Perceived barriers to self-collected HPV testing for cervical cancer screening, and knowledge of HPV: a survey of primary healthcare smear-takers across Aotearoa New Zealand.

AIMS: Cervical cancer remains a burden within Aotearoa New Zealand, with 2022 screening rates sitting 12.7% below target. The National Cervical Screening Programme has changed to primary human papillomavirus (HPV) testing for all screen-eligible people, with the aim for home self-testing. Little is known about the readiness of primary care for the change to self-testing and its associated challenges. A pilot HPV cervical cancer screening programme is being conducted in 17 practice centres. The aim of this study is to explore smear-taker knowledge at these centres about the use of primary HPV testing for cervical cancer screening. METHODS: This is an ethically approved questionnaire study, with data from a structured web-based questionnaire sent to all smear-takers at the pilot centres. RESULTS: We achieved a total completion rate of 57.8%. The average score for "Knowledge of HPV" was 56.5% (range=20-100%). The challenges to patient home HPV self-testing were felt to be overall "not at all" to "mildly challenging". Up to 73.3% of participants identified ongoing needs for further education. CONCLUSIONS: The findings indicate knowledge deficits regarding HPV testing for cervical cancer screening and a desire for the provision of further education. Overall, respondents felt that no major barriers to implementing HPV self-testing would occur.

Oncologic Safety of Close Margins in Patients With Low- to Intermediate-Grade Major Salivary Gland Carcinoma.

Importance: Postoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence. Objective: To evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins. Design, Setting, and Participants: The American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (>1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023. Main Outcomes and Measures: Main outcomes were risk factors for local recurrence. Results: A total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group. Conclusions and Relevance: In this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.

Impact of unilateral hearing loss in early development.

PURPOSE OF REVIEW: The purpose of this review is to provide an update on current literature as it relates to the impact of unilateral hearing loss for the pediatric population. RECENT FINDINGS: Current studies further corroborate past research findings which reveal the potential consequences of unilateral hearing loss on spatial hearing, language, and neurocognitive functioning. Deficits among children with unilateral hearing loss may parallel those seen in children with bilateral hearing loss, further challenging historic views that hearing in one ear in childhood is sufficient for normal development. The potential deficiencies seen in children with unilateral hearing loss can be subtler than those seen with bilateral hearing loss, but may nonetheless also impact school performance, patient fatigue, parental stress, and quality of life. Early interventions within a sensitive period of development of the central auditory system may circumvent potential barriers in cognitive, academic, and psychosocial development. SUMMARY: This review synthesizes the latest research on the impact of unilateral hearing loss in childhood and the role for possible interventions. The summarized information may serve to support the development of new guidelines for the evaluation and treatment of children with unilateral hearing loss.

Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging.

Decline in hematopoietic stem cell (HSC) function with age underlies limited health span of our blood and immune systems. In order to preserve health into older age, it is necessary to understand the nature and timing of initiating events that cause HSC aging. By performing a cross-sectional study in mice, we discover that hallmarks of aging in HSCs and hematopoiesis begin to accumulate by middle age and that the bone marrow (BM) microenvironment at middle age induces and is indispensable for hematopoietic aging. Using unbiased approaches, we find that decreased levels of the longevity-associated molecule IGF1 in the local middle-aged BM microenvironment are a factor causing HSC aging. Direct stimulation of middle-aged HSCs with IGF1 rescues molecular and functional hallmarks of aging, including restored mitochondrial activity. Thus, although decline in IGF1 supports longevity, our work indicates that this also compromises HSC function and limits hematopoietic health span.

Making meaning of cancer: A qualitative analysis of oral-digestive cancer survivors' reflections.

This qualitative study aimed to confirm and extend research on meaning making after cancer. In all, 119 adults aged 41 to 88 years (M = 65.50 years and standard deviation = 9.16 years) were interviewed 12 months after diagnosis of oral-digestive cancers. About half tried to understand why they got cancer (43%) and said that cancer changed their view of life (53%). Most (75%) reported that previous life experiences helped them cope with cancer. Cancer survivors made meanings in the areas of existential, social, and personal domains with both positive and negative content. Practitioners may wish to examine meaning making in these areas for those in distress after cancer.

