Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo Performance.

Antibody-drug conjugates (ADCs) have begun to fulfil their promise as targeted cancer therapeutics with ten clinical approvals to date. As the field matures, much attention has focused upon the key factors required to produce safe and efficacious ADCs. Recently the role that linker-payload reagent design has on the properties of ADCs has been highlighted as an important consideration for developers. We have investigated the effect of incorporating hydrophilic macrocycles into reagent structures on the in vitro and in vivo behavior of ADCs. Bis-sulfone based disulfide rebridging reagents bearing Val-Cit-PABC-MMAE linker-payloads were synthesized with a panel of cyclodextrins and crown ethers integrated into their structures via a glutamic acid branching point. Brentuximab was selected as a model antibody and ten ADCs with a drug-to-antibody ratio (DAR) of 4 were prepared for biological evaluation. In vitro, the ADCs prepared showed broadly similar potency (range: 16-34 pM) and were comparable to Adcetris® (16 pM). In vivo, the cyclodextrin containing ADCs showed greater efficacy than Adcetris® and the most efficacious variant (incorporating a 3'-amino-α-cyclodextrin component) matched a 24-unit poly(ethylene glycol) (PEG) containing comparator. The ADCs bearing crown ethers also displayed enhanced in vivo efficacy compared to Adcetris®, the most active variant (containing a 1-aza-42-crown-14 macrocycle) was superior to an analogous ADC with a larger 24-unit PEG chain. In summary, we have demonstrated that hydrophilic macrocycles can be effectively incorporated into ADC reagent design and offer the potential for enhanced alternatives to established drug-linker architectures.

Language matters: representations of 'heart failure' in English discourse-a large-scale linguistic study.

AIMS: Heart failure (HF) has a lower public profile compared with other serious health conditions, notably cancer. This discourse analysis study investigates the extent to which HF is discussed in general contemporary English, UK parliamentary debates and the ways in which HF is framed in discussions, when compared with two other serious health conditions, cancer and dementia. METHODS: The Oxford English Corpus (OEC) of 21st century English-language texts (2 billion words) and the UK Hansard Reports of parliamentary debates from 1945 to early 2021 were used to investigate the relative frequencies, contexts and use of the terms 'heart failure', 'cancer' and 'dementia'. RESULTS: In the OEC, the term 'heart failure' occurs 4.26 times per million words (pmw), 'dementia' occurs 3.68 times pmw and 'cancer' occurs 81.96 times pmw. Cancer is talked about 19 times more often than HF and 22 times more often than dementia. These are disproportionately high in relation to actual incidence: annual cancer incidence is 1.8 times that of the other conditions; annual cancer mortality is two times that caused by coronary heart disease (including HF) or dementia.'Heart failure' is used much less than 'cancer' in UK parliamentary debates (House of Commons and House of Lords) between 1945 and early 2021, and less than 'dementia' from 1990 onwards. Moreover, HF is even mentioned much less than pot-holes in UK roads and pavements. In 2018, for example, 'pot-hole/s' were mentioned over 10 times pmw, 37 times more often than 'heart failure', mentioned 0.28 times pmw. Discussions of HF are comparatively technical and formulaic, lacking survivor narratives that occur in discussions of cancer. CONCLUSIONS: HF is underdiscussed in contemporary English compared with cancer and dementia and underdiscussed in UK parliamentary debates, even compared with the less-obviously life-threatening topic of pot-holes in roads and pavements.

Management of symptomatic degenerative low-grade lumbar spondylolisthesis.

Degenerative low-grade lumbar spondylolisthesis is the most common form of spondylolisthesis.The majority of patients are asymptomatic and do not require surgical intervention.Symptomatic patients present with a combination of lower back pain, radiculopathy and/or neurogenic claudication and may warrant surgery if non-operative measures fail.There is widespread controversy regarding the indications for surgery and appropriate treatment strategies for patients with this type of spondylolisthesis.This article provides a comprehensive evidence-based review of the available literature to support the management of degenerative low-grade spondylolisthesis. Cite this article: EFORT Open Rev 2018;3:620-631. DOI: 10.1302/2058-5241.3.180020.

Updated perinatal palliative standards emphasise choice and bereavement support.

Ana Todorovic's baby, Nadia, died just before birth. Ana says she received excellent care and was told when 37 weeks pregnant that Nadia was not going to survive for long.

International experts call for atrial fibrillation screening programme.

Screening programmes need to be introduced to detect irregular heart rates among older patients, according to an international collaboration of experts.

NHS England promises to prioritise emergency care.

Emergency care has been identified as one of four priorities by NHS England chief executive Simon Stevens. The others are cancer care, general practice and mental health care.

Pressures force hospitals to declare major incidents.

