A randomized double-blinded trial to assess recurrence of systemic allergic reactions following COVID-19 mRNA vaccination.

BACKGROUND: Systemic allergic reactions (sARs) following coronavirus disease 2019 (COVID-19) mRNA vaccines were initially reported at a higher rate than after traditional vaccines. OBJECTIVE: We aimed to evaluate the safety of revaccination in these individuals and to interrogate mechanisms underlying these reactions. METHODS: In this randomized, double-blinded, phase 2 trial, participants aged 16 to 69 years who previously reported a convincing sAR to their first dose of COVID-19 mRNA vaccine were randomly assigned to receive a second dose of BNT162b2 (Comirnaty) vaccine and placebo on consecutive days in a blinded, 1:1 crossover fashion at the National Institutes of Health. An open-label BNT162b2 booster was offered 5 months later if the second dose did not result in severe sAR. None of the participants received the mRNA-1273 (Spikevax) vaccine during the study. The primary end point was recurrence of sAR following second dose and booster vaccination; exploratory end points included biomarker measurements. RESULTS: Of 111 screened participants, 18 were randomly assigned to receive study interventions. Eight received BNT162b2 second dose followed by placebo; 8 received placebo followed by BNT162b2 second dose; 2 withdrew before receiving any study intervention. All 16 participants received the booster dose. Following second dose and booster vaccination, sARs recurred in 2 participants (12.5%; 95% CI, 1.6 to 38.3). No sAR occurred after placebo. An anaphylaxis mimic, immunization stress-related response (ISRR), occurred more commonly than sARs following both vaccine and placebo and was associated with higher predose anxiety scores, paresthesias, and distinct vital sign and biomarker changes. CONCLUSIONS: Our findings support revaccination of individuals who report sARs to COVID-19 mRNA vaccines. Distinct clinical and laboratory features may distinguish sARs from ISRRs.

Hexavalent sperm-binding IgG antibody released from vaginal film for development of potent on-demand nonhormonal female contraception.

Nonhormonal products for on-demand contraception are a global health technology gap; this unmet need motivated us to pursue the use of sperm-binding monoclonal antibodies to enable effective on-demand contraception. Here, using the cGMP-compliant Nicotiana-expression system, we produced an ultrapotent sperm-binding IgG antibody possessing 6 Fab arms per molecule that bind a well-established contraceptive antigen target, CD52g. We term this hexavalent antibody "Fab-IgG-Fab" (FIF). The Nicotiana-produced FIF had at least 10-fold greater sperm-agglutination potency and kinetics than the parent IgG, while preserving Fc-mediated trapping of individual spermatozoa in mucus. We formulated the Nicotiana-produced FIF into a polyvinyl alcohol-based water-soluble contraceptive film and evaluated its potency in reducing progressively motile sperm in the sheep vagina. Two minutes after vaginal instillation of human semen, no progressively motile sperm were recovered from the vaginas of sheep receiving FIF Film. Our work supports the potential of multivalent contraceptive antibodies to provide safe, effective, on-demand nonhormonal contraception.

Water and Air Stable Copper(I) Complexes of Tetracationic Catenane Ligands for Oxidative C-C Cross-Coupling.

Aqueous soluble and stable Cu(I) molecular catalysts featuring a catenane ligand composed of two dicationic, mutually repelling but mechanically interlocked macrocycles are reported. The ligand interlocking not only fine-tunes the coordination sphere and kinetically stabilizes the Cu(I) against air oxidation and disproportionation, but also buries the hydrophobic portions of the ligands and prevents their dissociation which are necessary for their good water solubility and a sustained activity. These catenane Cu(I) complexes can catalyze the oxidative C-C coupling of indoles and tetrahydroisoquinolines in water, using H2O2 as a green oxidant with a good substrate scope. The successful use of catenane ligands in exploiting aqueous Cu(I) catalysis thus highlights the many unexplored potential of mechanical bond as a design element for exploring transition metal catalysis under challenging conditions.

Mechanical Interlocking Enhances the Electrocatalytic Oxygen Reduction Activity and Selectivity of Molecular Copper Complexes.

Efficient O2 reduction reaction (ORR) for selective H2O generation enables advanced fuel cell technology. Nonprecious metal catalysts are viable and attractive alternatives to state-of-the-art Pt-based materials that are expensive. Cu complexes inspired by Cu-containing O2 reduction enzymes in nature are yet to reach their desired ORR catalytic performance. Here, the concept of mechanical interlocking is introduced to the ligand architecture to enforce dynamic spatial restriction on the Cu coordination site. Interlocked catenane ligands could govern O2 binding mode, promote electron transfer, and facilitate product elimination. Our results show that ligand interlocking as a catenane steers the ORR selectivity to H2O as the major product via the 4e- pathway, rivaling the selectivity of Pt, and boosts the onset potential by 130 mV, the mass activity by 1.8 times, and the turnover frequency by 1.5 fold as compared to the noninterlocked counterpart. Our Cu catenane complex represents one of the first examples to take advantage of mechanical interlocking to afford electrocatalysts with enhanced activity and selectivity. The mechanistic insights gained through this integrated experimental and theoretical study are envisioned to be valuable not just to the area of ORR energy catalysis but also with broad implications on interlocked metal complexes that are of critical importance to the general fields in redox reactions involving proton-coupled electron transfer steps.