Sequentially inducible mouse models reveal that Npm1 mutation causes malignant transformation of Dnmt3a-mutant clonal hematopoiesis.

Clonal hematopoiesis (CH) is a common aging-associated condition with increased risk of hematologic malignancy. Knowledge of the mechanisms driving evolution from CH to overt malignancy has been hampered by a lack of in vivo models that orthogonally activate mutant alleles. Here, we develop independently regulatable mutations in DNA methyltransferase 3A (Dnmt3a) and nucleophosmin 1 (Npm1), observed in human CH and AML, respectively. We find Dnmt3a mutation expands hematopoietic stem and multipotent progenitor cells (HSC/MPPs), modeling CH. Induction of mutant Npm1 after development of Dnmt3a-mutant CH causes progression to myeloproliferative disorder (MPD), and more aggressive MPD is observed with longer latency between mutations. MPDs uniformly progress to acute myeloid leukemia (AML) following transplant, accompanied by a decrease in HSC/MPPs and an increase in myeloid-restricted progenitors, the latter of which propagate AML in tertiary recipient mice. At a molecular level, progression of CH to MPD is accompanied by selection for mutations activating Ras/Raf/MAPK signaling. Progression to AML is characterized by additional oncogenic signaling mutations (Ptpn11, Pik3r1, Flt3) and/or mutations in epigenetic regulators (Hdac1, Idh1, Arid1a). Together, our study demonstrates that Npm1 mutation drives evolution of Dnmt3a-mutant CH to AML and rate of disease progression is accelerated with longer latency of CH.

Whole-Genome Comparative Analysis of Salmonella enterica Serovar Newport Strains Reveals Lineage-Specific Divergence.

Salmonella enterica subsp. enterica serovar Newport has been associated with various foodborne outbreaks in humans and animals. Phylogenetically, serovar Newport is one of several Salmonella serovars that are polyphyletic. To understand more about the polyphyletic nature of this serovar, six food, environment, and human isolates from different Newport lineages were selected for genome comparison analyses. Whole genome comparisons demonstrated that heterogeneity mostly occurred in the prophage regions. Lineage-specific characteristics were also present in the Salmonella pathogenicity islands and fimbrial operons.

Progressive alterations in multipotent hematopoietic progenitors underlie lymphoid cell loss in aging.

Declining immune function with age is associated with reduced lymphoid output of hematopoietic stem cells (HSCs). Currently, there is poor understanding of changes with age in the heterogeneous multipotent progenitor (MPP) cell compartment, which is long lived and responsible for dynamically regulating output of mature hematopoietic cells. In this study, we observe an early and progressive loss of lymphoid-primed MPP cells (LMPP/MPP4) with aging, concomitant with expansion of HSCs. Transcriptome and in vitro functional analyses at the single-cell level reveal a concurrent increase in cycling of aging LMPP/MPP4 with loss of lymphoid priming and differentiation potential. Impaired lymphoid differentiation potential of aged LMPP/MPP4 is not rescued by transplantation into a young bone marrow microenvironment, demonstrating cell-autonomous changes in the MPP compartment with aging. These results pinpoint an age and cellular compartment to focus further interrogation of the drivers of lymphoid cell loss with aging.

Regional mechanical properties of human patellar tendon allografts.