More than 40% of hospitals in England were forced to declare major incidents during the first week of January, as bed shortages led to delays in emergency departments (EDs), thousands of trolley waits for beds and long queues of ambulances outside units. Even cancer operations, normally protected, were cancelled.

Post-implementation review of pulse oximetry screening of well newborns in an Australian tertiary maternity hospital.

AIM: Despite there being evidence that pulse oximetry screening is better than clinical examination alone in early detection of CHD, implementation has been slow. The aim of this paper was to evaluate the practice after its implementation into routine care at Royal Prince Alfred Hospital in 2008. METHODS: A single pulse oximetry measurement was incorporated in the routine discharge newborn examination or, with early discharge, as a part of the Midwife Discharge Support Programme. An oxygen saturation level greater than or equal to 95% was considered normal, and a level less than 95%, confirmed on a repeat measure, triggered a review and examination by a consultant neonatal paediatrician. The saturation levels were recorded in the hospital database. Ascertainment of major CHD requiring surgery in the first 12 months was performed by searching the cardiac surgery database of the Heart Centre for Children. RESULTS: A total of 18 801 babies were screened over a 42-month period. Of these, four babies with major CHD were diagnosed prior to discharge with the main clinical alert resulting from routine pulse oximetry screening (true positive). Of the 11 cases with saturation <95% but no CHD (false positive cases), six had respiratory pathology. One baby with normal saturation level needed surgery in the first year for a large ventricular septal defect (false negative). The false positive rate of pulse oximetry screening for CHD was 0.13% with sensitivity 80%, specificity of 99.8%, a positive predictive value of 13.3% and a negative predictive value of 99.9%. Nine additional echocardiogram were required over 42 months. CONCLUSIONS: These post-implementation data confirm that pulse oximetry screening increases early diagnosis of major CHD as well as other important pathology with a very low false positive rate and minimal requirement for extra echocardiograms. Pulse oximetry screening of apparently well newborns should become a standard of care.

Leukocyte adhesion deficiency type I in a mixed-breed dog.

A 6-month-old, neutered male, mixed-breed dog was examined for a 2-month persistent fever, nonhealing dermal metacarpal area wound, and leukocytosis (47.0-198.0 × 10(3)/µl). Serum chemistry findings included hypoalbuminemia, hyperglobulinemia, hyperphosphatemia, and hyperphosphatasemia. Complete blood cell count results revealed a moderate microcytic, hypochromic nonregenerative anemia with a profound leukocytosis (198.5 × 10(3)/µl), characterized by neutrophilia with toxicity and hypersegmentation, and significant band cells. Tick-borne disease titers (genera Anaplasma, Ehrlichia, and Borrelia) were negative, as were polymerase chain reaction for other infectious agents (genera Hepatozoon, Mycobacterium, Mycoplasma; and Canine distemper virus). No agents were identified in a deep dermal biopsy (conventional and special histochemical stains) of the chronic draining, metacarpal region lesion. Cytology of the draining tract revealed numerous mixed bacteria and a surprising lack of neutrophils. Chronic occult blood loss with iron deficiency was considered a possible cause of the anemia. Differentials for the leukon were chronic established inflammation (occult infectious agent), chronic neutrophilic leukemia, paraneoplastic leukocytosis (neoplastic source of granulocyte colony-stimulating factor [CSF] or granulocyte-macrophage CSF), and leukocyte adhesion deficiency (LAD). The possibility of a LAD disorder was further investigated because of the noted hypersegmented neutrophils, absence of neutrophils in the cytology sample, the animal's young age, and persistence of clinical and laboratory signs. Flow cytometry of blood neutrophils showed a 60% reduction in surface expression of the ß2-integrin (CD18) subunit, whereas neutrophil function tests (oxidative burst and phagocytosis) were normal. Genetic testing revealed a homozygous missense mutation in the ß2-integrin subunit gene, previously recognized only in purebred Irish Setters, leading to a diagnosis of LAD type 1 disorder in this mixed-breed dog.

Tissue engineering strategies in spinal arthrodesis: the clinical imperative and challenges to clinical translation.

Skeletal disorders requiring the regeneration or de novo production of bone present considerable reconstructive challenges and are one of the main driving forces for the development of skeletal tissue engineering strategies. The skeletal or mesenchymal stem cell is a fundamental requirement for osteogenesis and plays a pivotal role in the design and application of these strategies. Research activity has focused on incorporating the biological role of the mesenchymal stem cell with the developing fields of material science and gene therapy in order to create a construct that is not only capable of inducing host osteoblasts to produce bone, but is also osteogenic in its own right. This review explores the clinical need for reparative approaches in spinal arthrodesis, identifying recent tissue engineering strategies employed to promote spinal fusion, and considers the ongoing challenges to successful clinical translation.

