A Comparison of Recruitment Methods for a Remote, Nationwide Clinical Trial for COVID-19 Treatment.

This study describes decentralized recruitment and enrollment for a COVID-19 treatment trial, while comparing 5 primary recruitment methods: search engine ads, paid advertising within a national testing company, paid advertising within a regional testing company, electronic health record messages, and word of mouth. These are compared across patient demographics, efficiency, and cost. Clinical Trials Registration: NCT04510194.

Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19.

BACKGROUND: Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. METHODS: COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. RESULTS: The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. CONCLUSIONS: In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04510194.

Trends and Costs of Minimally Invasive Surgery for Kidney Cancer in the US: A Population-based Study.

OBJECTIVE: To analyze temporal trends and costs associated with the use of minimally invasive surgery (MIS) for kidney cancer in the US over the past decade. To examine the impact of social determinants of health (SDOH) on perioperative outcomes. METHODS: The PearlDiver Mariner, a national database of insurance billing records, was queried for this retrospective observational cohort analysis. The MIS population was identified and stratified according to treatment modality, using International Classification of Diseases and current procedural terminology codes. SDOH were assessed using International Classification of Diseases codes. Negative binomial regression was used to evaluate the overall number of renal MIS and Cochran-Armitage tests to compare the utilization of different treatment modalities, over the study period. Multivariable logistic regression analysis identified predictors of perioperative complications. RESULTS: A total of 80,821 MIS for kidney cancer were included. Minimally invasive partial nephrectomy adoption as a fraction of total MIS increased significantly (slope of regression line, reg. = 0.026, P <.001). Minimally invasive radical nephrectomy ($26.9k ± 40.9k) and renal ablation ($18.9k ± 31.6k) were the most expensive and cheapest procedures, respectively. No statistically significant difference was observed in terms of number of complications (P = .06) and presence of SDOH (P = .07) among the treatment groups. At multivariable analysis, patients with SDOH undergoing minimally invasive radical nephrectomy had higher odds of perioperative complications, while renal ablation had a significantly lower probability of perioperative complications. CONCLUSION: This study describes the current management of kidney cancer in the US, offering a socioeconomic perspective on the impact of this disease in everyday clinical practice.

Antibody-mediated cellular responses are dysregulated in Multisystem Inflammatory Syndrome in Children (MIS-C).

Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 infection characterized by multi-organ involvement and inflammation. Testing of cellular function ex vivo to understand the aberrant immune response in MIS-C is limited. Despite strong antibody production in MIS-C, SARS-CoV-2 nucleic acid testing can remain positive for 4-6 weeks after infection. Therefore, we hypothesized that dysfunctional cell-mediated antibody responses downstream of antibody production may be responsible for delayed clearance of viral products in MIS-C. In MIS-C, monocytes were hyperfunctional for phagocytosis and cytokine production, while natural killer (NK) cells were hypofunctional for both killing and cytokine production. The decreased NK cell cytotoxicity correlated with an NK exhaustion marker signature and systemic IL-6 levels. Potentially providing a therapeutic option, cellular engagers of CD16 and SARS-CoV-2 proteins were found to rescue NK cell function in vitro. Together, our results reveal dysregulation in antibody-mediated cellular responses unique to MIS-C that likely contribute to the immune pathology of this disease.

Optical spin hall effect in exciton-polariton condensates in lead halide perovskite microcavities.

An exciton-polariton condensate is a hybrid light-matter state in the quantum fluid phase. The photonic component endows it with characters of spin, as represented by circular polarization. Spin-polarization can form stochastically for quasi-equilibrium exciton-polariton condensates at parallel momentum vector k|| ∼ 0 from bifurcation or deterministically for propagating condensates at k|| > 0 from the optical spin-Hall effect (OSHE). Here, we report deterministic spin-polarization in exciton-polariton condensates at k|| ∼ 0 in microcavities containing methylammonium lead bromide perovskite (CH3NH3PbBr3) single crystals under non-resonant and linearly polarized excitation. We observe two energetically split condensates with opposite circular polarizations and attribute this observation to the presence of strong birefringence, which introduces a large OSHE at k|| ∼ 0 and pins the condensates in a particular spin state. Such spin-polarized exciton-polariton condensates may serve not only as circularly polarized laser sources but also as effective alternatives to ultracold atom Bose-Einstein condensates in quantum simulators of many-body spin-orbit coupling processes.

