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The objective of this study is to further patient-physician discussion regarding postoperative quality of life expectations after surgical acoustic neuroma resection.This study is retrospective prospective. Qualifying patients were identified and administered Penn Acoustic Neuroma Quality-of-Life (PANQOL) Scale.The setting was Loyola University Chicago Health System.Three hundred twenty-six patients at our center with surgically resected acoustic neuroma between January 1990 and July 2021 completed the PANQOL.During postresection follow-up visits, patients were administered the PANQOL survey.The total PANQOL is comprised of questions addressing quality of life in seven domains of hearing, balance, face, energy, pain, health, and anxiety. Univariate and multivariable analyses were performed to test for associations between surgical approach and/or patient characteristics.Patients who were treated with retrosigmoid approach reported slightly higher PANQOL pain scores when compared with translabyrinthine approach. No association was found between responses on hearing PANQOL and surgical approach. No association was found between approach and total PANQOL score. However, on average female patients reported lower total PANQOL compared with male patients.The lack of association between patient response on hearing PANQOL and surgical approach illustrates the impact of preoperative patient counseling in appropriately setting patient expectations. The difference in pain PANQOL response may be due to a higher rate of occipital neuralgia due to incision placement and soft tissue retraction in the retrosigmoid patient group. Surgeons may consider alternative surgical incisions and soft tissue dissection to improve patient's quality of life with respect to postoperative pain.

Community-level factors contribute to living donor kidney transplantation disparities but may also influence the interventions aimed to mitigate these disparities. The Living Donor Navigator Program was designed to separate the advocacy role from the patient in need of transplantation-friends/family are encouraged to participate as the patients' advocates to identify living donors, though some of the patients participate alone as self-advocates. Self-advocates have a lower living donor kidney transplantation likelihood compared to the patients with an advocate. We sought to evaluate the relationship between the patients' community-level vulnerability and living donor navigator self-advocacy as a surrogate for program fidelity.This single-center, retrospective study included 110 Living Donor Navigator participants (April 2017-June 2019). Program fidelity was assessed using the participants' advocacy status. Measures of community vulnerability were obtained from the Centers for Disease Control and Prevention Social Vulnerability Index. Modified Poisson regression was used to evaluate the association between community-level vulnerability and living donor navigator self-advocacy.Of the 110 participants, 19% (n = 21) were self-advocates. For every 10% increase in community-level vulnerability, patients had 17% higher risk of self-advocacy (adjusted relative risk 1.17, 95% confidence interval: 1.03-1.32, P = .01). Living in areas with greater unemployment (adjusted relative risk: 1.18, 95% confidence interval: 1.04-1.33, P = .01), single-parent households (adjusted relative risk: 1.23, 95% confidence interval: 1.06-1.42, P = .006), minority population (adjusted relative risk: 1.30, 95% confidence interval: 1.04-1.55, P = .02), or no-vehicle households (adjusted relative risk: 1.17, 95% confidence interval: 1.02-1.35, P = .02) were associated with increased risk of self-advocacy.Having a greater community-level vulnerability was associated with poor Living Donor Navigator Program fidelity. The potential barriers identified using the Social Vulnerability Index may direct resource allocation and program refinement to optimize program fidelity and efficacy for all participants.

Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. We transplanted a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and studied the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells were uncommon in the porcine kidney cortex early after xenotransplantation and consisted of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages expressed genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft was detected. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression is sufficient to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.

Interdisciplinary pain rehabilitation (IPR) is a recommended treatment for people with chronic pain. An inadequate description of the content of IPR programs makes it difficult to draw conclusions regarding their effects. The purpose of this study was to describe the perceptions and attitudes of healthcare professionals toward a content description of IPR programs for patients with chronic pain. Individual interviews with healthcare professionals (n = 11) working in IPR teams in Sweden were conducted between February and May 2019. Analysis of the interviews resulted in a theme: interdisciplinary pain rehabilitation is a complex intervention, with three categories: limitations in the description of IPR programs; lack of knowledge about IPR and chronic pain; and facilitating and hindering factors for using the content description of IPR programs. Conclusion: Healthcare professionals perceived that IPR programs could be described through a general content description. A general content description could enhance the quality of IPR programs through a better understanding of their content and a comparison of different IPR programs. Healthcare professionals also expressed the importance of a content description being a guide rather than a steering document.

