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Introduction Older people in care homes living with frailty are less likely to benefit from tight glycaemic control in the management of type 2 diabetes with increased risk of adverse effects for example hypoglycaemia, falls and hospital admission. We wished to ascertain the scale of the problem and reduce overtreatment. We defined overtreatment based on American Diabetes Association guidelines as being on an agent that can cause hypoglycaemia and having an HBA1C of ≤53 mmol/mol or, an HbA1c 53–64 mmol/mol with either three or more co-morbidities. Methods In 2016, we audited the management of type 2 diabetes in older people discharged from LTHT to care homes. We discussed our concerns with diabetes and geriatric medicine colleagues across medical, nursing and pharmacy disciplines. We engaged the support of the citywide diabetes network which comprises secondary care colleagues, general practitioners and pharmacists. We presented the findings of our initial audit to colleagues within primary and secondary care through departmental meetings and citywide network meetings. We wrote a new guideline, specifically for frail older people that was disseminated citywide through these networks. We re-audited in 2020. Results In total, 113 cases were reviewed in 2016 and 105 cases in 2020. In 2020, only 6% (6 patients) were overtreated compared to 38% (43 patients) in 2016. Conclusions There has been a marked reduction in overtreatment which should result in less adverse events. We believe the reasons for success lie in wide engagement of relevant stakeholder groups around an issue that is important, large in scale and meaningful to both patient and clinician. There are potential cost savings from reducing medications and reducing harm.

Introduction Discussing preferences around cardiopulmonary resuscitation (CPR) is recommended to patients who wish to discuss this, or where there is foreseeable risk of life-threatening clinical deterioration. Our team felt that we discussed this routinely for our inpatients but wished to investigate how we did this, when we did this, why decisions were made and who led these discussions. Methods We retrospectively reviewed the electronic patient notes of 118 patients recently discharged from elderly medicine between February and November 2020 and recorded demographic details, co-morbidities and outcomes of discussions regarding resuscitation. Results 100/118 patients had a RESPECT form documenting preferences. Of these 100 patients, 97% had a DNACPR recommendation, 2 had a ‘for resuscitation’ recommendation and one was undecided. 69% of patients had their preferences recorded during the current admission. 43% of discussions were led by a tier 1/2 doctor. 21% of discussions were led by a tier 3 doctor. 23% of discussions were led by a consultant. It was unclear who had led the discussion 13% of the time. 29/97 patients had a DNACPR due to their wishes. 16/97 patients had a DNACPR based on clinical grounds that it would not succeed. 33/97 patients had a DNACPR on the grounds that burden outweighed risks and they had capacity In 19/97 patients the reason for DNACPR was not clearly documented. There were 6 discussions where there was distress or disagreement—all of the discussions resulted in DNACPR recommendation 1 patient had a DNACPR reversed during their admission and none were reversed afterwards. Conclusion Systematically discussing preferences around resuscitation is feasible and rarely results in distress. The majority of patients have a recommendation for DNACPR and discussions are led by ‘junior’ doctors.

Protein oligomerization is one mechanism by which homogenous solutions can separate into distinct liquid phases, enabling assembly of membraneless organelles. Survival Motor Neuron (SMN) is the eponymous component of a large macromolecular complex that chaperones biogenesis of eukaryotic ribonucleoproteins and localizes to distinct membraneless organelles in both the nucleus and cytoplasm. SMN forms the oligomeric core of this complex, and missense mutations within its YG box domain are known to cause Spinal Muscular Atrophy (SMA). The SMN YG box utilizes a unique variant of the glycine zipper motif to form dimers, but the mechanism of higher-order oligomerization remains unknown. Here, we use a combination of molecular genetic, phylogenetic, biophysical, biochemical and computational approaches to show that formation of higher-order SMN oligomers depends on a set of YG box residues that are not involved in dimerization. Mutation of key residues within this new structural motif restricts assembly of SMN to dimers and causes locomotor dysfunction and viability defects in animal models.