Use of Methenamine for Urinary Tract Infection Prophylaxis: Systematic Review of Recent Evidence.

INTRODUCTION AND HYPOTHESIS: Antibiotic resistance is an unavoidable consequence of antibiotic use and growing rates of resistance are an urgent issue. Methenamine is a non-antibiotic alternative used for urinary tract infection (UTI) prophylaxis. The objective of this review is to evaluate recently published literature regarding the efficacy and safety of methenamine for UTI prophylaxis. METHODS: PubMed, Embase, and CENTRAL databases were queried in March 2023 using the following search terms: urinary tract infection, cystitis, bacteriuria, or dysuria, and methenamine. Studies prior to 2012 were excluded from this review to focus on appraisal of the most recent evidence. Prospective and controlled retrospective trials were included for review. RESULTS: A total of seven studies (three prospective and four retrospective) met the inclusion criteria for review. Two of the 3 prospective studies demonstrated no or non-inferior differences in clinical efficacy to prevent recurrent UTIs between methenamine and antibiotic prophylaxis and the third showed decreased rates of UTI with methenamine use in patients with short-term indwelling catheters compared with cranberry alone. The retrospective studies consistently supported the efficacy and safety of methenamine for UTI prophylaxis in a variety of populations and clinical settings. Adverse effects reported with methenamine were similar to comparators and included nausea, abdominal pain, and headache. CONCLUSIONS: The use of methenamine for UTI prophylaxis was shown to be effective in a variety of settings without an increased risk of adverse effects compared with prophylactic antibiotics. Larger blinded clinical trials are needed to further define the role of methenamine in UTI prophylaxis.

Evaluating the Morphology of Unique Superficial Fissured Cartilage Lesions at the Femoral Head-Neck Junction in Patients with Femoroacetabular Impingement Syndrome.

Background: While an association between femoroacetabular impingement (FAI) and osteoarthritis (OA) has been reported, the mechanistic differences and transition between the 2 conditions is not fully understood. In FAI, cartilage lesions at the femoral head-neck junction can sometimes be visualized during hip arthroscopy. Purpose/Hypothesis: The purpose of this study was to describe a unique dimpled pattern of superficial fissured cartilage lesions on the femoral head-neck junction at impingement site in patients with FAI syndrome (FAIS) and to evaluate the clinical, histological, and genetic phenotype of this cartilage. We hypothesized that the cartilage lesions may indicate risk for, or predict occurrence of, OA. Study Design: Controlled laboratory study. Methods: Six hips (6 patients; mean age, 34.2 ± 12.9 years; range, 19-54 years) with dimpled or fissured cartilage were included among patients who underwent hip arthroscopy for treatment of FAIS from October 2020 through December 2021. This affected cartilage (dimple-pattern group) and normal cartilage (control group) on the femoral head-neck junction were collected from the same patients and evaluated for histological quantification by Mankin scores and expression of proteins related to cartilage degeneration (eg, matrix metalloproteinase [MMP]-1, MMP-2, MMP-3, MMP-10, and MMP-12, tissue inhibitor of metalloproteinase [TIMP]-1 and TMP-2, aggrecan neopepitope CS846, and hyaluronic acid [HA]) with the use of Milliplex Multiplex Assays. Results: All 6 hips were of the mixed FAI subtype. Preoperatively, 4 of 6 hips had Tönnis grade 1 radiographic changes, which was associated with greater femoral head chondral damage visualized intraoperatively. Mankin scores for the normal cartilage group and the dimple-pattern group were 0.67 ± 0.82 and 3.3 ± 0.82, respectively. Dimple pattern fissured cartilage showed a significant increase in Mankin score (P = .031) and a significant increase in protein expression of CS846 (P = .031) compared with normal cartilage. There were no significant differences in MMPs, TIMPs, or HA levels between the 2 groups. Conclusion: The dimple pattern fissured cartilage, compared to normal cartilage, showed histologically significant cartilage degeneration and a significant increase in protein expression of CS846, a biomarker for early OA. Clinical Relevance: This lesion serves as helpful visual indicator of early degeneration of the cartilage of femoral head-neck junction caused by FAIS.

The importance of species-specific and temperature-sensitive parameterisation of A/Ci models: A case study using cotton (Gossypium hirsutum L.) and the automated 'OptiFitACi' R-package.