PURPOSE: Very little is known regarding regional biomechanical properties of patellar tendon allografts. METHODS: Ten human bone-tendon-bone (BTB) patellar grafts were separated into equal thirds and underwent cyclic and failure testing. Grafts were non-irradiated and processed using proprietary sterilization methods. RESULTS: The central third was the thickest region (4.9 ± 0.4 mm) compared to the medial and lateral (p < 0.05). The lateral third was the longest region (58.8 ± 8.8 mm) compared to the medial (47.9 ± 8.5 mm) and central (47.2 ± 8.8 mm) portions (p < 0.05). Cyclic testing demonstrated no regional differences with respect to elongation (n.s.) and creep strain (n.s.). Failure testing demonstrated increased maximum load and stiffness in the central region (1,680 ± 418 N and 278 ± 67 N/mm, respectively) as compared to the medial (1,033 ± 214 N, p < 0.002, 201 ± 37 N/mm, p < 0.03) and lateral thirds (908 ± 412 N, p < 0.03, 173 ± 66 N/mm, p < 0.002). Elongation at maximum load did not vary between regions. Central region maximum stress (41.0 ± 12.5 MPa) was greater than that of the medial third (28.1 ± 3.6 MPa, p < 0.02), with strain at maximum stress larger in the central third (0.21 ± 0.03) compared to lateral (0.16 ± 0.03, p < 0.01). CONCLUSIONS: The central third of a non-irradiated, human bone-patellar tendon-bone construct is thicker and biomechanically superior to the medial and lateral regions in most respects. These findings reinforce the use of the central third of a patellar tendon allograft in anterior cruciate ligament reconstruction. Further investigations are required to determine whether the decreased biomechanical properties of the medial and lateral third of the BTB construct negatively influence the mechanical function of hemi-BTB grafts.

Development of a mouse model of supraspinatus tendon insertion site healing.

Supraspinatus (SS) tendon tears are common musculoskeletal injuries whose surgical repair exhibits the highest incidence of re-tear of any tendon. Development of therapeutics for improving SS tendon healing is impaired by the lack of a model that allows biological perturbations to identify mechanisms that underlie ineffective healing. The objective of this study was to develop a mouse model of supraspinatus insertion site healing by creating a reproducible SS tendon detachment and surgical repair which can be applied to a wide array of inbred mouse strains and genetic mutants. Anatomical and structural analyses confirmed that the rotator cuff of the mouse is similar to that of human, including the presence of a coracoacromial (CA) arch and an insertion site that exhibits a fibrocartilagenous transition zone. The surgical repair was successfully conducted on seven strains of mice that are commonly used in Orthopaedic Research suggesting that the procedure can be applied to most inbred strains and genetic mutants. The quality of the repair was confirmed with histology through 14 days after surgery in two mouse strains that represent the variation in mouse strains evaluated. The developed mouse model will allow us to investigate mechanisms involved in insertion site healing.

Effect of interference screw depth on fixation strength in biceps tenodesis.

PURPOSE: The purpose of this study was to assess the biomechanical performance of the long head of the biceps tenodesis with an interference screw with respect to screw depth. METHODS: Twenty-one human cadaveric shoulders were randomized into 3 treatment groups (7 each): interference screw placed flush to the humeral cortex, 50% proud, or fully recessed. Bone density was determined, and subpectoral biceps tenodesis was performed with 8 × 12 mm Bio-Tenodesis screws (Arthrex, Naples, FL). Each construct was cyclically loaded from 5 to 70 N for 500 cycles at 1 Hz and then pulled to failure at 1 mm/s. Relative actuator displacement was calculated from cyclic testing. Maximum load, elongation, linear stiffness, and failure mode were recorded from pull-to-failure testing. Because of numerous failures during cyclic testing, the final load data from the fully recessed group were not statistically analyzed. The remaining groups were compared by use of a 2-tailed, Student unpaired t test and χ(2) analysis. RESULTS: There was no significant difference in displacement among groups during cyclic testing. Five specimens in the recessed group failed during cyclic testing, whereas 2 specimens and 0 specimens failed in the proud and flush groups, respectively. The maximum loads sustained were 281.6 ± 77.8 N, 184.5 ± 56.3 N, and 209.1 ± 57.0 N for the flush group, 50% proud group, and recessed group (in those specimens surviving cyclical loading), respectively. CONCLUSIONS: Placement of a Bio-Tenodesis screw flush to the humeral cortex is preferred for maximum fixation strength in subpectoral biceps tenodesis. A screw placed to 50% depth may be effective in the laboratory setting, but recessed placement is more variable and requires additional fixation. The fully recessed group resulted in 5 of 7 failures during cyclical loading, with no specimens failing in the flush group. CLINICAL RELEVANCE: This study shows the importance of determining the optimal depth of interference screw placement during biceps tenodesis to obtain optimal biomechanical performance and reduce the risk of fixation failure.