Time-zero biopsies can detect donor-derived lesions at the time of kidney transplantation, but their utility in predicting long-term outcomes is unclear under the updated Kidney Allocation System. We conducted a single-center retrospective cohort study of 272 consecutive post-reperfusion time-zero biopsies. We tested the hypothesis that abnormal time-zero histology is a strong indicator of donor quality that increases the precision of the kidney donor profile index (KDPI) score to predict long-term outcomes. We detected abnormal biopsies in 42% of the cohort, which were independently associated with a 1.2-fold increased hazard for a composite of acute rejection, allograft failure, and death after adjusting for clinical characteristics including KDPI. By Kaplan-Meier analysis, the relationship between abnormal time-zero histology and the composite endpoint was only significant in the subgroup of deceased donor kidney transplants with KDPI scores > 35. Abnormal time-zero histology, particularly vascular intimal fibrosis and arteriolar hyalinosis scores, was independently associated with lower 12-month estimated GFR. In conclusion, abnormal time-zero histology is relatively common and identifies a group of kidney recipients at increased risk for worse long-term outcomes. Further studies are needed to determine the optimal patient population in which to deploy time-zero biopsies as an additional surveillance tool.

Este ensaio explora de maneira breve as sugestões dos pragmatistas americanos com relação ao desenvolvimento do pensamento filosófico. Entre estas, estão incluídas a necessidade de aprender de outras disciplinas os modos úteis de investigação para o entendimento da experiência humana, a necessidade de manter um diálogo com a história das ideias tanto para prevenir a repetição quanto para sugerir novas direções do pensamento, bem como a travessia das fronteiras culturais para evitar a arrogância dogmática encontrada no interior das fronteiras de muitas culturas dominantes.

Os primeiros pragmatistas americanos são, muitas vezes, abordados separadamente com foco em suas diferenças. Este ensaio introdutório destina-se simplesmente a lembrar o quanto eles tinham em estima os trabalhos uns dos outros e compartilhavam entre si uma variedade de perspectivas em suas respectivas visões de mundo. Sobretudo, eles acreditavam que estamos sempre em busca de novos conhecimentos por meio da experiência, do pensamento e do experimento. Eles consideravam suas próprias visões de mundo serem hipóteses sobre as realidades do mundo que experimentamos. E cada um deles acreditava que os extremos de dogmatismo e ceticismo são perspectivas que nos impedirão de aprendermos mais. No que se segue, apenas recordo aos leitores alguns de seus pensamentos em comum.

A radical solution is needed for the organ supply crisis, and the domestic pig is a promising organ source. In preparation for a clinical trial of xenotransplantation, we developed an in vivo pre-clinical human model to test safety and feasibility tenets established in animal models. After performance of a novel, prospective compatible crossmatch, we performed bilateral native nephrectomies in a human brain-dead decedent and subsequently transplanted two kidneys from a pig genetically engineered for human xenotransplantation. The decedent was hemodynamically stable through reperfusion, and vascular integrity was maintained despite the exposure of the xenografts to human blood pressure. No hyperacute rejection was observed, and the kidneys remained viable until termination 74 h later. No chimerism or transmission of porcine retroviruses was detected. Longitudinal biopsies revealed thrombotic microangiopathy that did not progress in severity, without evidence of cellular rejection or deposition of antibody or complement proteins. Although the xenografts produced variable amounts of urine, creatinine clearance did not recover. Whether renal recovery was impacted by the milieu of brain death and/or microvascular injury remains unknown. In summary, our study suggests that major barriers to human xenotransplantation have been surmounted and identifies where new knowledge is needed to optimize xenotransplantation outcomes in humans.

