Acute hypertriglyceridemia induces platelet hyperactivity that is not attenuated by insulin in polycystic ovary syndrome.

Atherothrombosis is associated with platelet hyperactivity. Hypertriglyceridemia and insulin resistance (IR) are features of polycystic ovary syndrome (PCOS). The effect of induced hypertriglyceridemia on IR and platelet function was examined in young women with PCOS. Following overnight fasting, 13 PCOS and 12 healthy women were infused with saline or 20% intralipid for 5 hours on separate days. Insulin sensitivity was measured using a hyperinsulinemic euglycaemic clamp in the final 2 hours of each infusion. Platelet responses to adenosine diphosphate (ADP) and prostacyclin (PGI2) were measured by flow cytometric analysis of platelet fibrinogen binding and P-selectin expression using whole blood taken during each infusion (at 2 hours) and at the end of each clamp. Lipid infusion increased triglycerides and reduced insulin sensitivity in both controls (median, interquartile range ) (5.25 [3.3, 6.48] versus 2.60 [0.88, 3.88] mg kg(-1) min(-1), P<0.001) and PCOS (3.15 [2.94, 3.85] versus 1.06 [0.72, 1.43] mg kg(-1) min(-1), P<0.001). Platelet activation by ADP was enhanced and ability to suppress platelet activation by PGI2 diminished during lipid infusion in both groups when compared to saline. Importantly, insulin infusion decreased lipid-induced platelet hyperactivity by decreasing their response to 1 μmol/L ADP (78.7% [67.9, 82.3] versus 62.8% [51.8, 73.3], P=0.02) and increasing sensitivity to 0.01 μmol/L PGI2 (67.6% [39.5, 83.8] versus 40.9% [23.8, 60.9], P=0.01) in controls, but not in PCOS. Acute hypertriglyceridemia induced IR, and increased platelet activation in both groups that was not reversed by insulin in PCOS subjects compared to controls. This suggests that platelet hyperactivity induced by acute hypertriglyceridemia and IR could contribute athero-thrombotic risk. www.isrctn.org. Unique Identifier: ISRCTN42448814

Dynamic change in insulin resistance induced by free fatty acids is unchanged though insulin sensitivity improves following endurance exercise in PCOS

Background: Insulin resistance (IR) is the hallmark of PCOS and it is known that exercise may decrease it. What is unknown is whether exercise may mechanistically alter the underlying IR, attenuating the dynamic lipid induced IR in insulin resistant subjects.Methods: Twelve women with polycystic ovary syndrome (PCOS) and ten age and body mass index matched controls completed an eight week supervised exercise program at 60% maximal oxygen consumption. Before and after the exercise program, all participants underwent hyperinsulinaemic euglycaemic clamps with either saline or intralipid infusions. Skewed data were log transformed and expressed as mean ±SEM. Results: Before exercise, women with PCOS had a higher HOMA-IR and lower VO2 max than controls. Compared to saline, lipid infusion lowered the rate of insulin stimulated glucose disposal (M value; mg/kg/min) by 67±5% (from 0.5±0.03 to -0.25±0.2, p=0.01) in PCOS, and by 49±7% (from 0.65±0.06 to 0.3±0.1, p=0.01) in controls. The M value was significantly less in PCOS compared to controls for both saline (p less than 0.01) and lipid (p less than 0.05). Endurance exercise in PCOS improved VO2 max and HOMA-IR, but not weight, to those of pre-exercise control subjects. The glucose disposal rate during the lipid infusion was reduced following exercise in PCOS, indicating decreased IR (67 ± 5 vs. 50 ± 7%, p = 0.02), but IR was not altered in controls (49 ± 7 vs. 45 ± 6%, p = 0.58). The incrementally increased IR induced by the lipid infusion did not differ between controls and PCOS.Conclusion: Insulin sensitivity improved with exercise in the PCOS group alone showing that IR can be modified, though likely transiently. However, the maximal IR response to the lipid infusion did not differ within and between control and PCOS subjects, indicating that the fundamental mechanism underlying insulin resistance was unchanged with exercise.Precis: Maximal insulin resistance induced by lipid infusion determined at baseline and 8 weeks after exercise in control and PCOS women did not differ, though insulin sensitivity increased in PCOS after exercise