Leaf gas exchange measurements are an important tool for inferring a plant's photosynthetic biochemistry. In most cases, the responses of photosynthetic CO2 assimilation to variable intercellular CO2 concentrations (A/Ci response curves) are used to model the maximum (potential) rate of carboxylation by ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco, Vcmax) and the rate of photosynthetic electron transport at a given incident photosynthetically active radiation flux density (PAR; JPAR). The standard Farquhar-von Caemmerer-Berry model is often used with default parameters of Rubisco kinetic values and mesophyll conductance to CO2 (gm) derived from tobacco that may be inapplicable across species. To study the significance of using such parameters for other species, here we measured the temperature responses of key in vitro Rubisco catalytic properties and gm in cotton (Gossypium hirsutum cv. Sicot 71) and derived Vcmax and J2000 (JPAR at 2000 µmol m-2 s-1 PAR) from cotton A/Ci curves incrementally measured at 15°C-40°C using cotton and other species-specific sets of input parameters with our new automated fitting R package 'OptiFitACi'. Notably, parameterisation by a set of tobacco parameters produced unrealistic J2000:Vcmax ratio of <1 at 25°C, two- to three-fold higher estimates of Vcmax above 15°C, up to 2.3-fold higher estimates of J2000 and more variable estimates of Vcmax and J2000, for our cotton data compared to model parameterisation with cotton-derived values. We determined that errors arise when using a gm,25 of 2.3 mol m-2 s-1 MPa-1 or less and Rubisco CO2-affinities in 21% O2 (KC 21%O2) at 25°C outside the range of 46-63 Pa to model A/Ci responses in cotton. We show how the A/Ci modelling capabilities of 'OptiFitACi' serves as a robust, user-friendly, and flexible extension of 'plantecophys' by providing simplified temperature-sensitivity and species-specificity parameterisation capabilities to reduce variability when modelling Vcmax and J2000.

Magnetic Resonance Imaging Approximates Labral Width at the 9-, 12-, and 3-O'Clock Positions in the Setting of Revision Hip Arthroscopy.

PURPOSE: To compare preoperative magnetic resonance imaging (MRI) and intraoperative measurements of labral width and determine whether MRI can reliably predict labral width in the setting of revision surgery. METHODS: Patients who underwent revision hip arthroscopy with labral repair performed by a single surgeon from January 2008 to December 2015 were identified retrospectively from a prospectively collected database. The width of the labrum was measured intraoperatively at the time of surgery. Two orthopaedic surgeons performed labral width measurements on MRI scans at 3 standardized locations using the clock-face method. Interobserver and intraobserver reliabilities were calculated, and comparisons between intraoperatively measured labral widths and MRI measurements were performed. RESULTS: Fifty-eight patients who underwent revision hip arthroscopy were enrolled in the study. The average labral width measurements at the 3-, 12-, and 9-o'clock positions were 7.4 mm (standard deviation [SD], 1.2 mm), 7.5 mm (SD, 1.4 mm), and 6.6 mm (SD, 1.2 mm), respectively, on MRI compared with 6.7 mm (SD, 2.1 mm), 6.5 mm (SD, 2.5 mm), and 7.0 mm (SD, 1.9 mm), respectively, when measured intraoperatively. The average intraoperative measurements were smaller than the MRI measurements at the 3-o'clock (P = .03) and 12-o'clock (P = .01) positions. The inter-rater intraclass correlation coefficients between the 2 surgeons exhibited good agreement (0.612) at the 3-o'clock position, fair agreement (0.498) at the 12-o'clock position, and poor agreement (0.171) at the 9-o'clock position. The positive predictive values of the MRI measurements were 72% at the 3-o'clock position, 68% at the 12-o'clock position, and 88% at the 9-o'clock position for identifying a labral width of 6 mm or greater. CONCLUSIONS: The results of this study show that MRI-measured labral width and actual labral width measured at the time of revision arthroscopy are usually within 1 mm of each other. LEVEL OF EVIDENCE: Level II, diagnostic study investigating diagnostic test.

Improved Functional Outcomes of Combined Hip Arthroscopy and Periacetabular Osteotomy at Minimum 2-Year Follow-Up.