Modeling identifies variability in SARS-CoV-2 uptake and eclipse phase by infected cells as principal drivers of extreme variability in nasal viral load in the 48 h post infection.

The SARS-CoV-2 coronavirus continues to evolve with scores of mutations of the spike, membrane, envelope, and nucleocapsid structural proteins that impact pathogenesis. Infection data from nasal swabs, nasal PCR assays, upper respiratory samples, ex vivo cell cultures and nasal epithelial organoids reveal extreme variabilities in SARS-CoV-2 RNA titers within and between the variants. Some variabilities are naturally prone to clinical testing protocols and experimental controls. Here we focus on nasal viral load sensitivity arising from the timing of sample collection relative to onset of infection and from heterogeneity in the kinetics of cellular infection, uptake, replication, and shedding of viral RNA copies. The sources of between-variant variability are likely due to SARS-CoV-2 structural protein mutations, whereas within-variant population variability is likely due to heterogeneity in cellular response to that particular variant. With the physiologically faithful, agent-based mechanistic model of inhaled exposure and infection from (Chen et al., 2022), we perform statistical sensitivity analyses of the progression of nasal viral titers in the first 0-48 h post infection, focusing on three kinetic mechanisms. Model simulations reveal shorter latency times of infected cells (including cellular uptake, viral RNA replication, until the onset of viral RNA shedding) exponentially accelerate nasal viral load. Further, the rate of infectious RNA copies shed per day has a proportional influence on nasal viral load. Finally, there is a very weak, negative correlation of viral load with the probability of infection per virus-cell encounter, the model proxy for spike-receptor binding affinity.

Improved Survival After Adjuvant Therapy in Locally Advanced Rectal Cancer Patients With Pathologic Complete Response.

BACKGROUND: The benefit of adjuvant therapy is unclear in patients with rectal cancer achieving a pathologic complete response after neoadjuvant chemoradiotherapy and total mesorectal excision. OBJECTIVE: This study aimed to assess the benefit of adjuvant chemotherapy on survival among rectal cancer patients with a pathologic complete response after neoadjuvant chemoradiation. DESIGN: Retrospective cohort study. SETTING: National Cancer Database (2004-2017). PATIENTS: Patients with clinical stage 2 or 3 rectal adenocarcinoma who underwent neoadjuvant chemoradiation (50-50.4 Gy in 25-28 fractions) followed by total mesorectal excision with a pathologic complete response were included. INTERVENTION: Adjuvant chemotherapy. MAIN OUTCOME MEASURES: Overall survival. RESULTS: There were 20,518 patients and 2221 (11%) had a pathologic complete response after neoadjuvant chemoradiation. Of 2221 patients, 1441 (65%) did not receive adjuvant therapy and 780 (35%) did. Patients who received adjuvant therapy were more likely to be younger (median 58 vs 62 y), have private insurance (61% vs 49%), and have node-positive disease (57% vs 48%) (all p < 0.05). There were no differences in sex, race, Charlson-Deyo score, clinical T-stage, tumor size and differentiation, adequate lymphadenectomy (12 or more), or sphincter preservation between groups (all p > 0.05). Overall survival at 5, 10, and 14 years was significantly longer in the adjuvant group (93%, 85%, 83%, respectively) compared to patients who did not receive adjuvant therapy (87%, 67%, 51%, respectively) ( p < 0.001). In a subgroup analysis, adjuvant therapy was associated with improved survival in patients with clinical stage 2 and 3 rectal cancer ( p < 0.001). After adjusting for patient and tumor characteristics, omission of adjuvant chemotherapy was associated with significantly worse survival (HR 1.53, 95% 1.08-2.16). LIMITATIONS: Selection bias, unknown perioperative morbidity, chemotherapy regimen, recurrence status, and other unidentified factors limiting survival analysis. CONCLUSIONS: In patients with clinical stage 2 or 3 rectal cancer, adjuvant chemotherapy was associated with improved overall survival in patients achieving a pathological complete response after neoadjuvant chemoradiotherapy. See Video Abstract at http://links.lww.com/DCR/C139 . SOBREVIDA MEJORADA DESPUS DE LA TERAPIA ADYUVANTE EN PACIENTES CON CNCER DE RECTO LOCALMENTE AVANZADO CON RESPUESTA PATOLGICA COMPLETA: ANTECEDENTES:En los pacientes con cáncer de recto que logran una respuesta patológica completa después de la quimiorradioterapia neoadyuvante y la escisión total del mesorrecto, el beneficio de la terapia adyuvante no está claro.OBJETIVO:Evaluar el beneficio de la quimioterapia adyuvante en la sobrevida de los pacientes con cáncer de recto con una respuesta patológica completa después de la quimiorradioterapia neoadyuvante.DISEÑO:Estudio de cohorte retrospectivo.ESCENARIO:Base de Datos Nacional de Cáncer (2004-2017).PACIENTES:Pacientes con adenocarcinoma rectal en estadio clínico 2 ó 3 que se sometieron a quimiorradiación neoadyuvante (50-50,4 Gy en 25-28 fracciones) seguida de escisión mesorrectal total con una respuesta patológica completa.INTERVENCIÓN:Quimioterapia adyuvante.PRINCIPALES MEDIDAS DE RESULTADO:Sobrevida global.RESULTADOS:Hubo 20.518 pacientes y 2.221 (11%) tuvieron una respuesta patológica completa después de la quimiorradiación neoadyuvante. Entre estos 2221 pacientes, 1441 (65%) no recibieron terapia adyuvante y 780 (35%) sí. Los pacientes que recibieron terapia adyuvante tenían más probabilidades de ser más jóvenes (mediana de 58 frente a 62 años), tener un seguro privado (61% frente a 49%) y tener enfermedad con linfonodos positivos (57% frente a 48 %) (todos p < 0,05). No hubo diferencias en género, raza, puntuación de Charlson-Deyo, estadio T clínico, tamaño y diferenciación del tumor, linfadenectomía adecuada (≥12) o preservación del esfínter entre los grupos (todos p > 0,05). La sobrevida general a los 5, 10 y 14 años fue significativamente mayor en el grupo adyuvante (93%, 85%, 83%, respectivamente) en comparación con los pacientes que no recibieron terapia adyuvante (87%, 67%, 51% respectivamente) ( p < 0,001). En un análisis de subgrupos, la terapia adyuvante se asoció con una mejor sobrevida general en pacientes con cáncer de recto en estadio clínico 2 y 3 ( p < 0,001). Después de ajustar por las características del paciente y del tumor, la omisión de la quimioterapia adyuvante se asoció con una sobrevida global significativamente peor (HR 1,53, IC del 95%, 1,08-2,16).LIMITACIONES:Sesgo de selección; morbilidad perioperatoria desconocida, régimen de quimioterapia, estado de recurrencia y otros factores no identificados que limitan el análisis de sobrevida.CONCLUSIONES:En pacientes con cáncer de recto en estadio clínico 2 ó 3, la quimioterapia adyuvante se asoció con una mejor sobrevida general en pacientes que lograron una respuesta patológica completa después de la quimiorradioterapia neoadyuvante. Consulte Video Resumen en http://links.lww.com/DCR/C139 . (Traducción-Dr. Felipe Bellolio ).

