Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial.

We conducted a phase I trial to determine the optimal dose of triplet therapy with the tyrosine kinase inhibitor sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), 1-year survival probability, and sitravatinib pharmacokinetics.

Intensive Voice Treatment following Botulinum Neurotoxin Injection for a Speaker with Abductor Laryngeal Dystonia: An Exploratory Case Study.

Abductor laryngeal dystonia (ABLD) is a rare neurological voice disorder which results in sporadic opening of the vocal folds during speech. Etiology is unknown, and to date there is no identified effective behavioral treatment for it. It is hypothesized that LSVT LOUD®, which was developed to treat dysphonia secondary to Parkinson's disease, may have application to speakers with ABLD to improve outcomes beyond that with botulinum neurotoxin (BoNT) treatment alone.

Towards an empathic hidden curriculum in medical school: A roadmap.

The "hidden curriculum" in medical school includes a stressful work environment, un-empathic role models, and prioritisation of biomedical knowledge. It can provoke anxiety and cause medical students to adapt by becoming cynical, distanced and less empathic. Lower empathy, in turn, has been shown to harm patients as well as practitioners.

On the need for empathy in the acute hospital setting.

This article reviews the need for empathy, and what happens in its absence in an acute hospital setting, using the example of a homeless man in an emergency department. Three simple but meaningful changes that all healthcare practitioners can make are recommended to promote empathy.

2023 APHL/ISNS Newborn Screening Symposium.

Introduction and Abstracts of the 2023 APHL/ISNS Newborn Screening Symposium in Sacramento, CA, USA from 15-19 October 2023.

Selective impact of COVID-19 in patients presenting with non-specific abdominal pain.

The effect of COVID on surgical admissions was investigated by comparing such admissions from March to August 2020 with those in the same period in 2019. A significant reduction was noted in surgical admissions. The majority of this reduction was seen in the group with non-specific abdominal pain.

A Case Study Using a Multimodal Approach to Melodic Intonation Therapy.

Purpose: The purpose of this study was to assess the efficacy. of increasing spontaneous expressive language using a modified melodic intonation therapy (MIT) approach with a male participant diagnosed with acquired aphasia and apraxia who was 10 years post onset.

Method: A therapeutic protocol consisting of vocal and linguistic tasks was administered.

Developing and Initiating Validation of a Model Opioid Patient-Prescriber Agreement as a Tool for Patient-Centered Pain Treatment.

Background: Opioid treatment agreements generally are used in pain treatment to delineate the terms and consequences of opioid use and abuse.

Methods: The US Food and Drug Administration (FDA) Safe Use Initiative convened a multi-disciplinary working group with outside experts to draft a patient-centered, model opioid treatment agreement named the Model Patient-Prescriber Agreement (model PPA). The model PPA was evaluated for readability and usability in two tests that sampled both healthcare professional and non-healthcare professional FDA employees.

Prevalence of vocal fry in young adult male American English speakers.

The purpose of this study was to assess possible gender differences in the prevalence of vocal fry in the voices of young male college students. Results were compared with previously published findings derived from a matched sample of female speakers. Thirty-four male college students, native American English speakers, produced speech samples in two speaking conditions: (1) sustained isolated vowel /a/ and (2) reading task.

Functional activity of varicose human great saphenous vein at different sites.

Experiments on isolated preparations of varicose human great saphenous vein revealed different sensitivity of the distal and proximal portions to P2X receptor agonist α,β-methylene-ATP, but not to norepinephrine and histamine. It is suggested that restructuring of the P2 receptor system plays an important role in the pathogenesis of varicose veins, which affects the trunk of the great saphenous vein in varying degrees.

Habitual use of vocal fry in young adult female speakers.

The purpose of this study was to examine the use of vocal fry in young adult Standard American-English (SAE) speakers. This was a preliminary attempt (1) to determine the prevalence of the use of this register in young adult college-aged American speakers and (2) to describe the acoustic characteristics of vocal fry in these speakers. Subjects were 34 female college students.

Anaphylaxis following H1N1 pandemic vaccines: safety data in perspective.

We present here a detailed analysis of anaphylaxis cases reported to GlaxoSmithKline safety database following vaccination with its H1N1 pandemic influenza vaccines, Pandemrix™ and Arepanrix™. Cases were assessed according to the Brighton Collaboration Case Definition (BCCD) as either confirmed diagnosis (97/395, 24.6%), insufficient information to fulfil the minimal criteria of the case definition (117/395, 29.

Chk2 protects against radiation-induced genomic instability.

The murine Chk2 kinase is activated after exposure to ionizing radiation and is necessary for p53-dependent apoptosis, but the role Chk2 plays in determining genomic stability is poorly understood. By analyzing the sensitivity of Chk2-deficient murine and human cells to a range of DNA-damaging agents, we show that Chk2 deficiency results in resistance to agents that generate double-strand breaks but not to other forms of damage. Surprisingly, the absence of Chk2 results in increased sensitivity to UV-radiation-induced DNA damage.

A frequency/consequence-based technique for visualizing and communicating uncertainty and perception of risk.

This chapter presents an approach under development for communicating uncertainty regarding risk. The approach relies on a risk imaging technology that decomposes risk into two basic elements: (i) the frequency of each kind of harm associated with a hazard and (ii) the adversity of each of those harms. Because different kinds of harm are often measured along incompatible dimensions, adversity is quantified on an ordinal scale.

SUMO-targeted ubiquitin ligases in genome stability.