Magnetically separable ZnFe 2 O 4 photocatalyst was prepared by facile Molten Salt Method (MSS) using eutectic mixture of NaCl- KCl flux. The obtained products were characterized by Powder X-ray diffraction (XRD) and Scanning electron microscopy (SEM). XRD confirm single phase ZnFe 2 O 4 formed at 900°C for 1 h. Crystalline size was calculated to be 50 - 90 nm using Scherrer expression. SEM micrographs shown particles crystallized in submicron range of polygonal morphology. The photocatalytic activity was evaluated for degradation of Rhodamine B (RhB) under UV irradiation, it found to show 98% of degradation.

The survival motor neuron (SMN) protein forms the oligomeric core of a multiprotein complex required for the assembly of spliceosomal small nuclear ribonucleoproteins. Deletions and mutations in the SMN1 gene are associated with spinal muscular atrophy (SMA), a devastating neurodegenerative disease that is the leading heritable cause of infant mortality. Oligomerization of SMN is required for its function, and some SMA patient mutations disrupt the ability of SMN to self-associate. Here, we investigate the oligomeric nature of the SMN·Gemin2 complexes from humans and fission yeast (hSMN·Gemin2 and ySMN·Gemin2). We find that hSMN·Gemin2 forms oligomers spanning the dimer to octamer range. The YG box oligomerization domain of SMN is both necessary and sufficient to form these oligomers. ySMN·Gemin2 exists as a dimer-tetramer equilibrium with Kd = 1.0 ± 0.9 μM. A 1.9 Å crystal structure of the ySMN YG box confirms a high level of structural conservation with the human ortholog in this important region of SMN. Disulfide cross-linking experiments indicate that SMN tetramers are formed by self-association of stable, non-dissociating dimers. Thus, SMN tetramers do not form symmetric helical bundles such as those found in glycine zipper transmembrane oligomers. The dimer-tetramer nature of SMN complexes and the dimer of dimers organization of the SMN tetramer provide an important foundation for ongoing studies to understand the mechanism of SMN-assisted small nuclear ribonucleoprotein assembly and the underlying causes of SMA.

Introduction: Although older individuals are more prone to hypoglycaemia, it is not known if they have sufficient understanding of the risks of hypoglycaemia or the factors that predispose to it. We evaluated the effectiveness of hypoglycaemia education and examined the factors that increased susceptibility to hypoglycaemia among older people with diabetes. Methods: Forty-five patients (male/female) aged >65 years and known to have diabetes were identified through outpatient clinics at a secondary care hospital. Information relating to education received, awareness of hypoglycaemia and associated risk factors was collected using a standard questionnaire. Additionally, data regarding demographics, treatment regimes, patient attitudes, hypoglycaemic awareness and risks and barriers to self-management of diabetes was collected. Patients were categorised as low, moderate and high risk based on their responses. Independent sample t-tests and Analysis of Variance were carried out to identify factors contributing to high hypoglycaemic risk. Results: Overall, 70% of the patients reported receiving education about hypoglycaemia from health professionals and 95% of them reported good understanding of hypoglycaemia and were able to self-test. Proportion of women receiving education was, however, lower than men (52% women versus 88% men). Compared with men, women were less likely to recognise (59 versus 73%), or act appropriately to a hypoglycaemic episode (59 versus 78%). The mean number of hypoglycaemic episodes per year (41 versus 12) and the duration of hypoglycaemia (9.9 versus 6.3 min) was also greater among women compared with men. The duration of diabetes (P = 0.018), female gender, type 1 diabetes (0.002) and lack awareness of medications causing hypos (P = 0.006) were strong predictors of hypoglycaemia risk. Conclusions: There are significant gaps in education around hypoglycaemia in older people with diabetes. Women, people with longer duration and type 1 diabetes in particular, need additional attention and future educational initiatives need to address these issues.

Patients may be referred to Acute Medical Units (AMUs) with a diagnosis of ‘acopia’. This term is offensive and lazy, implying fault on the part of the patient and allowing the assessing doctor to erroneously label the patient as a ‘social admission’ when, in fact, such patients are likely to be frail with co-morbidities and have an acute (potentially reversible) illness. Frail older patients should be assessed using the principles of Comprehensive Geriatric Assessment, informed by an understanding of the concept of frailty and of geriatric syndromes such as falls and delirium.

Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.