Intrathecal baclofen (ITB) is a treatment modality used to improve the quality of life of patients with intractable spasticity and dystonia. Although it is an effective solution in patients failing oral interventions, it is associated with potential infectious complications. It is known that pediatric patients with ITB have significantly higher infection rates compared with adult patients. The cause of these higher rates in pediatric patients remains unclear. In the present study, we performed a meta-analysis focusing on the incidence of infection, and clarification of potential risk factors for infection in pediatric patients with ITB.This meta-analysis was performed in accordance with the PRISMA guidelines. An electronic database search was performed through PubMed, Web of Science, Embase, and Cochrane Library databases. Eligibility criteria and bias assessment were applied before statistical analysis.The 17 studies identified yielded 2238 pediatric patients treated with implanted ITB pumps between 1994 and 2014. Infection comprised 34% of observed complications, second only to catheter malfunction. Pediatric ITB primary infection ranged between 0% and 44% among included studies (interquartile range, 4.85%-18.85%). A linear mixed-effects regression model showed that subfascial implantation had 12% lower primary infection rates compared with subcutaneous implantations across the literature. The relative risk of infection was 56% lower in pediatric patients with subfascially implanted ITB pumps.Surgeons and clinicians should use these data to better assess patient risk-benefit when considering ITB pump implantation.

Antony van Leeuwenhoek's entire output is contained in the hundreds of letters that he wrote from 1673 to 1723. This article discusses the content, features, and circumstances of the letters and their contemporary publishing history, especially in the Royal Society's Philosophical Transactions, as well as a brief history of the project begun in 1932 to publish a complete edition of Leeuwenhoek's letters in Dutch and English translation with linguistic, scientific, and historical annotations.

This paper discusses the scientific instruments made and used by the microscopist Antony van Leeuwenhoek (1632–1723). The immediate cause of our study was the discovery of an overlooked document from the Delft archive: an inventory of the possessions that were left in 1745 after the death of Leeuwenhoek’s daughter Maria. This list sums up which tools and scientific instruments Leeuwenhoek possessed at the end of his life, including his famous microscopes. This information, combined with the results of earlier historical research, gives us new insights about the way Leeuwenhoek began his lens grinding and how eventually he made his best lenses. It also teaches us more about Leeuwenhoek’s work as a surveyor and a wine gauger. A further investigation of the 1747 sale of Leeuwenhoek’s 531 single lens microscopes has not only led us to the identification of nearly all buyers, but also has provided us with some explanation about why only a dozen of this large number of microscopes has survived.

While policy experts debate health-care models, citizens experience symptoms that cast them in the role of patient, often with frustrating results. The following is the rant of one such patient in the United States. The physical symptoms she describes have proven elusive to diagnosis thus far; of interest to us here, though, is diagnosing the systemic factors that led to those results. We're asking several experts to respond by 1) identifying what, in their view, led to the health-care outcomes described, and 2) outlining some policy prescriptions to enhance the delivery of care, with the goal of achieving more satisfactory outcomes.

