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Background: Arteriovenous malformations (AVMs) are developmental defects in the vascular system with abnormal connections between arteries and veins. A minority of AVMs are characterized by aggressive growth and continue to proliferate despite maximal surgical and interventional therapy. We report our outcomes with the use of thalidomide as the only UK specialist center adopting this novel approach for the management of AVMs refractory to conventional therapy., Methods: This was a retrospective case series which included only complex and proliferative AVM lesions (Schobinger grade III and IV). All patients prescribed thalidomide on a compassionate basis between September 2006 and August 2022 after attempts at embolosclerotherapy without satisfactory response were reviewed., Results: Eleven patients were included in our study. The median total duration of thalidomide use was 10 months. Two thirds of patients with pain (six of nine) reported an improvement, three quarters reported a reduction in swelling (six of eight) and all who presented with bleeding reported improvement in overall volume or frequency (four of four). Over the study period, 45% achieved a non-proliferative state with no further target vessel demonstrable on angiography. Mild, tolerable side effects such as fatigue were common (73%). There was only one major adverse reaction (neutropenia) necessitating cessation of therapy., Conclusions: We can conclude that thalidomide is able to reduce the symptom burden for patients with complex and proliferative AVMs that were refractory to established treatment modalities. Adverse effects are common, but the benefit achieved from taking thalidomide in otherwise treatment resistant cases outweighs the risks, most of which are manageable.

Background: The four-port laparoscopic technique is the standard approach for cholecystectomy. A three-port technique has been described, but there is no consensus over the outcomes and efficacy of this approach. The aim was to perform a systematic review and meta-analysis to compare the three- and four-port techniques in laparoscopic cholecystectomy for benign diseases of the gallbladder., Methods: The review was conducted according to a predefined protocol registered on PROSPERO. Two authors independently conducted an electronic database search of CENTRAL, MEDLINE, Embase, CINAHL, WHO International Clinical Trials Registry, and ClinicalTrials.gov. Outcomes are reported as risk ratios (RR), mean difference (m.d.), or standardized mean difference (s.m.d.) with 95 per cent confidence intervals., Results: Eighteen trials were included with 2085 patients. Length of hospital stay and postoperative analgesia requirement favoured the three-port group (m.d. -0.29, 95 per cent c.i. -0.43 to -0.16 (P < 0.001); and s.m.d. -0.68, 95 per cent c.i. -1.03 to -0.33 (P < 0.001), respectively). There were no differences in length of procedure or success rate between the two groups (m.d. 0.90, 95 per cent c.i. -3.78 to 5.58 (P = 0.71) and RR 0.99, 95 per cent c.i. 0.97 to 1.01 (P = 0.17), respectively). There were no differences in adverse events. The overall quality of evidence was low., Conclusion: The three-port technique for laparoscopic cholecystectomy is an option for appropriately trained surgeons who perform it regularly. However, the decision to use three ports should not be at the expense of safe dissection of Calot's triangle., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: Polygenic scores-which quantify inherited risk by integrating information from many common sites of DNA variation-may enable a tailored approach to clinical medicine. However, alongside considerable enthusiasm, we and others have highlighted a lack of standardized approaches for score disclosure. Here, we review the landscape of polygenic score reporting and describe a generalizable approach for development of a polygenic score disclosure tool for coronary artery disease., Methods: We assembled a working group of clinicians, geneticists, data visualization specialists, and software developers. The group reviewed existing polygenic score reports and then designed a two-page mock report for coronary artery disease. We then conducted a qualitative user-experience study with this report using an interview guide focused on comprehension, experience, and attitudes. Interviews were transcribed and analyzed for themes identification to inform report revision., Results: Review of nine existing polygenic score reports from commercial and academic groups demonstrated significant heterogeneity, reinforcing the need for additional efforts to study and standardize score disclosure. Using a newly developed mock score report, we conducted interviews with ten adult individuals (50% females, 70% without prior genetic testing experience, age range 20-70 years) recruited via an online platform. We identified three themes from interviews: (1) visual elements, such as color and simple graphics, enable participants to interpret, relate to, and contextualize their polygenic score, (2) word-based descriptions of risk and polygenic scores presented as percentiles were the best recognized and understood, (3) participants had varying levels of interest in understanding complex genomic information and therefore would benefit from additional resources that can adapt to their individual needs in real time. In response to user feedback, colors used for communicating risk were modified to minimize unintended color associations and odds ratios were removed. All 10 participants expressed interest in receiving a polygenic score report based on their personal genomic information., Conclusions: Our findings describe a generalizable approach to develop a polygenic score report understandable by potential patients. Although additional studies are needed across a wider spectrum of patient populations, these results are likely to inform ongoing efforts related to polygenic score disclosure within clinical practice., (© 2021. The Author(s).)

