Transmission dynamics and associated mortality of nosocomial COVID-19 throughout 2021: a retrospective study at a large teaching hospital in London.

BACKGROUND: The impact of nosocomial SARS-CoV-2 infections has changed significantly since 2020. However, there is a lack of up-to-date evidence of the epidemiology of these infections which is essential in order to appropriately guide infection control policy. AIMS: To identify the secondary attack rate of SARS-CoV-2 infection and associated mortality across different variants of concern. METHODS: A single-centre retrospective study of all nosocomial SARS-CoV-2 exposure events was conducted between 31st December 2020 and 31st December 2021. A secondary attack rate was calculated for nosocomial acquisition of SARS-CoV-2 infection and time to positivity. Positive contacts were assessed for all-cause 30-day mortality. RESULTS: A total of 346 sequential index exposure events were examined, and 1378 susceptible contacts identified. Two hundred susceptible contacts developed SARS-CoV-2 infection (secondary attack rate of 15.5%). The majority of index cases (59%) did not result in any secondary SARS-CoV-2 infection. Where close contacts developed SARS-CoV-2 infection, 80% were detected within the first five days since last contact with the index case. The overall associated mortality among positive contacts across 2021 was 9%, with an estimated reduction of 68% when comparing periods of high Omicron versus Alpha transmission. CONCLUSION: Our findings describe that most SARS-CoV-2 infections are detected within five days of contact with an index case; we have also demonstrated a considerably lower mortality rate with the Omicron variant in comparison to previous variants. These findings have important implications for informing and supporting infection control protocols to allow movement through the hospital, and ensure patients access care safely.

Choosing Wisely Canada: Canadian fertility and andrology society's list of top items physicians and patients should question in fertility medicine.

PURPOSE: To create a Choosing Wisely Canada list of the top 5 diagnostic and therapeutic interventions that should be questioned in Reproductive Endocrinology and Infertility in Canada. METHODS: The Canadian Fertility and Andrology Society (CFAS) National Working Group developed an initial list of recommendations of diagnostic and therapeutic interventions that are commonly used, but are not supported by evidence, and could expose patients to unnecessary harm. These were chosen based on their prevalence, cost, potential for harm, and quality of supporting evidence. A modified Delphi consensus was used over 5 rounds to generate ideas, review supporting evidence, assess clinical relevance, estimate recommendation impact and narrow the recommendations list to 5 items. RESULTS: Fifty unique ideas were first proposed by the working group, and after 5 rounds including a survey of Canadian Fertility and Andrology Society (CFAS) members, the final list of recommendations was created, including topics related to unnecessary investigations and interventions for patients with infertility and recurrent pregnancy loss, and those undergoing IVF. In this article, we describe not only the Delphi process used to determine the list, but also provide a summary of the evidence behind each of the final recommendations. CONCLUSIONS: The list of five recommendations highlights opportunities to initiate conversations between clinicians and patients about the risks, benefits, harms and costs of unnecessary fertility treatments and procedures in a Canadian context.

Effect of the UK Psychoactive Substances Act 2016 on episodes of toxicity related to new psychoactive substances as reported to the National Poisons Information Service. A time series analysis.