Nearly half a century ago, as Phillips Moulton was concluding work on his indispensable edition of John Woolman's journal, he arrived at a realization with which Woolman himself would have agreed. After several years of scrutiny, sifting through a sequence of manuscripts that require a substantial alphabet of editorial labels to categorize--MS A, MS B, MS C, MS P, MS S, MSS Ti and T2--along with a succession of prior editions published between 1774 and 1950, Moulton confessed that a definitive version of Woolman's book was unattainable. Even with the aid of "considerable guidance from leading authorities," Moulton wrote, "the present editor realizes that not all of the mysteries encountered in the manuscripts have been, or are likely ever to be, resolved" (282). (1) The term "mysteries" alone would have pleased Woolman, who grappled all his life with the irresolvable struggles involved as he tried to give voice to mental experiences that even the most gifted artists discover are notoriously averse to the corruptible medium of words. The fact that Moulton sought guidance from others as he wrestled with his editorial challenges echoes the collaborative wrestling process with which Woolman too engaged as he pursued his calling. Intense bouts of self-scrutiny often preceded his visits to far-flung groups of Friends as he examined the motives that seemed to be "drawing" him to leave home, sometimes for several weeks, on circuits that might cover over a thousand miles. The visits themselves entailed a collaborative immersion in "close" or "heavy" or "laborious exercises" aimed at intensifying, but not necessarily articulating, a shared inner life between Woolman and his hosts. The journeys that form the nominal occasion of his "journals" took him from the seacoast to the upper reaches of the Susquehanna River, well beyond the settlement frontier, through at least eight of the colonies that would combine to form the United States four years after Woolman's death. The United States in turn would prove to be an imperfect and laborious collaboration, as were the frequent administrative meetings of Friends that Woolman regularly at tended as the Society grappled with its spiritual obligations during the violent decades that preceded the American Revolution. Over these same decades, Woolman was his own indefatigable editor, extending and refining his journal in the disorderly stages that Moulton struggled to sort out: recopying passages from one manuscript to another, adding, deleting, revising, annotating, cutting and pasting, all along the way. The result is an erratic textual path that Woolman took pains to preserve, just as meticulously as he preserved the motley accumulation of place-names for the various Quaker meetings he visited, a sequence of subjective snapshots, rather than a map: Oblong, Nine Partners, Pipe Creek, Newbegun Creek, Swamp Meeting, Old Neck, London Grove, Gunpowder, Red Lands. At the conclusion of a trip he occasionally noted in his journal the days that he was on the road and the miles that he traveled as carefully as if he were keeping reimbursement records. But he never brings the same degree of specificity to bear on the particulars of the meetings themselves: on the blend of collective silence and sometimes anguished speech that made the worship exercises laborious. On those features of interior life, Woolman intended for his readers to encounter the same irresolvable mysteries that he did as he sought to cope with the range of psychological imperatives prompting him to travel, to speak, to sit in receptive silence, and to write. Early in the summer of 1763, after listening to Woolman pray in English before a mixed audience of tribal peoples who did not understand the language, Papunehang, their spiritual leader, expressed to an interpreter his satisfaction with Woolman's seemingly perverse performance: "I love to feel where words come from" (133). It may have been Woolman who left out the definite article that would have stressed the significance of "the" words spoken, on a very particular occasion, over the hidden sources from which all words ultimately emerge. …

In an oil spill response environment, urgency looms, and virtually every action is geared toward immediate needs. Clean-up, safety, and listed species protection are at the forefront of the collaborative efforts carried out by an incident management team. However, these needs do not complete the obligation of the Federal Action Agency responsible for the event. This agency must also complete an Endangered Species Act (ESA) Biological Assessment (BA). To do that for a spill of national significance, it is paramount that response personnel track certain details about their daily operations. Unfortunately, in the BA for the Deepwater Incident Response, the action record had to be reconstructed forensically. Although operational permits to work, otherwise known as Shoreline Treatment Recommendations, used standard geographic references and response action terms, they are merely prescriptions for activity and provide only maximum default assumptions. To gain vital insight into more specific temporal elements such as frequency, intensity, and duration, daily response reports were required. These reports were not gathered into a central geodatabase along the way. They were printed to paper, boxed, shipped to a documentation unit, and scanned into image files. These files were organized into approximately 30,000 document sets of up to 4,000 pages each. Qualitative document content analysis was used to distill the needed details from these image sets into a database. This technique for generating the needed data for an effects analysis is arduous. However, the process of its development has produced valuable lessons learned. Here we present the needed schema design and architecture to promote a seamless transition on future responses from the urgency of immediate need to inevitability of post-spill ESA obligation.