PURPOSE: To evaluate patient-reported outcomes (PROs) and survivorship at minimum 2-year follow-up after combined hip arthroscopy and periacetabular osteotomy (PAO) performed in the setting of a single anesthetic event. METHODS: Patients who underwent combined hip arthroscopy (M.J.P.) and PAO (J.M.M.) between January 2017 and June 2020 were identified. Preoperative and minimum 2-year postoperative PROs including Hip Outcome Score-Activities of Daily Living (HOS-ADL), HOS-Sport, modified Harris Hip Score (mHHS), Western Ontario and McMaster Universities Osteoarthritis Index, 12-Item Short Form Survey Mental Component Scores (SF-12 MCS), and 12-Item Short Form Survey Physical Component Score were collected and compared in addition to revision rate, conversion to total hip arthroplasty (THA), and patient satisfaction. RESULTS: Twenty-four of 29 patients (83%) eligible for the study were available for 2-year minimum follow-up with a median follow-up time of 2.5 years (range, 2.0-5.0). There were 19 females and 5 males with mean age of 31 ± 12 years. Mean preoperative lateral center edge angle was 20° ± 5° and alpha angle was 71° ± 11°. One patient underwent reoperation for removal of a symptomatic iliac crest screw at 11.7 months after operation. Two patients, a 33-year-old woman and a 37-year-old man, were converted to THA at 2.6 and 1.3 years, respectively, following the combined procedure. Both patients had a Tönnis grade of 1 on radiographs, as well as bipolar Outerbridge grade III/IV defects requiring microfracture of the acetabulum. For patients who did not convert to THA (n = 22), there was significant improvement from before to after surgery for all scores (P < .05) except SF-12 MCS. The minimal clinically significant difference and patient-acceptable symptom state rates for HOS-ADL, HOS-Sport, and mHHS were 72%, 82%, 86%, and 95%, 91%, and 95%, respectively. Median patient satisfaction was 10 (range, 4 to 10). CONCLUSIONS: Single-stage combined hip arthroscopy with periacetabular osteotomy for patients with symptomatic hip dysplasia results in improvement in PROs and arthroplasty free survivorship of 92% at median 2.5 year follow-up. LEVEL OF EVIDENCE: Level IV, case series.

LONG-TERM OUTCOMES OF SUTURELESS INTRASCLERAL INTRAOCULAR LENS FIXATION IN CHILDREN AND ADULTS: Single-Surgeon Case Series With and Without Haptic Flanging With Up to 11 Years of Follow-Up.

PURPOSE: Report and compare long-term outcomes and complications of sutureless scleral tunnel (SST) and flanged haptic (FH) scleral-fixated intraocular lens, with spontaneous intraocular lens (IOL) dislocation as primary outcome measure. METHODS: Retrospective single-surgeon case series of 95 SST and 458 FH eyes from 2011 to 2022 (553 total eyes). Demographics, surgical indications, ocular history, visual acuity, and complication rates were collected. RESULTS: Reoperation-requiring spontaneous IOL dislocation rate was significantly different ( P = 0.0167) between FH (3.7%) and SST (10.5%). Mean follow-up was 3.31 ± 0.30 versus 1.58 ± 0.07 years for SST and FH, respectively. There was no significant difference between preoperative (20/305 vs. 20/300) or final postoperative (20/77 vs. 20/62) visual acuity. Other complications included any cystoid macular edema (20.0% vs. 25.3%), elevated intraocular pressure (16.8% vs. 9.6%), IOL tilt requiring reoperation (5.3 vs. 0%), haptic exposure (2.1% vs. 3.3%), and reverse pupillary block (4.2% vs. 1.1%). CONCLUSION: Haptic flanging resulted in fewer eyes meeting the primary end point of IOL dislocation. We reported the longest-to-date follow-up of both nonflanged SST IOL fixation and our FH-modified Yamane technique. Our FH-modified Yamane technique represents a safe, durable, and potentially superior option for scleral-fixated intraocular lens.

Using Academic Consultation-Liaison Telepsychiatry to Meet the Mental Health Needs of Complex, Medically Ill Patients in Underserved Areas: A Case Report.

Background: The nationwide shortage of mental health resources often disproportionately affects rural areas. As innovative strategies are required to address mental health resource shortages in rural areas, telepsychiatry consultation (TPC) may represent a population health-oriented approach to bridge this gap. In this case report, we examine the use of TPC from an academic consultation-liaison psychiatry service to a rural community hospital. Case Report: We describe the case of a woman with Wernicke encephalopathy seeking to leave the hospital against medical advice and the role that the TPC service played in the patient's evaluation and management, including assessing decision-making capacity. Discussion: We then examine benefits and limitations of the service, including a narrative review of the relevant, but limited, available literature as well as suggestions for how the service may be improved and incorporated into psychiatry residency and fellowship training in the future.