Rectal Cancer: Clinical and Molecular Predictors of a Complete Response to Total Neoadjuvant Therapy.

BACKGROUND: Total neoadjuvant therapy in rectal cancer may increase pathological complete response rates, potentially allowing for a nonoperative approach. OBJECTIVE: The objective of this study was to identify patient and tumor characteristics that predict a complete response following total neoadjuvant therapy. DESIGN: This was a retrospective cohort study. SETTINGS: This study was conducted at a university-based National Cancer Institute-designated Comprehensive Cancer Center. PATIENTS: The patients include those with stage 2 or 3 rectal adenocarcinoma. INTERVENTIONS: Interventions included total neoadjuvant therapy, total mesorectal excision, and nonoperative management. MAIN OUTCOME MEASURES: Complete response was defined as either patients with a clinical complete response undergoing nonoperative management who remained cancer-free or patients undergoing surgery with a pathological complete response. RESULTS: Among 102 patients, median age was 54 years, 69% were male, median carcinoembryonic antigen level was 3.0 ng/mL, and the median distance of the tumor above the anorectal ring was 3 cm. Thirty-eight (37%) patients had a complete response, including 15 of 18 (83%) nonoperative patients who remained cancer free at a median of 22 months (range, 7-48 months) and 23 of 84 (27%) patients who underwent surgery and had a pathological complete response. The incomplete response group consisted of 61 patients who underwent initial surgery and 3 nonoperative patients with regrowth. There were no differences in gender, T-stage, or tumor location between groups. Younger age (median, 49 vs 55 years), normal carcinoembryonic antigen (71% vs 41%), clinical node-negative (24% vs 9%), smaller tumors (median 3.9 vs 5.4 cm), and wild-type p53 (79% vs 47%) and SMAD4 (100% vs 81%) were more likely to have a complete response (all p < 0.05). LIMITATIONS: This was a retrospective study with a small sample size. CONCLUSIONS: In patients with rectal cancer treated with total neoadjuvant therapy, more than one-third will achieve a pathological complete response or sustained clinical complete response with nonoperative management, making oncological resection superfluous in these patients. Smaller, wild-type p53 and SMAD4, and clinically node-negative cancers are predictive features of a complete response. See Video Abstract at http://links.lww.com/DCR/B889 . CNCER DE RECTO PREDICTORES CLNICOS Y MOLECULARES DE UNA RESPUESTA COMPLETA A LA TERAPIA NEOADYUVANTE TOTAL: ANTECEDENTES:La terapia neoadyuvante total en el cáncer de recto puede aumentar las tasas de respuesta patológica completa y permitir potencialmente un enfoque no quirúrgico.OBJETIVO:El objetivo fue identificar las características tanto del paciente y del tumor que logren predecir una respuesta completa después de la terapia neoadyuvante total.DISEÑO:Este fue un estudio de cohorte retrospectivo.AJUSTES:Este estudio se realizó en un Centro Integral de Cáncer designado por el Instituto Nacional del Cáncer con sede universitaria.PACIENTES:Los pacientes incluyen aquellos con adenocarcinoma de recto en estadio 2 o 3.INTERVENCIONES:Terapia neoadyuvante total, escisión total del mesorrecto, manejo conservador no quirúrgico.PRINCIPALES MEDIDAS DE RESULTADO:La respuesta completa se definió como pacientes con una respuesta clínica completa sometidos a tratamiento no quirúrgico que permanecieron libres de cáncer o pacientes sometidos a cirugía con una respuesta patológica completa.RESULTADOS:Entre 102 pacientes, la mediana de edad fue de 54 años, el 69% fueron hombres, la mediana del nivel de antígeno carcinoembrionario fue de 3.0 ng/ml y la mediana de la distancia del tumor por encima del anillo anorrectal fue de 3 cm. Thirty-eight (37%) pacientes tuvieron una respuesta completa que incluyó a 15 de 18 (83%) pacientes con manejo no operatorio y que permanecieron libres de cáncer en una mediana de 22 meses (rango 7- 48 meses) y 23 de 84 (27%) pacientes que fueron sometidos a cirugía y tuvieron una respuesta patológica completa. El grupo de respuesta incompleta consistió en 61 pacientes que fueron sometidos inicialmente a cirugía y 3 pacientes no quirúrgicos con recrecimiento. No se encontró diferencias de género, estadio T o ubicación del tumor entre los grupos. Edad más joven (mediana 49 frente a 55), antígeno carcinoembrionario normal (71% frente a 41%), ganglios clínicos negativos (24% frente a 9%), tumores más pequeños (mediana de 3,9 frente a 5,4 cm) y p53 de tipo salvaje (79 % vs 47%) y SMAD4 (100% vs 81%) tenían más probabilidades de tener una respuesta completa (todos p < 0,05).LIMITACIONES:Este fue un estudio retrospectivo y con un tamaño de muestra pequeño.CONCLUSIONES:En pacientes con cáncer de recto tratados con terapia neoadyuvante total, más de un tercio logrará una respuesta patológica completa o una respuesta clínica completa sostenida con manejo no operatorio, logrando que la resección oncológica sea superflua en estos pacientes. Los cánceres más pequeños, clínicamente con ganglios negativos, con p53 de tipo salvaje y SMAD4, son características predictoras de una respuesta completa. Consulte Video Resumen en http://links.lww.com/DCR/B889 . (Traducción-Dr. Osvaldo Gauto ).

