Background: Persistent anterolateral rotatory laxity after anterior cruciate ligament (ACL) reconstruction (ACLR) has been correlated with poor clinical outcomes and graft failure. Hypothesis: We hypothesized that a single-bundle, hamstring ACLR in combination with a lateral extra-articular tenodesis (LET) would reduce the risk of ACLR failure in young, active individuals. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: This is a multicenter, prospective, randomized clinical trial comparing a single-bundle, hamstring tendon ACLR with or without LET performed using a strip of iliotibial band. Patients 25 years or younger with an ACL-deficient knee were included and also had to meet at least 2 of the following 3 criteria: (1) grade 2 pivot shift or greater, (2) a desire to return to high-risk/pivoting sports, (3) and generalized ligamentous laxity (GLL). The primary outcome was ACLR clinical failure, a composite measure of rotatory laxity or a graft rupture. Secondary outcome measures included the P4 pain scale, Marx Activity Rating Scale, Knee injury Osteoarthritis and Outcome Score (KOOS), International Knee Documentation Committee score, and ACL Quality of Life Questionnaire. Patients were reviewed at 3, 6, 12, and 24 months postoperatively. Results: A total of 618 patients (297 males; 48%) with a mean age of 18.9 years (range, 14-25 years) were randomized. A total of 436 (87.9%) patients presented preoperatively with high-grade rotatory laxity (grade 2 pivot shift or greater), and 215 (42.1%) were diagnosed as having GLL. There were 18 patients lost to follow-up and 11 who withdrew (~5%). In the ACLR group, 120/298 (40%) patients sustained the primary outcome of clinical failure, compared with 72/291 (25%) in the ACLR+LET group (relative risk reduction [RRR], 0.38; 95% CI, 0.21-0.52; P < .0001). A total of 45 patients experienced graft rupture, 34/298 (11%) in the ACLR group compared with 11/291 (4%) in the ACL+LET group (RRR, 0.67; 95% CI, 0.36-0.83; P < .001). The number needed to treat with LET to prevent 1 patient from graft rupture was 14.3 over the first 2 postoperative years. At 3 months, patients in the ACLR group had less pain as measured by the P4 ( P = .003) and KOOS ( P = .007), with KOOS pain persisting in favor of the ACLR group to 6 months ( P = .02). No clinically important differences in patient-reported outcome measures were found between groups at other time points. The level of sports activity was similar between groups at 2 years after surgery, as measured by the Marx Activity Rating Scale ( P = .11). Conclusion: The addition of LET to a single-bundle hamstring tendon autograft ACLR in young patients at high risk of failure results in a statistically significant, clinically relevant reduction in graft rupture and persistent rotatory laxity at 2 years after surgery. Registration: NCT02018354 ( ClinicalTrials.gov identifier)

To test the hypothesis that tolerating some subretinal fluid (SRF) in patients with neovascular agerelated macular degeneration (nAMD) treated with ranibizumab using a treat-and-extend (T&E) regimen can achieve similar visual acuity (VA) outcomes as treatment aimed at resolving all SRF.Design: Multicenter, randomized, 24-month, phase 4, single-masked, noninferiority clinical trial.Participants: Participants with treatment-naïve active subfoveal choroidal neovascularization (CNV). Methods: Participants were randomized to receive ranibizumab 0.5 mg monthly until either complete resolution of SRF and intraretinal fluid (IRF; intensive arm: SRF intolerant) or resolution of all IRF only (relaxed arm: SRF tolerant except for SRF >200 mm at the foveal center) before extending treatment intervals. A 5-letter noninferiority margin was applied to the primary outcome.Main Outcome Measures: Mean change in best-corrected VA (BCVA), and central subfield thickness and number of injections from baseline to month 24.Results: Of the 349 participants randomized (intensive arm, n ¼ 174; relaxed arm, n ¼ 175), 279 (79.9%) completed the month 24. The mean change in BCVA from baseline to month 24 was 3.0 letters (standard deviation, 16.3 letters) in the intensive group and 2.6 letters (standard deviation, 16.3 letters) in the relaxed group, demonstrating noninferiority of the relaxed compared with the intensive treatment (P ¼ 0.99). Similar proportions of both groups achieved 20/40 or better VA (53.5% and 56.6%, respectively; P ¼ 0.92) and 20/200 or worse VA (8.7% and 8.1%, respectively; P ¼ 0.52). Participants in the relaxed group received fewer ranibizumab injections over 24 months (mean, 15.8 [standard deviation, 5.9]) than those in the intensive group (mean, 17 [standard deviation, 6.5]; P ¼ 0.001). Significantly more participants in the intensive group never extended beyond 4-week treatment intervals (13.5%) than in the relaxed group (2.8%; P ¼ 0.003), and significantly more participants in the relaxed group extended to and maintained 12-week treatment intervals (29.6%) than the intensive group (15.0%; P ¼ 0.005).Conclusions: Patients treated with a ranibizumab T&E protocol who tolerated some SRF achieved VA that is comparable, with fewer injections, with that achieved when treatment aimed to resolve all SRF completely.