Biceps tenodesis with interference screw fixation: a biomechanical comparison of screw length and diameter.

PURPOSE: To evaluate the effect of screw length and diameter on the mechanical properties of biceps tenodesis (BT) with an interference screw in 2 different locations (proximal and distal). METHODS: We randomized 42 fresh-frozen human cadaveric shoulders (mean age, 65 ± 8 years) into 6 groups (n = 7): arthroscopic proximal BT using 7 × 15-, 7 × 25-, 8 × 15-, or 8 × 25-mm interference screws or distal subpectoral BT with 7 × 15- or 8 × 15-mm interference screws. Each repaired specimen was mounted onto a materials testing machine, preloaded to 5 N for 2 minutes, cycled from 5 to 70 N for 500 cycles (1 Hz), and loaded to failure (1 mm/s). Displacement during cyclical loading, pullout stiffness, and ultimate load to failure were computed, and the mechanism of failure was noted. RESULTS: All failures occurred at the tendon-screw interface. There was no statistically significant difference in ultimate displacement among all groups in the ultimate load to failure, displacement at peak load, and stiffness. CONCLUSIONS: There is no difference in ultimate load to failure, displacement at peak load, and stiffness of BT with regard to screw length or diameter at both proximal and distal tenodesis locations. These data would support use of a smaller-diameter and shorter implant for BT both proximally and distally. CLINICAL RELEVANCE: The results may serve as a guide to the orthopaedic surgeon performing proximal BT in selecting the appropriate interference screw. When possible, we recommend using the smallest screw size available to minimize risk of stress fracture at the tenodesis site.

Docosahexaenoic acid (DHA) and docosapentaenoic acid (DPAn-6) algal oils reduce inflammatory mediators in human peripheral mononuclear cells in vitro and paw edema in vivo.

The anti-inflammatory activity associated with fish oil has been ascribed to the long-chain polyunsaturated fatty acids (LC-PUFA), predominantly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Here we examined the anti-inflammatory effects of two DHA-rich algal oils, which contain little EPA, and determined the contribution of the constituent fatty acids, particularly DHA and docosapentaenoic acid (DPAn-6). In vitro, lipopolysaccharide (LPS)-stimulated Interleukin-1 beta (IL-1beta) and Tumor Necrosis Factor-alpha (TNF-alpha) secretion in human peripheral blood mononuclear cells (PBMC) was inhibited with apparent relative potencies of DPAn-6 (most potent) > DHA > EPA. In addition, DPAn-6 decreased intracellular levels of cyclooxygenase-2 (COX-2) and was a potent inhibitor of pro-inflammatory prostaglandin E2 (PGE2) production. DHA/DPAn-6-rich DHA-S (DHA-S) algal oil was more effective at reducing edema in rats than DHA-rich DHA-T (DHA-T), suggesting that DPAn-6 has anti-inflammatory properties. Further in vivo analyses demonstrated that feeding DPAn-6 alone, provided as an ethyl ester, reduced paw edema to an extent approaching that of indomethacin and enhanced the anti-inflammatory activity of DHA when given in combination. Together, these results demonstrate that DPAn-6 has anti-inflammatory activity and enhances the effect of DHA in vitro and in vivo. Thus, DHA-S algal oil may have potential for use in anti-inflammatory applications.

Characterization of response to radiation mediated gene therapy by means of multimodality imaging.