Modeling insights into SARS-CoV-2 respiratory tract infections prior to immune protection.

Mechanistic insights into human respiratory tract (RT) infections from SARS-CoV-2 can inform public awareness as well as guide medical prevention and treatment for COVID-19 disease. Yet the complexity of the RT and the inability to access diverse regions pose fundamental roadblocks to evaluation of potential mechanisms for the onset and progression of infection (and transmission). We present a model that incorporates detailed RT anatomy and physiology, including airway geometry, physical dimensions, thicknesses of airway surface liquids (ASLs), and mucus layer transport by cilia. The model further incorporates SARS-CoV-2 diffusivity in ASLs and best-known data for epithelial cell infection probabilities, and, once infected, duration of eclipse and replication phases, and replication rate of infectious virions. We apply this baseline model in the absence of immune protection to explore immediate, short-term outcomes from novel SARS-CoV-2 depositions onto the air-ASL interface. For each RT location, we compute probability to clear versus infect; per infected cell, we compute dynamics of viral load and cell infection. Results reveal that nasal infections are highly likely within 1-2 days from minimal exposure, and alveolar pneumonia occurs only if infectious virions are deposited directly into alveolar ducts and sacs, not via retrograde propagation to the deep lung. Furthermore, to infect just 1% of the 140 m2 of alveolar surface area within 1 week, either 103 boluses each with 106 infectious virions or 106 aerosols with one infectious virion, all physically separated, must be directly deposited. These results strongly suggest that COVID-19 disease occurs in stages: a nasal/upper RT infection, followed by self-transmission of infection to the deep lung. Two mechanisms of self-transmission are persistent aspiration of infected nasal boluses that drain to the deep lung and repeated rupture of nasal aerosols from infected mucosal membranes by speaking, singing, or cheering that are partially inhaled, exhaled, and re-inhaled, to the deep lung.

The cervicovaginal mucus barrier to HIV-1 is diminished in bacterial vaginosis.

Bacterial vaginosis (BV), a condition in which the vaginal microbiota consists of community of obligate and facultative anaerobes rather than dominated by a single species of Lactobacillus, affects ~30% of women in the US. Women with BV are at 60% increased risk for HIV acquisition and are 3-times more likely to transmit HIV to an uninfected partner. As cervicovaginal mucus (CVM) is the first line of defense against mucosal pathogens and the home of the resident vaginal microbiota, we hypothesized the barrier function of CVM to HIV may be diminished in BV. Here, we characterized CVM properties including pH, lactic acid content, and Nugent score to correlate with the microbiota community composition, which was confirmed by 16S rDNA sequencing on a subset of samples. We then quantified the mobility of fluorescently-labeled HIV virions and nanoparticles to characterize the structural and adhesive barrier properties of CVM. Our analyses included women with Nugent scores categorized as intermediate (4-6) and BV (7-10), women that were either symptomatic or asymptomatic, and a small group of women before and after antibiotic treatment for symptomatic BV. Overall, we found that HIV virions had significantly increased mobility in CVM from women with BV compared to CVM from women with Lactobacillus crispatus-dominant microbiota, regardless of whether symptoms were present. We confirmed using nanoparticles and scanning electron microscopy that the impaired barrier function was due to reduced adhesive barrier properties without an obvious degradation of the physical CVM pore structure. We further confirmed a similar increase in HIV mobility in CVM from women with Lactobacillus iners-dominant microbiota, the species most associated with transitions to BV and that persists after antibiotic treatment for BV. Our findings advance the understanding of the protective role of mucus and highlight the interplay between vaginal microbiota and the innate barrier function mucus.