Perspectives on improving crop Rubisco by directed evolution.

Rubisco catalyses the entry of almost all CO2 into the biosphere and is often the rate-limiting step in plant photosynthesis and growth. Its notoriety as the most abundant protein on Earth stems from the slow and error-prone catalytic properties that require plants, cyanobacteria, algae and photosynthetic bacteria to produce it in high amounts. Efforts to improve the CO2-fixing properties of plant Rubisco has been spurred on by the discovery of more effective isoforms in some algae with the potential to significantly improve crop productivity. Incompatibilities between the protein folding machinery of leaf and algae chloroplasts have, so far, prevented efforts to transplant these more effective Rubisco variants into plants. There is therefore increasing interest in improving Rubisco catalysis by directed (laboratory) evolution. Here we review the advances being made in, and the ongoing challenges with, improving the solubility and/or carboxylation activity of differing non-plant Rubisco lineages. We provide perspectives on new opportunities for the directed evolution of crop Rubiscos and the existing plant transformation capabilities available to evaluate the extent to which Rubisco activity improvements can benefit agricultural productivity.

High efficiency radio frequency antennas for amplifier free quantum sensing applications.

Radio frequency (RF) signals are frequently used in emerging quantum applications due to their spin state manipulation capability. Efficient coupling of RF signals into a particular quantum system requires the utilization of carefully designed and fabricated antennas. Nitrogen vacancy (NV) defects in diamond are commonly utilized platforms in quantum sensing experiments with the optically detected magnetic resonance (ODMR) method, where an RF antenna is an essential element. We report on the design and fabrication of high efficiency coplanar RF antennas for quantum sensing applications. Single and double ring coplanar RF antennas were designed with -37 dB experimental return loss at 2.87 GHz, the zero-field splitting frequency of the negatively charged NV defect in diamond. The efficiency of both antennas was demonstrated in magnetic field sensing experiments with NV color centers in diamond. An RF amplifier was not needed, and the 0 dB output of a standard RF signal generator was adequate to run the ODMR experiments due to the high efficiency of the RF antennas.

Adhesions in the setting of hip arthroscopy.

With the growing number of primary arthroscopies performed, patients requiring revision hip arthroscopies for various issues is high including postoperative adhesion formation, a source of pain, mechanical symptoms, range of motion limitation, stiffness, and microinstability. Adhesions are a consequence of biological pathways that have been stimulated by injury or surgical interventions leading to an increased healing response. Preventative efforts have included surgical adjuncts during/after primary hip arthroscopy, biologic augmentation, and postoperative rehabilitation. Treatment options for adhesion formation includes surgical lysis of adhesions with or without placement of biologic membranes aimed at inhibiting adhesion reformation as well as systemic medications to further reduce the risk. Postoperative rehabilitation exercises have also been demonstrated to prevent adhesions as a result of hip arthroscopy. Ongoing clinical trials are further investigating pathways and prevention of adhesion formation.

Strategies used for the COVID-OUT decentralized trial of outpatient treatment of SARS-CoV-2.

The COVID-19 pandemic accelerated the development of decentralized clinical trials (DCT). DCT's are an important and pragmatic method for assessing health outcomes yet comprise only a minority of clinical trials, and few published methodologies exist. In this report, we detail the operational components of COVID-OUT, a decentralized, multicenter, quadruple-blinded, randomized trial that rapidly delivered study drugs nation-wide. The trial examined three medications (metformin, ivermectin, and fluvoxamine) as outpatient treatment of SARS-CoV-2 for their effectiveness in preventing severe or long COVID-19. Decentralized strategies included HIPAA-compliant electronic screening and consenting, prepacking investigational product to accelerate delivery after randomization, and remotely confirming participant-reported outcomes. Of the 1417 individuals with the intention-to-treat sample, the remote nature of the study caused an additional 94 participants to not take any doses of study drug. Therefore, 1323 participants were in the modified intention-to-treat sample, which was the a priori primary study sample. Only 1.4% of participants were lost to follow-up. Decentralized strategies facilitated the successful completion of the COVID-OUT trial without any in-person contact by expediting intervention delivery, expanding trial access geographically, limiting contagion exposure, and making it easy for participants to complete follow-up visits. Remotely completed consent and follow-up facilitated enrollment.