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Cutaneous Merkel cell carcinoma (MCC) typically involves the dermis. Less than 10% of MCC have epidermal involvement. Only one MCC confined exclusively to the epidermis has been previously reported but was not recognized until the lesion recurred with typical MCC in the dermis. We present a case of a wholly intraepidermal pagetoid MCC without dermal involvement in a 74-year-old man with a 2.0-cm solitary verrucous papule on the left index finger. The initial biopsy and complete excision specimens showed marked epidermal hyperplasia, focal prominent squamous cell atypia, and MCC with florid pagetoid spread through the epidermis. There was no evidence of tumor within the dermis. The pagetoid MCC tumor cells showed diffuse cytoplasmic staining with antibodies to cytokeratin 20, and negative staining for chromogranin, neurofilament, S-100, vimentin, HMB45, leukocyte common antigen, and CD3. The cell of origin of MCC is still debated. The existence of an entirely intraepidermal variant of MCC would lend support to the view that MCC is a neoplastic expression of Merkel cells in at least some cases. Dermal-based MCC is a high-grade primary cutaneous neoplasm, but MCC confined exclusively to the epidermis may have a better prognosis.

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Background: Anterior cruciate ligament (ACL) reconstruction (ACLR) has higher failure rates in young active patients returning to sports as compared with older, less active individuals. Augmentation of ACLR with an anterolateral procedure has been shown to reduce failure rates; however, indications for this procedure have yet to be clearly defined. Purpose/Hypothesis: The purpose of this study was to identify predictors of ACL graft failure in high-risk patients and determine key indications for when hamstring ACLR should be augmented by a lateral extra-articular tenodesis (LET). We hypothesized that different preoperative characteristics and surgical variables may be associated with graft failure characterized by asymmetric pivot shift and graft rupture. Study Design: Case-control study; Level of evidence, 3. Methods: Data were obtained from the Stability 1 Study, a multicenter randomized controlled trial of young active patients undergoing autologous hamstring ACLR with or without a LET. We performed 2 multivariable logistic regression analyses, with asymmetric pivot shift and graft rupture as the dependent variables. The following were included as predictors: LET, age, sex, graft diameter, tear chronicity, preoperative high-grade knee laxity, preoperative hyperextension on the contralateral side, medial meniscal repair/excision, lateral meniscal repair/excision, posterior tibial slope angle, and return-to-sports exposure time and level. Results: Of the 618 patients in the Stability 1 Study, 568 with a mean age of 18.8 years (292 female; 51.4%) were included in this analysis. Asymmetric pivot shift occurred in 152 (26.8%) and graft rupture in 43 (7.6%). The addition of a LET (odds ratio [OR], 0.56; 95% CI, 0.37-0.83) and increased graft diameter (OR, 0.62; 95% CI, 0.44-0.87) were significantly associated with lower odds of asymmetric pivot shift. The addition of a LET (OR, 0.40; 95% CI, 0.18-0.91) and older age (OR, 0.83; 95% CI, 0.72-0.96) significantly reduced the odds of graft rupture, while greater tibial slope (OR, 1.15; 95% CI, 1.01-1.32), preoperative high-grade knee laxity (OR, 3.27; 95% CI, 1.45-7.41), and greater exposure time to sport (ie, earlier return to sport) (OR, 1.18; 95% CI, 1.08-1.29) were significantly associated with greater odds of rupture. Conclusion: The addition of a LET and larger graft diameter were significantly associated with reduced odds of asymmetric pivot shift. Adding a LET was protective of graft rupture, while younger age, greater posterior tibial slope, high-grade knee laxity, and earlier return to sport were associated with increased odds of graft rupture. Orthopaedic surgeons should consider supplementing hamstring autograft ACLR with a LET in young active patients with morphological characteristics that make them at high risk of reinjury.