Critical appraisal of the contemporary use of atherectomy to treat femoropopliteal atherosclerotic disease.

OBJECTIVE: Atherectomy has become increasingly used as an endovascular treatment of lower extremity atherosclerotic disease in the United States. However, concerns and controversies about its indications and outcomes exist. The goal of the present systematic review and meta-analysis was to investigate the outcomes and complications related to atherectomy to treat femoropopliteal atherosclerotic disease. METHODS: A systematic review in accordance with the recommendations from the PRISMA (preferred reporting items for systematic reviews and meta-analyses) statement was performed. Four major scientific repositories (MEDLINE, Embase, the Cochrane Library, and Thompson Web of Sciences) were queried from their inception to April 5, 2020. We reviewed and entered the data in a dedicated dataset. The outcomes included the patency rates, clinical and hemodynamic improvement, and morbidity and mortality associated with atherectomy interventions. RESULTS: Twenty-four studies encompassing 1900 patients met the inclusion criteria for the present study. Of the 1900 patients, 74.3% had presented with Rutherford class 1 to 3 and 25.7% presented with Rutherford class 4 to 6; 1445 patients had undergone atherectomy, and 455 patients had been treated without atherectomy. The atherectomy group had undergone directional atherectomy (n = 851), rotational atherectomy (n = 851), laser atherectomy (n = 201), and orbital atherectomy (n = 78). Most of these patients had also received adjunct treatments, which varied across the studies and included a combination of stenting, balloon angioplasty, or drug-coated balloon angioplasty. Technical success was achieved in 92.3% of the cases. Distal embolization, vessel perforation, and dissection occurred in 3.4%, 1.9%, and 4% of the cases, respectively. The initial patency was 95.4%. At the 12-month median follow-up, the primary patency was 72.6%. The ankle brachial index had improved from a preoperative mean of 0.6 to a postoperative mean of 0.84. The incidence of major amputation and mortality during the follow-up period was 2.2% and 3.4%, respectively. CONCLUSIONS: The results from our review of the reported data suggest that femoropopliteal atherectomy can be completed safely, modestly improving the ankle brachial index and maintaining the 1-year patency in nearly three of four patients. However, these findings were based on heterogeneous studies that skewed the generalizable conclusions about atherectomy's efficacy. Atherectomy places a high cost burden on the healthcare system and is used in the United States at a higher rate than in other countries. Our review of the literature did not demonstrate clear atherectomy superiority to alternatives that would warrant the pervasive and increasing use of this costly technology. Future work should focus on developing high-quality randomized controlled trials to determine the specific patient and lesion characteristics for which atherectomy can add value.

Macrocycle Dynamics in a Branched [8]Catenane Controlled by Three Different Stimuli in Three Different Regions.

A branched [8]catenane from an efficient one-pot synthesis (72 % HPLC yield, 59 % isolated yield) featuring the simultaneous use of three kinds of templates and cucurbit[6]uril-mediated azide-alkyne cycloaddition (CBAAC) for ring-closing is reported. Design and assembly of the [8]catenane precursors are unexpectedly complex that can involve cooperating, competing and non-influencing interactions. Due to the branched structure, dynamics of the [8]catenane can be modulated in different extent by rigidifying/loosening the mechanical bonds at different regions by using solvent polarity, acid-base and metal ions as the stimuli. This work not only highlights the importance of understanding the delicate interplay of the weak and non-obvious supramolecular interactions in the synthesis of high-order [n]catenane, but also demonstrates a complex control of dynamics and flexibility for exploiting [n]catenanes applications.

Effect of commercial wearables and digital behaviour change resources on the physical activity of adolescents attending schools in socio-economically disadvantaged areas: the RAW-PA cluster-randomised controlled trial.