A 58-year-old woman with a previous clam ileocystoplasty was referred to the urology department for the investigation of haematuria. CT urogram showed a large left-sided soft tissue mass arising from the bladder. Histological analysis of the shavings from transurethral resection revealed a G3pT2 transitional cell carcinoma and T4N1Mx adenocarcinoma. The patient was referred to oncology for the discussion of palliative chemotherapy; however, in the interim she deteriorated and was admitted to hospital with a post-renal acute kidney injury. A right-sided nephrostomy was inserted relieving her obstruction and she subsequently made a good recovery. This case report illustrates the difficulties in the long-term follow-up of patients having undergone what is now a rarely performed procedure. In the absence of regular cystoscopic follow-up post ileocystoplasty, malignancy may present late and with complications from advanced disease., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

CRISPR-associated (Cas) DNA-endonucleases are remarkably effective tools for genome engineering, but have limited target ranges due to their protospacer adjacent motif (PAM) requirements. We demonstrate a critical expansion of the targetable sequence space for a type II-A CRISPR-associated enzyme through identification of the natural 5[Formula: see text]-NAAN-3[Formula: see text] PAM preference of Streptococcus macacae Cas9 (SmacCas9). To achieve efficient editing activity, we graft the PAM-interacting domain of SmacCas9 to its well-established ortholog from Streptococcus pyogenes (SpyCas9), and further engineer an increased efficiency variant (iSpyMac) for robust genome editing activity. We establish that our hybrids can target all adenine dinucleotide PAM sequences and possess robust and accurate editing capabilities in human cells.

We report an approach to barcode cells through cell-surface expression of programmable zinc-finger DNA-binding domains (surface zinc fingers, sZFs). We show that sZFs enable sequence-specific labeling of living cells by dsDNA, and we develop a sequential labeling approach to image more than three cell types in mixed populations using three fluorophores. We demonstrate the versatility of sZFs through applications in which they serve as surrogate reporters, function as selective cell capture reagents and facilitate targeted cellular delivery of viruses.

The mechanism of tetracycline-induced inhibition of matrix metalloproteinases (MMP) was studied by measuring the MMP secretion and MMP-2 mRNA levels in unkeratinizing periodontal ligament epithelial cells and skin keratinocytes cultured in the presence of doxycycline or chemically modified tetracyclines (CMT) lacking antimicrobial activity. Doxycycline, CMT-1, and CMT-8 exerted a direct dose-dependent inhibition of porcine periodontal ligament epithelial cell medium MMP activity as assayed by gelatin enzymography. Both the 92-kDa (MMP-9) and 72-kDa (MMP-2) gelatinases were inhibited by the tetracyclines added to the conditioned medium. Culturing the cells in the presence of the tetracyclines required considerably smaller concentrations to reduce the secreted MMP activity. The drugs were not toxic to the epithelial cells at concentrations from 4 to 250 micrograms/mL up to 24 h of culture. Tetracycline effects on the MMP-2 mRNA levels were studied in human skin keratinocytes using Northern hybridization analysis with a specific cDNA probe. A marked inhibition in the MMP-2 gene expression was observed by 6 h with 5 micrograms/mL of doxycycline, CMT-1 or CMT-8. Doxycycline inhibition was somewhat stronger than the two other tetracyclines. After 24 h of culture with 50 micrograms/mL of the drugs, the total RNA levels also decreased by 33 to 40%. The 72-kDa gelatinase activity in culture medium of the keratinocytes followed roughly the pattern of inhibition of the gene expression. We conclude that doxycycline and the chemically modified tetracyclines, in addition to inhibiting the MMP activity may also reduce the enzyme expression at the transcriptional level.

The hemopoietic growth factor, interleukin 3, has been shown to activate protein kinase C without causing hydrolysis of inositol phospholipids. The potential involvement of phosphatidylcholine hydrolysis as an alternative source of diacylglycerol was investigated in an interleukin 3-dependent murine mast/megakaryocyte cell line, R6-XE.4. Treatment of these cells with interleukin 3 rapidly stimulated both the release of water-soluble choline metabolites and the resynthesis of phosphatidylcholine. Therefore, a phosphatidylcholine cycle may operate as part of the signal transduction pathway in cells responding to interleukin 3.