Background The natural history of thyroid function in adults with Down syndrome is relatively unknown with limited long-term follow-up data. Method This study investigated annual thyroid function tests in 200 adults with Down syndrome over a 15-year period. Results For healthy adults with Down syndrome there is a gradual increase in thyroxine and possible gradual decline in thyroid-stimulating hormone with age. The 15-year incidence for definite hypothyroidism remains low and subclinical hypothyroidism is not a precursor for the onset of definite hypothyroidism. Conclusions The incidence of thyroid dysfunction is markedly less than would be expected from prevalence studies. Subclinical hypothyroidism is not necessarily a precursor to definite hypothyroidism. Prevalence studies have overstated the association between thyroid dysfunction and Down syndrome. Routine screening for adults with Down syndrome who are euthyroid can be reduced to every 5 years rather than the 1–2 years, as is the present policy.

Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described.

Acute bloody diarrhoea may be commonly encountered in the acute medical unit. Among young patients, the main differential diagnoses are acute infectious colitis, and first presentation of inflammatory bowel disease (IBD). A combination of clinical, laboratory, radiological, endoscopic and histological investigations are required to make the diagnosis. If inflammatory bowel disease is suspected, then the patient should be admitted to a specialist gastroenterology ward and receive input from the surgical team, IBD nurses and specialist stoma nurses. Intravenous steroid therapy for acute severe disease should be started before stool cultures are back unless there is a strong clinical suspicion of amoebiasis. All patients require thromboprophylaxis and close attention paid to fluid balance and nutritional requirements. Daily clinical review is required. The Travis criteria may be employed at day 3 to assess the likelihood of requiring surgery and plans for rescue therapy, medical or surgical should be made between day 3-7 if the patient is not responding adequately to initial medical therapy.

Camphor-3-thioxo-2-oxime (HCTO) is proposed as a new sensitive analytical reagent for the extractive spectrophotometric determination of trace amounts of lead. The method is based on the instantaneous formation of a stable yellow-orange colored 1:2 chelate with lead at room temperature in the pH range 9.3–9.6 selectively extracted in carbon tetrachloride. The extracted species exhibits an absorption maximum at 400 nm with a molar absorptivity of 4.14×104 mol−1 cm−1, complying with Beer’s law over the concentration range 0.1–0.5 μg ml-1 of lead with an optimum concentration range 0.18–0.37 μg ml−1. The effects of pH, concentration of reagent and salting-out agents, time of equilibration, order of addition of diluents and the tolerance limit of the method towards various cations and anions usually associated with lead are reported. The developed method is successfully used for the determination of traces of lead in synthetic mixtures, alloys and ore samples.

The BTB/POZ domain defines a conserved region of about 120 residues and has been found in over 40 proteins to date. It is located predominantly at the N terminus of Zn-finger DNA-binding proteins, where it may function as a repression domain, and less frequently in actin-binding and poxvirus-encoded proteins, where it may function as a protein-protein interaction interface. A prototypic human BTB/POZ protein, PLZF (promyelocytic leukemia zinc finger) is fused to RARalpha (retinoic acid receptor alpha) in a subset of acute promyelocytic leukemias (APLs), where it acts as a potent oncogene. The exact role of the BTB/POZ domain in protein-protein interactions and/or transcriptional regulation is unknown. We have overexpressed, purified, characterized, and crystallized the BTB/POZ domain from PLZF (PLZF-BTB/POZ). Gel filtration, dynamic light scattering, and equilibrium sedimentation experiments show that PLZF-BTB/POZ forms a homodimer with a Kd below 200 nM. Differential scanning calorimetry and equilibrium denaturation experiments are consistent with the PLZF-BTB/POZ dimer undergoing a two-state unfolding transition with a Tm of 70.4 degrees C, and a DeltaG of 12.8 +/- 0.4 kcal/mol. Circular dichroism shows that the PLZF-BTB/POZ dimer has significant secondary structure including about 45% helix and 20% beta-sheet. We have prepared crystals of the PLZF-BTB/POZ that are suitable for a high resolution structure determination using x-ray crystallography. The crystals form in the space group I222 or I212121 with a = 38.8, b = 77.7, and c = 85.3 A and contain 1 protein subunit per asymmetric unit with approximately 40% solvent. Our data support the hypothesis that the BTB/POZ domain mediates a functionally relevant dimerization function in vivo. The crystal structure of the PLZF-BTB/POZ domain will provide a paradigm for understanding the structural basis underlying BTB/POZ domain function.

