .78) or contralateral reoperation (HR, 1.33; 95% CI, 0.60-2.97; P = .48). CONCLUSION: The use of autograft at rACLR was associated with a 70% lower risk of rrACLR compared with allograft in this cohort from the Kaiser Permanente ACLR registry. When accounting for all reoperations outside of rrACLR after rACLR, the authors found no significant difference in risk between autograft and allograft. To minimize the risk of rrACLR, surgeons should consider using autograft for rACLR when possible.

Single Wedge Femoral Stem Designs are Associated With a Higher Risk for Revision After Cementless Primary Total Hip Arthroplasty.

BACKGROUND: Cementless total hip arthroplasty (THA) femoral stems are the most commonly selected prostheses in the United States. Optimal stem geometry remains controversial with excellent survivorship reported for many designs. We compared cause-specific stem revision of single-wedge versus double-wedge designs from a multicenter US cohort. METHODS: Data from an integrated healthcare network's total joint replacement registry were used to conduct a cohort study. Primary elective cementless THAs were identified (2001 to 2018). Implant exposure groups were classified by design geometry using the system proposed by Khanuja et al. Type 1 single-wedge (n = 11,082) and type 2 double-wedge (n = 32,380) designs were compared, and other design types were excluded; the final study cohort comprised 43,462 THAs. Cause-specific multivariable Cox regressions were used to evaluate risk for revision due to infection or aseptic reasons, including loosening, instability, periprosthetic fracture, or other reasons. RESULTS: After adjustment for covariates, a higher aseptic revision risk was observed for type 1 when compared to type 2 designs (hazard ratio = 1.91, 95% confidence interval = 1.33-2.75). When looking at specific revision reasons, revision for aseptic loosening (hazard ratio = 3.46, 95% confidence interval = 2.24-5.34) was higher for type 1 versus type 2 designs. No differences were found for septic revision, instability, periprosthetic fracture, or revisions for other reasons. CONCLUSIONS: Type 1 single-wedge designs were found to have a higher risk of revision due to aseptic loosening relative to type 2 double-wedge designs. Femoral stem geometry should be considered when selecting a cementless femoral implant. LEVEL OF EVIDENCE: Level III.

Association Between Race/Ethnicity and Total Joint Arthroplasty Utilization in a Universally Insured Population.

INTRODUCTION: Previous studies have documented racial and ethnic disparities in total joint arthroplasty (TJA) utilization in the United States. A potential mediator of healthcare disparities is unequal access to care, and studies have suggested that disparities may be ameliorated in systems of universal access. The purpose of this study was to assess whether racial/ethnic disparities in TJA utilization persist in a universally insured population of patients enrolled in a managed healthcare system. METHODS: This retrospective cohort study used data from a US integrated healthcare system (2015 to 2019). Patients aged 50 years and older with a diagnosis of hip or knee osteoarthritis were included. The outcome of interest was utilization of primary total hip arthroplasty and/or total knee arthroplasty, and the exposure of interest was race/ethnicity. Incidence rate ratios (IRRs) were modeled using multivariable Poisson regression controlling for confounders. RESULTS: There were 99,548 patients in the hip analysis and 290,324 in the knee analysis. Overall, 10.2% of the patients were Black, 20.5% were Hispanic, 9.6% were Asian, and 59.7% were White. In the multivariable analysis, utilization of primary total hip arthroplasty was significantly lower for all minority groups including Black (IRR, 0.55, 95% confidence interval [CI], 0.52-0.57, P < 0.0001), Hispanic (IRR, 0.63, 95% CI, 0.60-0.66, P < 0.0001), and Asian (IRR, 0.64, 95% CI, 0.61-0.68, P < 0.0001). Similarly, utilization of primary total knee arthroplasty was significantly lower for all minority groups including Black (IRR, 0.52, 95% CI, 0.49-0.54, P < 0.0001), Hispanic (IRR, 0.72, 95% CI, 0.70-0.75, P < 0.0001), and Asian (IRR, 0.60, 95% CI, 0.57-0.63, P < 0.0001) (all in comparison with White as reference). CONCLUSIONS: In this study of TJA utilization in a universally insured population of patients enrolled in a managed healthcare system, disparities on the basis of race and ethnicity persisted. Additional research is required to determine the reasons for this finding and to identify interventions which could ameliorate these disparities.