Derived faunivores are the forerunners of major synapsid radiations.

Evolutionary radiations generate most of Earth's biodiversity, but are there common ecomorphological traits among the progenitors of radiations? In Synapsida (the mammalian total group), 'small-bodied faunivore' has been hypothesized as the ancestral state of most major radiating clades, but this has not been quantitatively assessed across multiple radiations. To examine macroevolutionary patterns in a phylogenetic context, we generated a time-calibrated metaphylogeny ('metatree') comprising 1,888 synapsid species from the Carboniferous through the Eocene (305-34 Ma) based on 269 published character matrices. We used comparative methods to investigate body size and dietary evolution during successive synapsid radiations. Faunivory is the ancestral dietary regime of each major synapsid radiation, but relatively small body size is only established as the common ancestral state of radiations near the origin of Mammaliaformes in the Late Triassic. The faunivorous ancestors of synapsid radiations typically have numerous novel characters compared with their contemporaries, and these derived traits may have helped them to survive faunal turnover events and subsequently radiate.

A high-throughput structural system biology approach to increase structure representation of proteins from Clostridioides difficile.

Clostridioides difficile causes life-threatening gastrointestinal infections. It is a high-risk pathogen due to a lack of effective treatments, antimicrobial resistance, and a poorly conserved genomic core. Herein, we report 30 X-ray structures from a structure genomics pipeline spanning 13 years, representing 10.2% of the X-ray structures for this important pathogen.

Cep104 is a component of the centriole distal tip complex that regulates centriole growth and contributes to Drosophila spermiogenesis.

Proper centrosome number and function relies on the accurate assembly of centrioles, barrel-shaped structures that form the core duplicating elements of the organelle. The growth of centrioles is regulated in a cell cycle-dependent manner; while new daughter centrioles elongate during the S/G2/M phase, mature mother centrioles maintain their length throughout the cell cycle. Centriole length is controlled by the synchronized growth of the microtubules that ensheathe the centriole barrel. Although proteins exist that target the growing distal tips of centrioles, such as CP110 and Cep97, these proteins are generally thought to suppress centriolar microtubule growth, suggesting that distal tips may also contain unidentified counteracting factors that facilitate microtubule polymerization. Currently, a mechanistic understanding of how distal tip proteins balance microtubule growth and shrinkage to either promote daughter centriole elongation or maintain centriole length is lacking. Using a proximity-labeling screen in Drosophila cells, we identified Cep104 as a novel component of a group of evolutionarily conserved proteins that we collectively refer to as the distal tip complex (DTC). We found that Cep104 regulates centriole growth and promotes centriole elongation through its microtubule-binding TOG domain. Furthermore, analysis of Cep104 null flies revealed that Cep104 and Cep97 cooperate during spermiogenesis to align spermatids and coordinate individualization. Lastly, we mapped the complete DTC interactome and showed that Cep97 is the central scaffolding unit required to recruit DTC components to the distal tip of centrioles.

Retrospective study of testosterone deficiency and symptom burden in patients with pancreatic cancer.

Background: Pancreatic cancer patients have poor quality of life. Testosterone deficiency is associated with constitutional symptoms and sexual dysfunction which may contribute to poor quality of life. We investigated the prevalence of screening for and presence of testosterone deficiency in male pancreatic cancer patients. Methods: To determine the frequency of screening for testosterone deficiency in pancreatic cancer patients, our institution's electronic medical record system was queried for male patients diagnosed with a pancreatic mass between 2006 and 2020 and an available testosterone level. In a separate analysis, total testosterone was measured in serum samples from a cohort of 89 male pancreatic ductal adenocarcinoma (PDAC) patients. Low serum testosterone was defined as <300 ng/dL. Results: One thousand five hundred and sixty-six male patients were identified with a pancreatic mass, and 35 (2.2%) also had a testosterone level. In our analysis cohort, 44 of 89 patients (49.4%) were found to have low serum testosterone. Symptoms consistent with testosterone deficiency were documented for 70% of these patients, with fatigue being the most common. Testosterone level had no significant association with progression-free survival (PFS) (P=0.66) or overall survival (OS) (P=0.95). Conclusions: Testosterone deficiency is common but rarely assessed in male patients with pancreatic cancer. Further studies are warranted to explore the possibility of testosterone supplementation to improve quality of life in this patient population.