Anabolic androgenic steroids: a survey of 500 users.

PURPOSE: The use of anabolic androgenic steroids (AAS) to increase muscle size and strength is widespread. Information regarding self-administered AAS used nonmedically to enhance athletic performance or improve physical appearance is sparse and poorly documented. The purpose of this study is to identify current trends in the drug-taking habits of AAS users. METHODS: An anonymous self-administered questionnaire was posted on the message boards of Internet Web sites popular among AAS users. RESULTS: Of the 500 AAS users who participated in the survey, 78.4% (392/500) were noncompetitive bodybuilders and nonathletes; 59.6% (298/500) of the respondents reported using at least 1000 mg of testosterone or its equivalent per week. The majority (99.2%) of AAS users (496/500) self-administer injectable AAS formulations, and up to 13% (65/500) report unsafe injection practices such as reusing needles, sharing needles, and sharing multidose vials. In addition to using AAS, 25% of users admitted to the adjuvant use of growth hormone and insulin for anabolic effect, and 99.2% (496/500) of users reported subjective side effects from AAS use. CONCLUSIONS: This survey reveals several trends in the nonmedical use of AAS. Nearly four out of five AAS users are nonathletes who take these drugs for cosmetic reasons. AAS users in this sample are taking larger doses than previously recorded, with more than half of the respondents using a weekly AAS dose in excess of 1000 mg. The majority of steroid users self-administer AAS by intramuscular injection, and approximately 1 in 10 users report hazardous injection techniques. Polypharmacy is practiced by more than 95% of AAS users, with one in four users taking growth hormone and insulin. Nearly 100% of AAS users reported subjective side effects.

Chronic postoperative endophthalmitis caused by Actinomyces neuii.

Uneventful phacoemulsification with implantation of a foldable, acrylic posterior chamber intraocular lens was performed in the right eye of a 73-year-old white man. Postoperatively, the patient developed a chronic, low-grade intraocular inflammation. Cultures from the aqueous specimen grew Actinomyces neuii, an unusual gram-positive bacillus. The low-grade intraocular inflammation persisted with intensive topical steroid-antibiotic medication and systemic antibiotics. A diagnostic, 3-port, pars plana vitrectomy was performed, and aqueous aspirate specimens were sent for culture and sensitivity and to look for abnormal cells. Intracameral antibiotics were not injected. The specimens were sterile to culture, and chronic inflammatory cells were reported on the vitreous specimen. On examination 6 months later, inflammation had not recurred and the best corrected visual acuity was 6/18.

Patient-controlled bupivacaine infusion into the infrapatellar fat pad after anterior cruciate ligament reconstruction.

PURPOSE: The goal of the study was to determine the safety and analgesic efficacy of a patient-controlled infusion pump that dispenses bupivacaine extra-articularly to the infrapatellar fat pad after anterior cruciate ligament (ACL) reconstruction with ipsilateral bone-patellar tendon-bone autogenous graft. TYPE OF STUDY: Prospective clinical study. METHODS: Twenty-one consecutive patients were enrolled in the study. After surgery, the catheter of a bupivacaine infusion pump was implanted extra-articularly onto the infrapatellar fat pad. Ten patients were given infusion pumps with 50 mL of 0.5% bupivacaine to be self-administered for analgesia. Eleven patients were given infusion pumps with 50 mL of 0.25% bupivacaine. Opioid analgesics were available if patients were unable to control the pain solely with the bupivacaine pump. Historic controls consisted of 62 consecutive patients who underwent ACL reconstruction before study initiation. Patients recorded volumes of self-administered bupivacaine; also recorded were postoperative pain levels using a visual analog scale (VAS). Opioid analgesic usage was measured and compared with historic controls. RESULTS: Amount of bupivacaine infused and VAS recorded pain levels were not significantly different between the 0.5% and the 0.25% bupivacaine groups. Opioid analgesic usage was significantly reduced when the 0.5% bupivacaine group was compared with historic controls (mean morphine equivalents via intramuscular route: 0.5% group, 17.6 mg; historic controls, 66.4 mg; P =.015). This was also significant when normalized by patient weight (0.5% group, 0.227 mg/kg; historic controls, 0.880 mg/kg; P =.023). Opioid usage in the 0.25% group (35.7 mg and 0.540 mg/kg) was also less than historic controls; however, this was not statistically significant. CONCLUSIONS: Infrapatellar fat pad infusion with 0.5% bupivacaine may provide enhanced analgesia after ACL reconstruction with ipsilateral bone-patellar tendon-bone autogenous graft. A double-blinded, randomized control trial with a greater number of patients is required to confirm these findings.