Risk of Revision After Hip Fracture Fixation Using DePuy Synthes Trochanteric Fixation Nail or Trochanteric Fixation Nail Advanced: A Cohort Study of 7,979 Patients.

BACKGROUND: Prior reports of the DePuy Synthes Trochanteric Fixation Nail Advanced (TFNA) revealed a potential mode of fatigue failure at the proximal screw aperture following fixation of extracapsular hip fractures. We sought to compare the revision risk between the TFNA and its prior-generation forebear, the Trochanteric Fixation Nail (TFN). METHODS: A retrospective cohort study was performed using data from a U.S. integrated health-care system's hip fracture registry. The study sample comprised patients who underwent cephalomedullary nail fixation for hip fracture with a TFN (n = 4,007) or TFNA (n = 3,972) from 2014 to 2019. We evaluated the charts and radiographs for patients who underwent any revision. Multivariable Cox regression was used to evaluate the risk of revision related to the index fracture. RESULTS: At the 3-year follow-up, the cumulative probability of revision related to the index fracture was 1.8% for the TFN and 1.9% for the TFNA. After adjustment for covariates, no difference was observed in revision risk (hazard ratio [HR], 1.18 [95% confidence interval (CI), 0.80 to 1.75]; p = 0.40) for the TFNA compared with the TFN. The TFNA was associated with a higher risk of revision for nonunion than the TFN (HR, 1.86 [95% CI, 1.11 to 3.12]; p = 0.018). At the 3-year follow-up, implant breakage was 0.06% for the TFN and 0.2% for the TFNA; with regard to aperture failures related to the index fracture, there were 1 failure for the TFN group and 3 failures for the TFNA group. CONCLUSIONS: In a large cohort from a U.S. hip fracture registry, the TFNA had an overall revision rate that was similar to that of the earlier TFN, with implant breakage being a rare revision reason for both groups. Chart and radiographic review found that the TFNA was associated with a higher risk of revision for nonunion. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Acute and subacute anterior cruciate ligament reconstructions are associated with a higher risk of revision and reoperation.

PURPOSE: (1) Report concomitant cartilage and meniscal injury at the time of anterior cruciate ligament reconstruction (ACLR), (2) evaluate the risk of aseptic revision ACLR during follow-up, and (3) evaluate the risk of aseptic ipsilateral reoperation during follow-up. METHODS: Using a United States integrated healthcare system's ACLR registry, patients who underwent primary isolated ACLR were identified (2010-2018). Multivariable Cox proportional-hazards regression was used to evaluate the risk of aseptic revision, with a secondary outcome evaluating ipsilateral aseptic reoperation. Outcomes were evaluated by time from injury to ACLR: acute (< 3 weeks), subacute (3 weeks-3 months), delayed (3-9 months), and chronic (≥ 9 months). RESULTS: The final sample included 270 acute (< 3 weeks), 5971 subacute (3 weeks-3 months), 5959 delayed (3-9 months), and 3595 chronic (≥ 9 months) ACLR. Medial meniscus [55.4% (1990/3595 chronic) vs 38.9% (105/270 acute)] and chondral injuries [40.0% (1437/3595 chronic) vs 24.8% (67/270 acute)] at the time of ACLR were more common in the chronic versus acute groups. The crude 6-year revision rate was 12.9% for acute ACLR, 7.0% for subacute, 5.1% for delayed, and 4.4% for chronic ACLR; reoperation rates a 6-year follow-up was 15.0% for acute ACLR, 9.6% for subacute, 6.4% for delayed, and 8.1% for chronic ACLR. After adjustment for covariates, acute and subacute ACLR had higher risks for aseptic revision (acute HR 1.70, 95% CI 1.07-2.72, p = 0.026; subacute HR 1.25, 95% CI 1.01-1.55, p = 0.040) and aseptic reoperation (acute HR 2.04, 95% CI 1.43-2.91, p < 0.001; subacute HR 1.31, 95% CI 1.11-1.54, p = 0.002) when compared to chronic ACLR. CONCLUSIONS: In this cohort study, while more meniscal and chondral injuries were reported for ACLR performed ≥ 9 months after the date of injury, a lower risk of revision and reoperation was observed following chronic ACLR relative to patients undergoing surgery in acute or subacute fashions.