BACKGROUND: There has been increasing interest in using wearable activity trackers to promote physical activity in youth. This study examined the short- and longer-term effects of a wearable activity tracker combined with digital behaviour change resources on the physical activity of adolescents attending schools in socio-economically disadvantaged areas. METHODS: The Raising Awareness of Physical Activity (RAW-PA) Study was a 12-week, multicomponent intervention that combined a Fitbit Flex (and accompanying app), and online digital behaviour change resources and weekly challenges delivered via Facebook. RAW-PA was evaluated using a cluster-randomised controlled trial with 275 adolescents (50.2% female; 13.7 ± 0.4 years) from 18 Melbourne secondary schools (intervention n = 9; wait-list control group n = 9). The primary outcome was moderate- to vigorous-intensity physical activity (MVPA), measured using hip-worn ActiGraph accelerometers. The secondary outcome was self-reported physical activity. Data were collected at baseline, 12-weeks (immediately post-intervention), and 6-months post-intervention (follow-up). Multilevel models were used to determine the effects of the intervention on daily MVPA over time, adjusting for covariates. RESULTS: No significant differences were observed between intervention and wait-list control adolescents' device-assessed MVPA immediately post-intervention. At 6-months post-intervention, adolescents in the intervention group engaged in 5 min (95% CI: - 9.1 to - 1.0) less MVPA per day than those in the wait-list control group. Males in the intervention group engaged in 11 min (95% CI: - 17.6 to - 4.5) less MVPA than males in the wait-list control group at 6-months post-intervention. No significant differences were observed for females at either time point. For self-reported physical activity, no significant effects were found at 12-weeks and 6-months post-intervention. CONCLUSIONS: Combining a wearable activity tracker with digital behaviour change resources and weekly challenges did not increase inactive adolescents' accelerometer-derived and self-reported physical activity levels immediately post-intervention. This contrasts previous research that has suggested wearable activity tracker may increase youth physical activity levels in the short-term. Lower engagement in MVPA 6-months post-intervention was observed for males but not for females, though it is unclear why this finding was observed. The results suggest wearable activity trackers, in combination with supporting materials, may not be effective for increasing physical activity levels in adolescents. TRIAL REGISTRATION: ACTRN12616000899448 . Australian and New Zealand Clinical Trials Registry. Registered 7 July 2016.

Diagnosis and Management of Colonic Volvulus.

CASE SUMMARY: An 88-year-old man with no significant medical history, and in a good state of health, presented to the emergency department with 4 days of obstipation, progressive abdominal pain, and bloating. Examination revealed abdominal distension and generalized tenderness without signs of peritonitis. Laboratory values, including lactate and complete blood count, were within normal limits. Computed tomography imaging of the abdomen and pelvis revealed radiological signs of sigmoid volvulus and no evidence of bowel perforation (Fig. 1). Flexible sigmoidoscopic examination revealed no evidence of mucosal ischemia and enabled detorsion of the colon. The patient's symptoms resolved after the detorsion. He was seen in consultation by a surgeon who advised surgical treatment only if the volvulus recurred. After hospital discharge, the patient self-educated about sigmoid volvulus and sought a second surgical opinion. Five weeks after his initial presentation and 1 week after complete colonoscopy, he underwent laparoscopic sigmoidectomy with colorectal anastomosis. His postoperative course was uneventful. At 6-month follow-up, he remained well with no bowel-related concerns.

Experimental Data and PBPK Modeling Quantify Antibody Interference in PEGylated Drug Carrier Delivery.

Physiologically-based pharmacokinetic (PBPK) modeling is a popular drug development tool that integrates physiology, drug physicochemical properties, preclinical data, and clinical information to predict drug systemic disposition. Since PBPK models seek to capture complex physiology, parameter uncertainty and variability is a prevailing challenge: there are often more compartments (e.g., organs, each with drug flux and retention mechanisms, and associated model parameters) than can be simultaneously measured. To improve the fidelity of PBPK modeling, one approach is to search and optimize within the high-dimensional model parameter space, based on experimental time-series measurements of drug distributions. Here, we employ Latin Hypercube Sampling (LHS) on a PBPK model of PEG-liposomes (PL) that tracks biodistribution in an 8-compartment mouse circulatory system, in the presence (APA+) or absence (naïve) of anti-PEG antibodies (APA). Near-continuous experimental measurements of PL concentration during the first hour post-injection from the liver, spleen, kidney, muscle, lung, and blood plasma, based on PET/CT imaging in live mice, are used as truth sets with LHS to infer optimal parameter ranges for the full PBPK model. The data and model quantify that PL retention in the liver is the primary differentiator of biodistribution patterns in naïve versus APA+ mice, and spleen the secondary differentiator. Retention of PEGylated nanomedicines is substantially amplified in APA+ mice, likely due to PL-bound APA engaging specific receptors in the liver and spleen that bind antibody Fc domains. Our work illustrates how applying LHS to PBPK models can further mechanistic understanding of the biodistribution and antibody-mediated clearance of specific drugs.

Convolutional neural networks automate detection for tracking of submicron-scale particles in 2D and 3D.

Particle tracking is a powerful biophysical tool that requires conversion of large video files into position time series, i.e., traces of the species of interest for data analysis. Current tracking methods, based on a limited set of input parameters to identify bright objects, are ill-equipped to handle the spectrum of spatiotemporal heterogeneity and poor signal-to-noise ratios typically presented by submicron species in complex biological environments. Extensive user involvement is frequently necessary to optimize and execute tracking methods, which is not only inefficient but introduces user bias. To develop a fully automated tracking method, we developed a convolutional neural network for particle localization from image data, comprising over 6,000 parameters, and used machine learning techniques to train the network on a diverse portfolio of video conditions. The neural network tracker provides unprecedented automation and accuracy, with exceptionally low false positive and false negative rates on both 2D and 3D simulated videos and 2D experimental videos of difficult-to-track species.

Engineering monoclonal antibody-based contraception and multipurpose prevention technologies†.