We identify the SUMO-Targeted Ubiquitin Ligase (STUbL) family of proteins and propose that STUbLs selectively ubiquitinate sumoylated proteins and proteins that contain SUMO-like domains (SLDs). STUbL recruitment to sumoylated/SLD proteins is mediated by tandem SUMO interaction motifs (SIMs) within the STUbLs N-terminus. STUbL-mediated ubiquitination maintains sumoylation pathway homeostasis by promoting target protein desumoylation and/or degradation.

Are mesh anchoring sutures necessary in ventral hernioplasty? Multicenter study.

Background: Avoiding mesh fixation to the surrounding tissue in ventral hernioplasty would simplify the operation, decrease the time of the procedure, and decrease the risk of suture-related complications.

Methods: Four hospitals included 111 patients according to the common protocol for prospective clinical evaluation of sutureless ventral hernioplasty. Surgical technique involves placement of the polypropylene mesh with flat-shape memory in either the retromuscular or preperitoneal space without suture anchoring.

RXRalpha regulates the pregnancy-specific glycoprotein 5 gene transcription through a functional retinoic acid responsive element.

Human pregnancy-specific glycoproteins (PSG) are major placental polypeptides encoded by eleven highly conserved genes expressed by the syncytiotrophoblast. The minimal promoter region of all PSG genes contains a putative Retinoic Acid Responsive Element (RARE) though the ability of retinoids to regulate PSG gene expression has not been established. Retinoid signaling pathway plays a key role for overall placenta biology and is essential for trophoblast differentiation.

A cost-effectiveness approach to the qualification and acceptance of biomarkers.

The flow of new medicines to patients depends on the development of new biomarkers and their correct interpretation, yet there are no widely accepted and practically applicable criteria that facilitate adequate biomarker qualification. As a result, case-by-case qualifications are based on subjective assessments that do not lead to optimal decisions for patients, which have contributed to the 'stagnation' in drug productivity identified by the FDA. An alternative is to qualify biomarkers in terms of cost effectiveness using a set of principles that enable the evaluation of biomarkers even with incomplete knowledge.

Spy1 expression prevents normal cellular responses to DNA damage: inhibition of apoptosis and checkpoint activation.

Spy1 is the originally identified member of the Speedy/Ringo family of vertebrate cell cycle regulators, which can control cell proliferation and survival through the atypical activation of cyclin-dependent kinases. Here we report a role for Spy1 in apoptosis and checkpoint activation in response to UV irradiation. Using an inducible system allowing for regulated expression of Spy1, we show that Spy1 expression prevents activation of caspase-3 and suppresses apoptosis in response to UV irradiation.

Rating the severity of the medical consequences of drug-induced liver injury.

Risk analysis in drug development aims to allow for clear decisions showing whether or not the benefit of an intervention outweighs the risk. One of the difficulties in doing this in a repeatable and clear way is the problem of comparing different adverse events, as seriousness is often subjective. Using drug-induced liver injury as our model, we show that clinical, laboratory, and histological manifestations of liver reactions can be ranked by experienced hepatologists and these rankings can be used to rank the consequences of drug-induced side effects as a continuum.

A new role for the Kruppel-like transcription factor KLF6 as an inhibitor of c-Jun proto-oncoprotein function.

Kruppel-like transcription factors (KLFs) represent one of the most diverse set of regulators in vertebrate organisms. KLF family members are involved in cell proliferation and differentiation control in normal as well as in pathological situations. Here, we demonstrate that KLF6 behaves as a functional antagonist of the c-Jun proto-oncoprotein.

Use of antibacterial agents in renal failure.

This article provides background information on the pharmacokinetics of antibacterial agents in patients with normal and impaired renal function. Tables are provided to allow quick determination of appropriate dosages for varying degrees of renal failure. The use of serum levels, newer strategies for cefazolin, vancomycin, and aminoglycoside dosing, methods of dialysis and associated antibiotics dosage adjustments, and antibiotic toxicity in renal failure are reviewed.

Human pregnancy-specific glycoprotein 1a (PSG1a) induces alternative activation in human and mouse monocytes and suppresses the accessory cell-dependent T cell proliferation.

It has been proposed that pregnancy-specific factors induce the suppression of a specific arm of the maternal response accompanied by activation of the nonspecific, innate immune system. The aim of this study was to determine whether pregnancy-specific glycoprotein 1a (PSG1a), the major variant of PSG polypeptides, is able to modulate the monocyte/macrophage (Mo) metabolism to regulate T cell activation and proliferation. Using the recombinant form of this glycoprotein (rec-PSG1a), expressed in mammalian cells with a vaccinia-based expression vector, we have demonstrated that human PSG1a induces arginase activity in peripheral blood human Mo and human and murine Mo cell lines.

Use of antibacterial agents in renal failure.

This article reviews the pharmacokinetics of antibacterial agents in patients with normal and decreased renal function. The concepts of volume and distribution, rate of elimination, loading and maintenance doses, and therapeutic drug monitoring are delineated. Special reference is made to the intermittent dosing of cefazolin with hemodialysis.

Use of antibacterial agents in renal failure.

This article provides information on the pharmacokinetics of antibacterial agents in patients with normal renal function and those with impaired renal function. Specific discussion includes the use of serum levels, dosage adjustments in dialysis, new strategies for cefazolin dosages in dialysis patients, and antibiotic toxicity in renal failure, and tabular data is presented for determining appropriate dosages for varying degrees of renal failure.