BACKGROUND: There have been recent increases in use of new psychoactive substances (NPS) associated with acute health harms including hospital presentations due to toxicity and increasing numbers of deaths. In response, the UK Government enacted generic legislation on 26th May 2016 (the Psychoactive Substances Act) making it an offence to produce, possess with intent to supply, supply, import or export, or possess within a custodial setting a psychoactive substance. We studied the impact of this Act on monthly frequency of enquiries made by health professionals to the UK National Poisons Information Service (NPIS) about NPS. We also studied five commonly used 'conventional' drugs of misuse that had been controlled prior to January 2009. METHOD: Anonymised clinical enquiries to the NPIS and accesses to the poisons information database TOXBASE were reviewed retrospectively from January 2009 to December 2018 to ascertain the trends in reported toxicity for NPS, cocaine, heroin, cannabis, amphetamines and MDMA. Data were analysed using interrupted time series analysis with the date of the PSA used as an independent predictor. RESULTS: Over the period of study there were 3,866 NPIS telephone enquiries and 79,271 TOXBASE user accesses made by UK health professionals concerning NPS. There were increases in monthly TOXBASE accesses (t = 7.408, P < 0.0001) and telephone enquiries (t = 4.74, P < 0.001) over the pre-specified period January 2009 to May 2016. Comparing the period after the PSA with that before, there were significant reductions in TOXBASE accesses (t = -3.327, P < 0.001) and telephone enquiries (t = -6.97, P < 0.001), although reductions started before May 2016. There were no significant changes for the five conventional drugs. There were significant reductions in telephone enquiries (t = -3.418, P < 0.001) and non-significant reductions in TOXBASE accesses (t = -1.713, P = 0.089) for NPS between June 2016 and December 2018. Increases in telephone enquiries for cocaine and reductions TOXBASE accesses for MDMA were also observed over that period. CONCLUSIONS: There have been significant recent reductions in NPIS enquiry activity relating to NPS; although these began before enactment of the PSA in May 2016.

Development and Implementation of Health and Wellness CBT for Individuals with Depression and HIV.

Rates of depression are reported to be between 22-33% in adults with HIV, which is double that of the general population. Depression negatively affects treatment adherence and health outcomes of those with medical illnesses. Further, it has been shown in adults that reducing depression may improve both adherence and health outcomes. To address the issues of depression and non-adherence, Health and Wellness (H&W) Cognitive Behavioral Therapy (CBT) and medication management (MM) treatment strategies have been developed specifically for youth living with both HIV and depression. H&W CBT is based on other studies with uninfected youth and upon research on adults with HIV. H&W CBT uses problem-solving, motivational interviewing, and cognitive-behavioral strategies to decrease adherence obstacles and increase wellness. The intervention is delivered in 14 planned sessions over a 6-month period, with three different stages of CBT. This paper summarizes the feasibility and acceptability data from an open depression trial with 8 participants, 16-24 years of age, diagnosed with HIV and with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis of depression, conducted at two treatment sites in the Adolescent Trials Network (ATN). Both therapists and subjects completed a Session Evaluation Form (SEF) after each session, and results were strongly favorable. Results from The Quick Inventory of Depressive Symptomatology-Clinician (QIDS-C) also showed noteworthy improvement in depression severity. A clinical case vignette illustrates treatment response. Further research will examine the use of H&W CBT in a larger trial of youth diagnosed with both HIV and depression.

Uterine length and fertility outcomes: a cohort study in the IVF population.