Sexually transmitted infections are highly prevalent, and over 40% of pregnancies are unplanned. We are producing new antibody-based multipurpose prevention technology products to address these problems and fill an unmet need in female reproductive health. We used a Nicotiana platform to manufacture monoclonal antibodies against two prevalent sexually transmitted pathogens, HIV-1 and HSV-2, and incorporated them into a vaginal film (MB66) for preclinical and Phase 1 clinical testing. These tests are now complete and indicate that MB66 is effective and safe in women. We are now developing an antisperm monoclonal antibody to add contraceptive efficacy to this product. The antisperm antibody, H6-3C4, originally isolated by Shinzo Isojima from the blood of an infertile woman, recognizes a carbohydrate epitope on CD52g, a glycosylphosphatidylinositol-anchored glycoprotein found in abundance on the surface of human sperm. We engineered the antibody for production in Nicotiana; the new antibody which we call "human contraception antibody," effectively agglutinates sperm at concentrations >10 µg/ml and maintains activity under a variety of physiological conditions. We are currently seeking regulatory approval for a Phase 1 clinical trial, which will include safety and "proof of principle" efficacy endpoints. Concurrently, we are working with new antibody production platforms to bring the costs down, innovative antibody designs that may produce more effective second-generation antibodies, and delivery systems to provide extended protection.

Outcomes of atherectomy for lower extremity ischemia in an office endovascular center.

OBJECTIVE: To evaluate the safety and effectiveness of infrainguinal artery revascularization via atherectomy supplemented with other endovascular techniques in an office endovascular center (OEC) setting. METHODS: A retrospective study was conducted examining 352 lower extremity atherectomy revascularization procedures between 2011 and 2016 at an OEC by five board-certified vascular surgeons. Patients received laser atherectomy or orbital atherectomy followed by angioplasty or angioplasty and stent placement as needed. Reintervention was indicated based on evidence of clinical symptoms and imaging studies. Demographics, vessel-specific data, treatment information, and outcome of procedures were recorded. Data analysis was carried out using Kaplan-Meier survival curves. RESULTS: Lower extremity atherectomy was carried out in 282 patients in 352 limbs with average age of 69 ± 11 years. Technical success of <30% residual stenosis by angiogram was achieved in 571/594 vessels treated. Within 30 days of procedure, 23/352 limbs required major amputation resulting from pre-existing disease, ranging from 3 Rutherford class 4, 17 Rutherford class 5, to 3 Rutherford class 6 limbs. No 30-day mortality was noted. The primary patency of the 571 treated vessels at 12 months was 90%, and 84% at 29 months. The patency of treated vessels that reached >50% stenosis on follow-up and required reintervention (51/571 vessels) or did not require reintervention (79/571) was 72% and 87% at 23 months' follow-up, respectively, with no difference in risk of occlusion identified (P = .181). There was a significantly increased risk of occlusion for vessels treated with laser atherectomy as compared with orbital atherectomy (odds ratio, 2.552; 95% confidence interval, 1.375-4.735; P = .003). No significant difference in risk of occlusion was found between treatment with atherectomy and angioplasty (466/571 vessels) compared with atherectomy, angioplasty, and stenting (102/571) with secondary patency of 90% and 85% at 6 months' follow-up, respectively. There was no difference in patency between claudicants and patients with critical limb ischemia. CONCLUSIONS: Atherectomy in conjunction with angioplasty and/or stenting has satisfactory patency with minimal complications when the procedure is carried out in an OEC. Asymptomatic >50% restenosis of treated vessels does not warrant reintervention unless the patient presents with clinical symptoms. Various atherectomy devices may result in different outcomes.

Using the Technology Acceptance Model to Explore Adolescents' Perspectives on Combining Technologies for Physical Activity Promotion Within an Intervention: Usability Study.

BACKGROUND: Wearable activity trackers and social media have been identified as having the potential to increase physical activity among adolescents, yet little is known about the perceived ease of use and perceived usefulness of the technology by adolescents. OBJECTIVE: The aim of this study was to use the technology acceptance model to explore adolescents' acceptance of wearable activity trackers used in combination with social media within a physical activity intervention. METHODS: The Raising Awareness of Physical Activity study was a 12-week physical activity intervention that combined a wearable activity tracker (Fitbit Flex) with supporting digital materials that were delivered using social media (Facebook). A total of 124 adolescents aged 13 to 14 years randomized to the intervention group (9 schools) participated in focus groups immediately post intervention. Focus groups explored adolescents' perspectives of the intervention and were analyzed using pen profiles using a coding framework based on the technology acceptance model. RESULTS: Adolescents reported that Fitbit Flex was useful as it motivated them to be active and provided feedback about their physical activity levels. However, adolescents typically reported that Fitbit Flex required effort to use, which negatively impacted on their perceived ease of use. Similarly, Facebook was considered to be a useful platform for delivering intervention content. However, adolescents generally noted preferences for using alternative social media websites, which may have impacted on negative perceptions concerning Facebook's ease of use. Perceptions of technological risks included damage to or loss of the device, integrity of data, and challenges with both Fitbit and Facebook being compatible with daily life. CONCLUSIONS: Wearable activity trackers and social media have the potential to impact adolescents' physical activity levels. The findings from this study suggest that although the adolescents recognized the potential usefulness of the wearable activity trackers and the social media platform, the effort required to use these technologies, as well as the issues concerning risks and compatibility, may have influenced overall engagement and technology acceptance. As wearable activity trackers and social media platforms can change rapidly, future research is needed to examine the factors that may influence the acceptance of specific forms of technology by using the technology acceptance model. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12616000899448; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370716.