Implications of the Gut Microbiome in Sports.

CONTEXT: Two-thirds of an individual's gut microbiota is unique and influenced by dietary and exercise habits, age, sex, genetics, ethnicity, antibiotics, health, and disease. It plays important roles in nutrient and vitamin metabolism, inflammatory modulation, immune system function, and overall health of an individual. Specifically, in sports it may help decrease recovery time and improve athletic performance. EVIDENCE ACQUISITION: PubMed and Medline databases were used for the literature search. Bibliographies based on the original search were utilized to pursue further literature search. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Diet and exercise play very important roles in the composition of the gut microbiota in the athletic and nonathletic individual. Ingestion of carbohydrates during and after exercise seems to have an anti-inflammatory effect postexercise. Supplementation with probiotic seems to aid in recovery after exercise, too, especially restoring the "normal" gut microbiota. Physically active individuals of all levels have more alpha diversity and "health-promoting gut species" in their microbiome than nonactive individuals, along with higher concentrations of short-chain fatty acids (SCFA) and SCFA-producing organisms. However, exercise interventions should be longer than 8 weeks to see these positive characteristics. Immune function is highly influenced by the gut microbiota's response to exercise. A transient immune dysfunction occurs after prolonged high-intensity exercise, which correlates with microbiota dysregulation. Nevertheless, long-term exposure to exercise will enhance the immune response and lead to positive changes in the gut microbiota. CONCLUSION: Although the exact mechanisms of the effects that diet, exercise, and genetics have on the gut microbiota remain largely unknown, there is evidence that suggests overall health benefits. In the athletic population, these benefits can ultimately lead to performance improvement.

Evaluating Biochemically Recurrent Prostate Cancer: Histologic Validation of 18F-DCFPyL PET/CT with Comparison to Multiparametric MRI.

Background Prostate cancer recurrence is found in up to 40% of men with prior definitive (total prostatectomy or whole-prostate radiation) treatment. Prostate-specific membrane antigen PET agents such as 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) may improve detection of recurrence compared with multiparametric MRI; however, histopathologic validation is lacking. Purpose To determine the sensitivity, specificity, and positive predictive value (PPV) of 18F-DCFPyL PET/CT based on histologic analysis and to compare with pelvic multiparametric MRI in men with biochemically recurrent prostate cancer. Materials and Methods Men were prospectively recruited after prostatectomy and/or radiation therapy with rising prostate-specific antigen level (median, 2.27 ng/mL; range, 0.2-27.45 ng/mL) and a negative result at conventional imaging (bone scan and/or CT). Participants underwent 18F-DCFPyL PET/CT imaging and 3.0-T pelvic multiparametric MRI. Statistical analysis included Wald and modified χ2 tests. Results A total of 323 lesions were visualized in 77 men by using 18F-DCFPyL or multiparametric MRI, with imaging detection concordance of 25% (82 of 323) when including all lesions in the MRI field of view and 53% (52 of 99) when only assessing prostate bed lesions. 18F-DCFPyL depicted more pelvic lymph nodes than did MRI (128 vs 23 nodes). Histologic validation was obtained in 80 locations with sensitivity, specificity, and PPV of 69% (25 of 36; 95% confidence interval [CI]: 51%, 88%), 91% (40 of 44; 95% CI: 74%, 98%), and 86% (25 of 29; 95% CI: 73%, 97%) for 18F-DCFPyL and 69% (24 of 35; 95% CI: 50%, 86%), 74% (31 of 42; 95% CI: 42%, 89%), and 69% (24 of 35; 95% CI: 50%, 88%) for multiparametric MRI (P = .95, P = .14, and P = .07, respectively). In the prostate bed, sensitivity, specificity, and PPV were 57% (13 of 23; 95% CI: 32%, 81%), 86% (18 of 21; 95% CI: 73%, 100%), and 81% (13 of 16; 95% CI: 59%, 100%) for 18F-DCFPyL and 83% (19 of 23; 95% CI: 59%, 100%), 52% (11 of 21; 95% CI: 29%, 74%), and 66% (19 of 29; 95% CI: 44%, 86%) for multiparametric MRI (P = .19, P = .02, and P = .17, respectively). The addition of 18F-DCFPyL to multiparametric MRI improved PPV by 38% overall (P = .02) and by 30% (P = .09) in the prostate bed. Conclusion Findings with 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) were histologically validated and demonstrated high specificity and positive predictive value. In the pelvis, 18F-DCFPyL depicted more lymph nodes and improved positive predictive value and specificity when added to multiparametric MRI. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Zukotynski and Rowe in this issue.