The functions of parathyroid hormone-related protein (PTHrP) on morphogenesis, cell proliferation, apoptosis, and calcium homeostasis have been attributed to its N terminus. Evidence suggests that many of these effects are not mediated by the N terminus but by the midregion, a nuclear localization sequence (NLS), and C terminus of the protein. A knock-in mouse lacking the midregion, NLS, and C terminus of PTHrP (Pthrp(Delta/Delta)) was developed. Pthrp(Delta/Delta) mice had craniofacial dysplasia, chondrodysplasia, and kyphosis, with most mice dying by d 5 of age. In bone, there were fewer chondrocytes and osteoblasts per area, bone mass was decreased, and the marrow was less cellular, with erythroid hypoplasia. Cellular proliferation was impaired, and apoptosis was increased. Runx2, Ocn, Sox9, Crtl1, beta-catenin, Runx1, ephrin B2, cyclin D1, and Gata1 were underexpressed while P16/Ink4a, P21, GSK-3beta, Il-6, Ffg3, and Ihh were overexpressed. Mammary gland development was aberrant, and energy metabolism was deregulated. These results establish that the midregion, NLS, and C terminus of PTHrP are crucial for the commitment of osteogenic and hematopoietic precursors to their lineages, and for survival, and many of the effects of PTHrP on development are not mediated by its N terminus. The down-regulation of Runx1, Runx2, and Sox9 indicates that PTHrP is a modulator of transcriptional activation during stem cell commitment.

The neuronal ceroid lipofuscinoses (NCLs) are hereditary neurodegenerative diseases characterized by seizures and progressive cognitive decline, motor impairment, and vision loss accompanied by accumulation of autofluorescent lysosomal storage bodies in the central nervous system and elsewhere in the body. Mutations in at least 14 genes underlie the various forms of NCL. One of these genes, CLN8, encodes an intrinsic membrane protein of unknown function that appears to be localized primarily to the endoplasmic reticulum. Most CLN8 mutations in people result in a form of NCL with a late infantile onset and relatively rapid progression. A mixed breed dog with Australian Shepherd and Blue Heeler ancestry developed neurological signs characteristic of NCL starting at about 8months of age. The signs became progressively worse and the dog was euthanized at 21months of age due to seizures of increasing frequency and severity. Postmortem examination of the brain and retinas identified massive accumulations of intracellular autofluorescent inclusions characteristic of the NCLs. Whole genome sequencing of DNA from this dog identified a CLN8:c.585G>A transition that predicts a CLN8:p.Trp195* nonsense mutation. This mutation appears to be rare in both ancestral breeds. All of our 133 archived DNA samples from Blue Heelers, and 1481 of our 1488 archived Australian Shepherd DNA samples tested homozygous for the reference CLN8:c.585G allele. Four of the Australian Shepherd samples tested heterozygous and 3 tested homozygous for the mutant CLN8:c.585A allele. All 3 dogs homozygous for the A allele exhibited clinical signs of NCL and in 2 of them NCL was confirmed by postmortem evaluation of brain tissue. The occurrence of confirmed NCL in 3 of 4 CLN8:c.585A homozygous dogs, plus the occurrence of clinical signs consistent with NCL in the fourth homozygote strongly suggests that this rare truncating mutation causes NCL. Identification of this NCL-causing mutation provides the opportunity for identifying dogs that can be used to establish a canine model for the CLN8 disease (also known as late infantile variant or late infantile CLN8 disease).