Translatability of a Wearable Technology Intervention to Increase Adolescent Physical Activity: Mixed Methods Implementation Evaluation.

BACKGROUND: Wearable technology interventions combined with digital behavior change resources provide opportunities to increase physical activity in adolescents. The implementation of such interventions in real-world settings is unknown. The Raising Awareness of Physical Activity (RAW-PA) study was a 12-week cluster randomized controlled trial targeting inactive adolescents attending schools in socioeconomically disadvantaged areas of Melbourne, Australia. The aim was to increase moderate- to vigorous-intensity physical activity using (1) a wrist-worn Fitbit Flex and app, (2) weekly challenges, (3) digital behavior change resources, and (4) email or text message alerts. OBJECTIVE: This paper presents adolescents' and teachers' perceptions of RAW-PA in relation to program acceptability, feasibility and perceived impact, adolescent engagement and adherence, and the potential for future scale-up. METHODS: A mixed methods evaluation of the RAW-PA study assessed acceptability, engagement, feasibility, adherence, and perceived impact. A total of 9 intervention schools and 144 intervention adolescents were recruited. Only adolescents and teachers (n=17) in the intervention group were included in the analysis. Adolescents completed web-based surveys at baseline and surveys and focus groups postintervention. Teachers participated in interviews postintervention. Facebook data tracked engagement with web-based resources. Descriptive statistics were reported by sex. Qualitative data were analyzed thematically. RESULTS: Survey data were collected from 142 adolescents at baseline (mean age 13.7 years, SD 0.4 years; 51% males) and 132 adolescents postintervention. A total of 15 focus groups (n=124) and 9 interviews (n=17) were conducted. RAW-PA had good acceptability among adolescents and teachers. Adolescents perceived the intervention content as easy to understand (100/120, 83.3%) and the Fitbit easy to use (112/120; 93.3%). Half of the adolescents perceived the text messages to be useful (61/120; 50.8%), whereas 47.5% (57/120) liked the weekly challenges and 38.3% (46/120) liked the Facebook videos. Facebook engagement declined over time; only 18.6% (22/118) of adolescents self-reported wearing the Fitbit Flex daily postintervention. Adolescents perceived the Fitbit Flex to increase their physical activity motivation (85/120, 70.8%) and awareness (93/119, 78.2%). The web-based delivery facilitated implementation of the intervention, although school-level policies restricting phone use were perceived as potential inhibitors to program roll-out. CONCLUSIONS: RAW-PA showed good acceptability among adolescents attending schools in socioeconomically disadvantaged areas and their teachers. Low levels of teacher burden enhanced their perceptions concerning the feasibility of intervention delivery. Although adolescents perceived that RAW-PA had short-term positive effects on their motivation to be physically active, adolescent adherence and engagement were low. Future research exploring the feasibility of different strategies to engage adolescents with wearable technology interventions and ways of maximizing system-level embeddedness of interventions in practice would greatly advance the field.

Analysis of the retrograde tibial artery approach in lower extremity revascularization in an office endovascular center.

OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of a retrograde tibial approach in revascularization of lower extremities for treatment of ischemia in anatomically challenging patients. METHODS: This is a retrospective study of 57 procedures performed between 2012 and 2016 using the retrograde approach to treat patients with flush occlusion, inability to cross the lesion, failed bypass, or hostile groin. Demographic data, Rutherford classes, vessels treated, and approach were noted. Type of procedure, complications, amputations, deaths, and patency of access tibial vessels and treated vessels were recorded. Ultrasound-guided tibial access was achieved through the anterior tibial artery, posterior tibial artery, or peroneal artery. Technical success was defined as residual stenosis of <30%. Restenosis was defined as two times increase in velocity at the site of treatment. In follow-up, access vessel patency and treated vessel patency were evaluated by physical examination and ultrasound. Kaplan-Meier survival curves were used to assess proportional hazards before using the marginal Cox model to determine statistical significance in risk of postintervention occlusion. RESULTS: In 53 patients (32 men) with an average age of 67 ± 10.6 years, Rutherford categories were as follows: class 2, n = 1; class 3, n = 37; class 4, n = 5; class 5, n = 12; and class 6, n = 2. Tibial arteries were successfully accessed in all limbs. Lesions were crossed in 56 of 57 limbs. One procedure was terminated because of local arterial dissection. Revascularization was achieved in 55 of 57 limbs. Within 30 days of the procedure, 2 of 2 Rutherford class 6 patients and 1 of 12 class 5 patients needed major amputation because of pre-existing disease. There was no 30-day mortality. Of 103 vessels treated, technical success was achieved in 97 (94%). Secondary patency for 103 vessels was 79% with mean follow-up of 6.66 ± 5.4 months. The primary patency was 90% compared with a primary assisted patency of 51%. There was no statistically significant difference in access vessel primary patency in follow-up: 86% (30/35) for anterior tibial artery, 80% (16/20) for posterior tibial artery, and 100% (2/2) for peroneal artery. In addition, in follow-up, there was no significant difference in incidence of occlusion of target vessels based on choice of access vessel used (P = .109). CONCLUSIONS: In this group of anatomically challenging patients, a retrograde tibial approach was safely used. Accessing the tibial artery does not usually cause access vessel occlusion and resulted in no adverse outcomes. The majority of access vessels remained patent for future bypass if necessary.