At age 80, Antony van Leeuwenhoek was a world-famous scientist who came from a prosperous Delft family with a heritage of public service. He continued that tradition by serving in paid municipal offices. Self-taught, he began his scientific career in his 40s, when he began making hundreds of tiny single-lens microscopes. Pioneering the use of now-common microscopic techniques, he was the first human to see microbes and microscopic structures in animals, plants, and minerals. Over 50 years, he wrote only letters, more than 300 of them, and published half of them himself. More than a hundred were published in translation in the Royal Society's Philosophical Transactions. Today, Leeuwenhoek is considered in the lesser rank of scientists and is not well known outside of his homeland. Recent archival research in Delft has contributed new information about his life that helps to contextualize his science, but much remains to be learned.

The vast majority of benign tumors of the cerebellopontine angle, temporal bone, and parotid gland can be successfully resected without permanent injury to the facial nerve. Malignant tumors or recurrent disease may require facial nerve sacrifice, especially if preoperative facial paresis is present. This article will present case examples of the various methods to reconstruct facial animation after lateral skull base resections that require sacrifice of cranial nerve VII, and the associated mimetic facial musculature. Facial mimetic outcome after reanimation was graded using the House-Brackmann scale. Primary neurorrhaphy or interposition grafting may be performed when both the proximal and distal portions of the facial nerve are available and viable facial musculature is present. If only the distal facial nerve and viable facial musculature are available, a split hypoglossal to facial nerve anastomosis is used. A proximal facial nerve to microvascular free flap is performed when the proximal facial nerve is available without distal nerve or viable musculature. A cross-facial to microvascular free flap is performed when the proximal and distal facial nerve and facial musculature are unavailable. The above methods resulted in a House-Brackmann score of III/VI in all case examples postoperatively. The method of facial reanimation used depends on the availability of viable proximal facial nerve, the location of healthy, tumor-free distal facial nerve, and the presence of functioning facial mimetic musculature.