STUDY QUESTION: What is the relationship between pre-cycle uterine length and IVF outcome (chemical pregnancy, clinical pregnancy, spontaneous abortion and live birth)? SUMMARY ANSWER: Women at extremes of uterine length (<7.0 or >9.0 cm) were less likely to achieve live birth and women with uterine lengths <6.0 cm were also more likely to experience spontaneous abortion. WHAT IS KNOWN ALREADY: A prospective study of 807 women published in 2000 found that implantation and clinical pregnancy rates were highest in women with uterine lengths between 7.0 and 9.0 cm, though the difference was not significant. The relationship between pre-cycle uterine length and live birth has not been evaluated. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of all cycles performed after uterine length measurement at an academic hospital IVF clinic from 2001 to 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 8981 fresh cycles were performed in 5120 adult women with normal uterine anatomy. Women with uterine anomalies (unicornuate, bicornuate, septate or uterus exposed to diethylstilbestrol) were excluded and women with fibroids were identified for subanalysis. Uterine length was measured by uterine sounding. Cycles were divided by uterine length into groups: <6.0 cm (very short, n = 76), 6.0-6.9 cm (short, n = 2014), 7.0-7.9 cm (referent, n = 4984), 8.0-8.9 cm (long, n = 1664) and ≥9 cm (very long, n = 243). Multivariate logistic regression (first-cycle analyses) and generalized estimating equations (all-cycle analyses) were adjusted for age, fibroids and ART treatment (assisted hatching, intracytoplasmic sperm injection) to generate relative risk (RR) of cycle outcomes by uterine length. MAIN RESULTS AND THE ROLE OF CHANCE: Median uterine length in the IVF population was 7.0 cm (interquartile range 7.0-7.8) and was positively associated with BMI (P < 0.001) and fibroids (P = 0.02). Compared with the referent group, women with uterine lengths <6.0 cm were half as likely to achieve live birth (RR: 0.53; 95% confidence interval (CI): 0.35-0.81) and women with lengths of 6.0-6.9 cm were also less likely (RR: 0.91; CI: 0.85-0.98). Cubic regression spline identified a significant inverse U-shaped association whereby women with uterine lengths <7.0 or >9.0 cm were less likely to achieve live birth. Women with lengths <6.0 cm were also more likely to experience spontaneous abortion (RR: 2.16; CI: 1.23-3.78). Results remained consistent when excluding women with a uterine factor diagnosis (n = 8823), when limiting to the first cycle at our institution (n = 5120) and when further restricting to first-ever cycles (n = 3941). LIMITATIONS, REASONS FOR CAUTION: Optimal assessment of uterine length by ultrasound was not feasible due to time and cost limitations, though uterine sounding is a clinically relevant measurement allowing for results with practical implications. Findings from our predominantly Caucasian clinic population may not be generalizable to infertile populations with different ethnic compositions. WIDER IMPLICATIONS OF THE FINDINGS: Reproducibility of results would solidify findings and inform patient counseling in women undergoing IVF. STUDY FUNDING/COMPETING INTEREST(S): No funding was sought for this investigation. MD declares relationships with UpToDate (royalties) and WINFertlity (consultant).

Micro-computed X-ray tomography: a new non-destructive method of assessing sectional, fly-through and 3D imaging of a soft-bodied marine worm.

The detailed examination of the internal and functional anatomy of soft-bodied marine worms has, until now, only been possible using the time consuming and destructive techniques of dissection, histology and electron microscopy. This is the first description of soft body morphology in polychaetes (Nephtys hombergii) derived by means of a bench-top X-ray micro-CT scanner. The data are augmented, for comparison, by dissections, microscopy and scanning electron microscopy of the same species to show how this non-destructive technique can rapidly and reliably produce high-quality morphological data. It can also be applied to rare or unique invertebrate soft tissue material from museum collections and also to large-scale invertebrate comparative anatomical studies possibly leading to greater evolutionary and taxonomic understanding. High-definition images were obtained without the use of special tissue enhancing stains or radio-opaque fluids and it is believed that this is the first time the technique has been successfully applied to this group of invertebrates. Extrapolation of the sectional imaging of regions of the gut and the production of three-dimensional rotating and 'fly-through' imaging can assist in assessment of aspects of functional anatomy.

Field evaluations of concentrated spray applications of microencapsulated sex pheromone for codling moth (Lepidoptera: Tortricidae).

The application of a microencapsulated (MEC) sex pheromone formulation (Checkmate CM-F) for codling moth, Cydia pomonella (L.), in low volume, concentrated sprays was evaluated in a series of small plot and grower trials in apple, Malus domestica Borkhausen, and pear, Pyrus communis L. Preliminary tests found that MEC sprays applied at 172-207 kilopascals in 12-23 liters/ha deposited the highest density of microcapsules per leaf. The addition of a latex sicker did not increase the deposition of microcapsules. Small plot tests in 2004 compared the effectiveness of two low-volume sprayers against a standard high-volume spray (926 liters/ha) applied at 1,379 kilopascals. Moth catches and fruit injury were significantly lower in plots treated with the low-volume sprays compared with plots treated with the standard sprayer. These results suggest that concentrating the MEC formulation increases the deposition of microcapsules and improves its effectiveness. Larger trials were conducted with a low-volume sprayer in 4-ha plots within commercial apple (2005-2006) and pear orchards (2005) paired with similar plots treated with hand-applied pheromone dispensers. Levels of fruit injury were not significantly different between pheromone treatments in any of the three tests. Moth catches, however, were significantly higher in the MEC- versus the dispenser-treated apple plots in 2005. No difference was found in the fruit injury levels in MEC-treated apple orchards in 2005 caused by irrigation method, but moth catches were significantly higher in overhead versus undertree orchards. The advantages and current limitations of using MEC sex pheromone sprays to supplement current grower's management strategies for codling moth is discussed.