Treatment seeking and antibiotic use for urinary tract infection symptoms in the time of COVID-19 in Tanzania and Uganda

Funding: CARE: COVID-19 and Antimicrobial Resistance in East Africa – impact and response is a Global Effort on COVID-19 (GECO) Health Research Award (MR/V036157/1) funded by UK Research and Innovation (Medical Research Council) and the Department of Health and Social Care (National Institute for Health Research).Background There is still little empirical evidence on how the outbreak of coronavirus disease 2019 (COVID-19) and associated regulations may have disrupted care-seeking for non-COVID-19 conditions or affected antibiotic behaviours in low- and middle-income countries (LMICs). We aimed to investigate the differences in treatment-seeking behaviours and antibiotic use for urinary tract infection (UTI)-like symptoms before and during the pandemic at recruitment sites in two East African countries with different COVID-19 control policies: Mbarara, Uganda and Mwanza, Tanzania. Methods In this repeated cross-sectional study, we used data from outpatients (pregnant adolescents aged >14 and adults aged >18) with UTI-like symptoms who visited health facilities in Mwanza, Tanzania and Mbarara, Uganda. We assessed the prevalence of self-reported behaviours (delays in care-seeking, providers visited, antibiotics taken) at three different time points, labelled as ‘pre-COVID-19 phase’ (February 2019 to February 2020), ‘COVID-19 phase 1’ (March 2020 to April 2020), and ‘COVID-19 phase 2’ (July 2021 to February 2022). Results In both study sites, delays in care-seeking were less common during the pandemic than they were in the pre-COVID phase. Patients in Mwanza, Tanzania had shorter care-seeking pathways during the pandemic compared to before it, but this difference was not observed in Mbarara, Uganda. Health centres were the dominant sources of antibiotics in both settings. Over time, reported antibiotic use for UTI-like symptoms became more common in both settings. During the COVID-19 phases, there was a significant increase in self-reported use of antibiotics like metronidazole (<30% in the pre-COVID-19 phase to 40% in COVID phase 2) and doxycycline (30% in the pre-COVID-19 phase to 55% in COVID phase 2) that were not recommended for treating UTI-like symptoms in the National Treatment Guidelines in Mbarara, Uganda. Conclusions There was no clear evidence that patients with UTI-like symptoms attending health care facilities had longer or more complex treatment pathways despite strict government-led interventions related to COVID-19. However, antibiotic use increased over time, including some antibiotics not recommended for treating UTI, which has implications for future antimicrobial resistance.Publisher PDFPeer reviewe

Predominance of multidrug-resistant bacteria causing urinary tract infections among symptomatic patients in East Africa : a call for action

Background In low- and middle-income countries, antibiotics are often prescribed for patients with symptoms of urinary tract infections (UTIs) without microbiological confirmation. Inappropriate antibiotic use can contribute to antimicrobial resistance (AMR) and the selection of MDR bacteria. Data on antibiotic susceptibility of cultured bacteria are important in drafting empirical treatment guidelines and monitoring resistance trends, which can prevent the spread of AMR. In East Africa, antibiotic susceptibility data are sparse. To fill the gap, this study reports common microorganisms and their susceptibility patterns isolated from patients with UTI-like symptoms in Kenya, Tanzania and Uganda. Within each country, patients were recruited from three sites that were sociodemographically distinct and representative of different populations. Methods UTI was defined by the presence of >104 cfu/mL of one or two uropathogens in mid-stream urine samples. Identification of microorganisms was done using biochemical methods. Antimicrobial susceptibility testing was performed by the Kirby–Bauer disc diffusion assay. MDR bacteria were defined as isolates resistant to at least one agent in three or more classes of antimicrobial agents. Results Microbiologically confirmed UTI was observed in 2653 (35.0%) of the 7583 patients studied. The predominant bacteria were Escherichia coli (37.0%), Staphylococcus spp. (26.3%), Klebsiella spp. (5.8%) and Enterococcus spp. (5.5%). E. coli contributed 982 of the isolates, with an MDR proportion of 52.2%. Staphylococcus spp. contributed 697 of the isolates, with an MDR rate of 60.3%. The overall proportion of MDR bacteria (n = 1153) was 50.9%. Conclusions MDR bacteria are common causes of UTI in patients attending healthcare centres in East African countries, which emphasizes the need for investment in laboratory culture capacity and diagnostic algorithms to improve accuracy of diagnosis that will lead to appropriate antibiotic use to prevent and control AMR.Peer reviewe