Targeted agents have greatly improved outcomes for patients (pts) with chronic lymphocytic leukemia (CLL) and other B cell lymphomas; however, single agents have been limited by intolerance, resistance and depth/durability of responses. Current novel targeted agent combinations may improve depth of response, but such "full dose" strategies have been associated with significant AEs, dose reductions/interruptions and discontinuations. Our in vitro & in vivo screening/optimization studies identified that concurrent inhibition of BTK & mTOR targets plus IMiD at low doses of each inhibitor can synergistically kill B-cell malignancies and may address drug-resistance. DTRM-555 is an optimized oral triplet combination of a novel BTK inhibitor DTRMWXHS-12 (DTRM-12) with everolimus (EV) & pomalidomide (POM). This once daily therapy was tested in a stepwise, phase I, US multicenter study in patients with highest unmet medical needs including r/r CLL, Richter's transformation (RT) of CLL, DLBCL, transformed B-cell lymphomas. We conducted a 3+3 design phase I, first human trial exploring DTRM-555 in pts ≥18 years, ECOG PS ≤1 with CLL, B-cell NHL, or Hodgkin lymphoma (HL) with no available standard therapy (NCT02900716). Our goal was to determine optimal doses for triplet combination therapy through 3 escalating phases of study: DTRM-12 in escalating doses (50, 100, 200, & 300 mg/day) in Part Ia, DTRM-12 at 200 mg or 300 mg & EV at 5 mg (doublet or DTRM-505) in Part Ib Arm A while DTRM-12 at 200 mg or 300 mg, EV at 5 mg & POM at 2 mg in Part Ib Arm B. For all arms, treatment was administered for 21 consecutive days of a 28-day cycle, until disease progression or unacceptable toxicity. Safety was the primary endpoint, and the dose-limiting toxicity (DLT) period was cycle 1. Secondary endpoints included response (iwCLL 2018 or Cheson 2014), progression free survival, duration of response and pharmacokinetics. Intra-patient migration between arms (Mono to doublet to triplet) was permitted if subsequent doses were tolerated. The trial commenced 9/27/2016 and completed enrollment 7/25/2019. Thirty-three pts were enrolled, including 2 screen failures and 4 intra-cohort migrations, with r/r DLBCL (n=8), CLL/SLL (n=5), RT (n=6), FL (n=5), MCL (n=4), MZL/LPL (n=3), HL (n=2). 30 of 31 treated pts were evaluated: 8 pts participated in phase Ia (DTRM-12) while 23 pts were treated on phase Ib combinations (DTRM-505 & DTRM-555). Baseline characteristics: 70% male (n=23), median age 70 years (range 46-94) and 94% white. Median prior therapies were 3 (range 1-10), 53% had been treated with ≥1 prior targeted agent (i.e., CD19/CD3 bispecific antibody, obtinutuzumab, pembrolizumab, nivolumab, ibrutinib, venetoclax, PI3k-i), CAR-T or HSCT. 35% pts were previously treated with ibrutinib. Table 1 describes Grade (Gr) 3 and 4 AEs (all causality, stratified by treatment arm). Regarding safety, AEs were manageable, with a total of 5 DLTs were observed: 2 (Gr 3 febrile neutropenia, URI) in part Ib arm A, 3 (Gr 4 thrombocytopenia, Gr 3 diarrhea, G3 febrile neutropenia) in Part Ib arm B. No MTD was reached for the mono & doublet arms, with the MTD of the triplet determined to be DTRM-12 200 mg, EV 5 mg, & POM 2 mg. Spider plot (Figure 1a) shows the clinical response for individual CLL and lymphoma pts treated with mono, doublet and triplet therapies. Depth and durability of response improved with combination therapies (vs. mono). Of note, 48% of all patients had a ≥50% reduction in sum of the products of lymph node diameters. Representative PET-CT scans are in Figure 1b-c. Responses in multi-refractory pts are ongoing (including 15+ mos in a pt with r/r DLBCL and 5+ mos PR in a pt aged > 90 yrs with r/r DLBCL; 4+ & 13+ mos PRs in two pts with RT). DTRM-12 plasma concentrations were unaffected by EV & POM (Once Daily Oral Therapies) in Figure 1d. The clinical trial met its primary endpoint as the triple combination DTRM-555 had an acceptable safety profile. Dose dependent drug levels with minimal inter-pt variations were observed in all arms, supporting once daily oral administration of this low-dose combination therapy. Encouraging clinical activity was observed in several high-risk, multi-refractory CLL and lymphoma pts, including those previously treated with ibrutinib. Thus synthetic lethality is a viable treatment approach. A phase II US expansion study is underway targeting pts with transformed lymphomas (follicular or prior CLL) and r/r DLBCL cohorts. Table 1. Disclosures Mato: AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding. Schuster:DTRM Biopharma: Research Funding. Foss:Mallinckrodt: Consultancy; Acrotech: Consultancy; miRagen: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; Eisai: Consultancy; Spectrum: Other: fees for non-CME/CE services . Isufi:Novartis: Consultancy; Astra Zeneca: Consultancy; Celgene: Consultancy. Ding:Merck: Research Funding; DTRM Biopharma: Research Funding. Brander:Novartis: Consultancy; MEI: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Research Funding; AstraZeneca: Consultancy, Research Funding; Acerta: Research Funding; Tolero: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; DTRM Biopharma: Research Funding. Tun:Mundi-pharma: Research Funding; TG Therapeutics: Research Funding; Curis: Research Funding; DTRM Biopharma: Research Funding; Celgene: Research Funding; BMS: Research Funding. He:DTRM Biopharma: Employment, Equity Ownership. Kearney:DTRM Biopharma: Employment, Equity Ownership. Gui:DTRM Biopharma: Employment, Equity Ownership. Anderson:Theradex: Employment. Roeker:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Huntington:Bayer: Consultancy, Honoraria; AbbVie: Consultancy; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Honoraria; DTRM Biopharm: Research Funding. OffLabel Disclosure: Everolimus in B cell lymphomas and CLL Pomalidomide in B cell lymphomas and CLL