Tumor localization and biochemical response to cure in tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor-23 (FGF23)-secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and postoperative biochemical changes in 31 subjects with TIO. All had failed either initial localization, or relocalization (in case of recurrence or metastases) at outside institutions. Functional imaging with ¹¹¹Indium-octreotide with single photon emission computed tomography (octreo-SPECT or SPECT/CT), and ¹8fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) were performed, followed by anatomic imaging (CT, MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20 of 31 subjects (64.5%). Nineteen of 20 subjects underwent octreo-SPECT imaging, and 16 of 20 FDG-PET/CT imaging. Eighteen of 19 (95%) were positive on octreo-SPECT, and 14 of 16 (88%) on FDG-PET/CT. Twelve of 20 subjects underwent VS; 10 of 12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were as follows: sensitivity = 0.95, specificity = 0.64, PPV = 0.82, and NPV = 0.88 for octreo-SPECT; sensitivity = 0.88, specificity = 0.36, PPV = 0.62, and NPV = 0.50 for FDG-PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease-free at last follow-up. Serum phosphorus returned to normal in all subjects within 1 to 5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C-terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25-dihydroxyvitamin D3 (1,25D) rose and exceeded the normal range. In this systematic approach to tumor localization in TIO, octreo-SPECT was more sensitive and specific, but in many cases FDG-PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation.

Postoperative intraperitoneal 5-fluoro-2'-deoxyuridine added to chemoradiation in patients curatively resected (R0) for locally advanced gastric and gastroesophageal junction adenocarcinoma.

PURPOSE: Chemoradiation after surgery for locally advanced gastric cancer improves overall and relapse-free survival compared with observation. However, locoregional recurrences remain high. Accordingly, we instituted this pilot/feasibility study, including intraperitoneal 5-fluoro-2'-deoxyuridine (IP FUDR) as part of the treatment. METHODS: Gastric/gastroesophageal junction adenocarcinoma stage Ib-IV (M0) patients who underwent R(0) resection were eligible and had IP catheters inserted at time of surgery. IP FUDR (3 g/dose/day) was given during study days 1-3 and 15-17 before combined 5-fluorouracil, leucovorin, and external beam radiation (45 Gy). Endpoints included toxicity, completion rate, locoregional recurrence, and survival. RESULTS: Twenty-eight patients (22 men) were enrolled from 2002-2006 at two institutions; their median age was 59.5 years. After R(0) resection, a median 22 (range, 8-102) lymph nodes were examined, and 22 patients had positive nodes. AJCC stages were IB (n = 8), II (n = 10), IIIA (n = 5), IIIB (n = 1), and IV (n = 4). Full-dose IP FUDR and chemoradiation treatment was completed in 20 and 25 patients, respectively. At nearly 4-year median follow-up, 11 patients were disease-free, 5 were alive with disease, 7 were dead of disease, and 1 was dead from other cause; 4 have been lost to follow-up. Recurrences were local in one, intra-abdominal in six, distant in two, multiple sites in two, and unknown in one. The median relapse-free survival is 65.3 months, and the median overall survival has not yet been reached. CONCLUSIONS: IP FUDR before chemoradiation after R(0) gastric cancer resection is well tolerated without compromising completion of postoperative adjuvant treatment. Larger randomized trials studying IP FUDR as part of gastric cancer multidisciplinary treatment are needed to prove efficacy in reducing regional recurrence and improving survival.