Treatment seeking behaviours, antibiotic use and relationships to multi-drug resistance : a study of urinary tract infection patients in Kenya, Tanzania and Uganda

Antibacterial resistance (ABR) is a major public health threat. An important accelerating factor is treatment-seeking behaviour, including inappropriate antibiotic (AB) use. In many low- and middle-income countries (LMICs) this includes taking ABs with and without prescription sourced from various providers, including health facilities and community drug sellers. However, investigations of complex treatment-seeking, AB use and drug resistance in LMICs are scarce. The Holistic Approach to Unravel Antibacterial Resistance in East Africa (HATUA) Consortium collected questionnaire and microbiological data from adult outpatients with urinary tract infection (UTI)-like symptoms presenting at healthcare facilities in Kenya, Tanzania and Uganda. Using data from 6,388 patients, we analysed patterns of self-reported treatment seeking behaviours (‘patient pathways’) using process mining and single-channel sequence analysis. Among those with microbiologically confirmed UTI (n = 1,946), we used logistic regression to assess the relationship between treatment seeking behaviour, AB use, and the likelihood of having a multi-drug resistant (MDR) UTI. The most common treatment pathway for UTI-like symptoms in this sample involved attending health facilities, rather than other providers like drug sellers. Patients from sites in Tanzania and Uganda, where over 50% of patients had an MDR UTI, were more likely to report treatment failures, and have repeat visits to providers than those from Kenyan sites, where MDR UTI proportions were lower (33%). There was no strong or consistent relationship between individual AB use and likelihood of MDR UTI, after accounting for country context. The results highlight the hurdles East African patients face in accessing effective UTI care. These challenges are exacerbated by high rates of MDR UTI, suggesting a vicious cycle of failed treatment attempts and sustained selection for drug resistance. Whilst individual AB use may contribute to the risk of MDR UTI, our data show that factors related to context are stronger drivers of variations in ABR.Peer reviewe

Capillary pressure in patients with type 1 diabetes mellitus : an examination of the haemodynamic hypothesis

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The coastal landslides of Shetland

Little is known of hard-rock coastal landsliding in Scotland. We identify 128 individual coastal landslides or landslide complexes &gt;50 m wide along the coasts of Shetland. Most are apparently translational slides characterized by headscarps, displaced blocks and/or debris runout, but 13 deep-seated failures with tension cracks up to 200 m inland from cliff crests were also identified. Thirty-one sites exhibit evidence of at least localized recent activity. Landslide distribution is primarily determined by the distribution of coastal cliffs &gt;30 m high, and they are preferentially developed on metasedimentary rocks. Analysis of 16 landslides on Fetlar (NE Shetland) indicates that most are translational dip-slip failures; 3 represent deep-seated failures and several exhibit active frontal erosion attributable to basal sapping by storm waves. As these landslides terminate in shallow water, failure was probably initiated when rising sea level resulted in footslope erosion and upslope propagation of instability, causing downslope displacement of landslide blocks on upper slopes. 10Be exposure dating of two headscarps yielded ages of 4.8 ± 0.2 ka and 4.4 ± 0.2 ka, consistent with the onset of footslope erosion as sea level rose. Our results suggest that landslides have played a hitherto undocumented but important role in retreat of cliffed coastlines in Scotland