Background:In an emergency, the non-availability of a conventional paediatric tracheostomy tube is a therapeutic challenge for the attending surgeon.Objective:To describe a simple alternative to a paediatric tracheostomy tube for use in an emergency situation.Method:Case report of a 14-year-old boy who developed tracheomalacia following partial cricotracheal resection for subglottic stenosis. As a suitably sized tracheostomy tube (with a long narrow segment) was not available, an endotracheal tube was modified and used successfully. Details of the modification, and a relevant literature review, are also discussed.Conclusion:In the paediatric age group, when an appropriately sized tracheostomy tube is not available, a modified endotracheal tube is a simple temporary alternative; this may be especially useful in an emergency.

The natural history of thyroid function in adults with Down syndrome is relatively unknown with limited long-term follow-up data.This study investigated annual thyroid function tests in 200 adults with Down syndrome over a 15-year period.For healthy adults with Down syndrome there is a gradual increase in thyroxine and possible gradual decline in thyroid-stimulating hormone with age. The 15-year incidence for definite hypothyroidism remains low and subclinical hypothyroidism is not a precursor for the onset of definite hypothyroidism.The incidence of thyroid dysfunction is markedly less than would be expected from prevalence studies. Subclinical hypothyroidism is not necessarily a precursor to definite hypothyroidism. Prevalence studies have overstated the association between thyroid dysfunction and Down syndrome. Routine screening for adults with Down syndrome who are euthyroid can be reduced to every 5 years rather than the 1-2 years, as is the present policy.

We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described.

Inhibiting the classical pathway of complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia-reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a Ki of 10nM and >1000-fold selectivity over uPA, tPA, FX(a), thrombin, and plasmin.

The discovery, SAR, and X-ray crystal structure of novel biarylaminoacyl-(S)-2-cyano-pyrrolidines and biarylaminoacylthiazolidines as potent inhibitors of dipeptidyl peptidase IV (DPP IV) are reported.

Renal allografts are sensitive to ischemic insult. During aortic cross clamping prevention of ischemic damage to a kidney below an aneurysm is vital. Many maneuvers have been reported. We describe a simple technique of protecting the transplant kidney from ischemic damage during aortic surgery.During vascular cross clamping a sterile ice slush was placed around the kidney for surface cooling, obviating the need for some of the complicated procedures previously reported.After removal of the ice slush and clamps, urine production resumed and creatinine levels remained unchanged.External cooling with ice slush provides adequate renal protection during aortic cross clamping and requires no special expertise or equipment.

Spontaneous appendicocutaneous fistula is a rare complication of appendicitis. We report a case of appendicular carcinoid who presented with appendicocutaneous fistula.

Severe blood loss from dysfunctional uterine bleeding may be refractory to medical therapy and hysterectomy the only option. In two young women with severe bleeding where medical measures were ineffective and hysterectomy was a hazardous option, we performed a transcervical endometrial resection. In both of them the bleeding stopped immediately and no further treatment was required for dysfunctional uterine bleeding. They have had amenorrhea now for over six months. Transcervical endometrial resection is an option when hysterectomy is hazardous and the bleeding is refractory to medical treatment.

Summary The survival motor neuron (SMN) protein forms the oligomeric core of a multiprotein complex that functions in spliceosomal snRNP biogenesis. Loss of function mutations in the SMN gene cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Nearly half of the known SMA patient missense mutations map to the SMN YG-box, a highly conserved oligomerization domain of unknown structure that contains a (YxxG) 3 motif. Here, we report that the SMN YG-box forms helical oligomers similar to the glycine zippers found in transmembrane channel proteins. A network of tyrosine-glycine packing between helices drives formation of soluble YG-box oligomers, providing a structural basis for understanding SMN oligomerization and for relating defects in oligomerization to the mutations found in SMA patients. These results have important implications for advancing our understanding of SMN function and glycine zipper-mediated helix-helix interactions.