Imaging techniques are under development to facilitate early analysis of spatial patterns of tumor response to combined radiation and antivascular gene therapy. A genetically modified, replication defective adenoviral vector (Ad.EGR-TNFalpha), injected intratumorally, mediates infected cells to express tumor necrosis factor alpha (TNFalpha), which is increased after exposure to radiation. The goal of this study was to characterize an image based "signature" for response to this combined radiation and gene therapy in mice with human prostate xenografts. This study is part of an imaged guided therapy project where such a signature would be useful in guiding subsequent treatments. Changes in the tumor micro-environment were assessed using MRI registered with electron paramagnetic resonance imaging which provides images of tissue oxygenation. Dynamic contrast-enhanced MRI was used to assess tissue perfusion. When compared with null vector (control) treatment, the ratio of contrast agent (Gd-DTPA-BMA) washout rate to uptake rate was lower (P = 0.001) after treatment, suggesting a more balanced perfusion. Concomitantly, oxygenation significantly increased in the treated animals and decreased or did not change in the control animals (P < 0.025). This is the first report of minimally invasive, quantitative, absolute oxygen measurements correlated with tissue perfusion in vivo.

Electron paramagnetic resonance oxygen image hypoxic fraction plus radiation dose strongly correlates with tumor cure in FSa fibrosarcomas.

PURPOSE: Tumor hypoxia has long been known to produce resistance to radiation. In this study, electron paramagnetic resonance (EPR) oxygen imaging was investigated for its power to predict the success of tumor control according to tumor oxygenation level and radiation dose. METHODS AND MATERIALS: A total of 34 EPR oxygen images were obtained from the legs of C3H mice bearing 0.5-cm(3) FSa fibrosarcomas under both normal (air breathing) and clamped tumor conditions. Under the same conditions as those during which the images were obtained, the tumors were irradiated to a variety of doses near the FSa dose at which 50% of tumors were cured. Tumor tissue was distinguished from normal tissue using co-registration of the EPR oxygen images with spin-echo magnetic resonance imaging of the tumor and/or stereotactic localization. The tumor voxel statistics in the EPR oxygen image included the mean and median partial pressure of oxygen and the fraction of tumor voxels below the specified partial pressure of oxygen values of 3, 6, and 10 mm Hg. Bivariate logistic regression analysis using the radiation dose and each of the EPR oxygen image statistics to determine which best separated treatment failure from success. RESULTS: The measurements of the dose at which 50% of tumors were cured were similar to those found in published data for this syngeneic tumor. Bivariate analysis of 34 tumors demonstrated that tumor cure correlated with dose (p = 0.004) and with a <10 mm Hg hypoxic fraction (p = 0.023). CONCLUSION: Our results have shown that, together, radiation dose and EPR image hypoxic fraction separate the population of FSa fibrosarcomas that are cured from those that fail, thus predicting curability.

A laparoscopic simulator tool for objective measurement of residents' laparoscopic ability.

OBJECTIVE: We sought to develop an objective measurement of residents' laparoscopic ability by using a laparoscopic simulator assessment tool. METHODS: An inexpensive laparoscopic simulator was developed. Three laparoscopic assessment procedures were created: 1) bead/pom-pom drop, 2) checkerboard drill, and 3) bead manipulation. Two minimally invasive surgeons and 8 PGY 3/4 and 15 PGY 1 residents were timed performing the 3 procedures. Ten of the PGY 1 residents were retested at the end of their PGY 1 year. RESULTS: The minimally invasive surgeons completed the laparoscopic drills in approximately half the time of the PGY 3/4 (P=0.02), and PGY 3/4 were 60% faster than PGY 1 (P=0.01). PGY 1 completed the drills in half the time at the end of the PGY 1 year (P=0.005). As an objective measurement of residents' laparoscopic surgery competency, by the completion of the academic year, all PGY 1 residents must be able to complete the drills as fast as or faster than the original PGY 3/4 times. CONCLUSION: We developed an inexpensive, objective, simple laparoscopic simulator assessment tool for measurement of residents' laparoscopic ability.