Comparison of the E3 and L3 regions for arming oncolytic adenoviruses to achieve a high level of tumor-specific transgene expression.

Arming oncolytic adenoviral vectors with anticancer transgenes that can be expressed in a tumor-selective manner may enable the engineering of vectors with increased potency, while retaining their safety profile. Armed oncolytic adenoviral vectors were constructed in which transgene expression has been linked via modified splice acceptor sequences that did not necessitate the deletion of any part of the adenoviral genome. Several oncolytic adenoviral vectors were compared in which the transgene was inserted in place of either the E3 or the L3 region. While all vectors had similar viral growth and cytotoxicity characteristics, the highest level of transgene expression was observed from a vector in which the transgene had been inserted downstream of the L3 23K protease gene, the Ad-23K-GM vector. Notably, no transgene expression occurred with this vector in the absence of DNA replication either in vitro or in vivo. In contrast, viruses in which the transgene was inserted into E3 locations exhibited a low level of transgene expression even in the absence of DNA replication. In summary, by utilizing the L3 region for arming oncolytic viruses, higher levels of tumor-specific transgene expression can be obtained without the need to delete any parts of the viral genome.

Paracetamol (acetaminophen) pack size restrictions and poisoning severity: time trends in enquiries to a UK poisons centre.

BACKGROUND AND OBJECTIVE: In September 1998, legislation was introduced in the United Kingdom to limit paracetamol pack sizes to 16 tablets of 500 mg at general sales outlets and 32 tablets of 500 mg at pharmacies. The effect of the regulations on severity of paracetamol poisoning is unclear. The aim of this study was to describe trends in the severity of paracetamol poisoning and to assess the impact of the 1998 Regulations on the enquiries to a UK poisons centre. METHODS: We extracted data about the age, sex and number of tablets or capsules of paracetamol ingested by patients notified to Guy's and St Thomas' Poisons Unit (London, UK) between 1996 and 2004. RESULTS AND DISCUSSION: During the study period, there were approximately 140 000 patients with suspected paracetamol poisoning, accounting for around 11% of all patients reported to the poisons unit. The median number of tablets fell from 25 to 20 for males and 20 to 16 for females after 1998. There was also a reduction in the proportion of patients who ingested 17-32 tablets (from 36% to 30%) and 33-100 tablets (from 25% to 19%). CONCLUSION: Following the 1998 Regulations there was a decline in the severity, but not frequency, of paracetamol poisoning cases reported to Guy's and St Thomas' Poisons Unit. It is unclear whether the decline in severity was a direct consequence of the regulations.

Spatial and non-spatial risk factors associated with cage-level distribution of infectious salmon anaemia at three Atlantic salmon, Salmo salar L., farms in Maine, USA.

The distribution of infectious salmon anaemia (ISA) was examined among 80 cages from three Atlantic salmon grow-out farms in Maine, USA that were stocked with smolts from a single hatchery. Cage-level disease was broadly defined as one or more moribund fish testing positive for infectious salmon anaemia virus (ISAV) by RT-PCR and a second confirmatory test (IFAT, culture or genotype sequence). Spatio-temporal and cage-level risks were explored using logistic regression and survival analysis. Non-spatial risk factors associated with ISA, or shortened survival time to disease, included increased predation, trucking company choice for smolt transfers, a finely-sedimented benthic substrate, and smaller average size of smolts at stocking. Univariable analysis identified the time-dependent spatial factor 'adjacency to newly infected cages' to be predictive of new infection in neighbouring cages 11-12 weeks later. However, none of the spatial factors, or their lags retained relevance in multiple-variable models. The results suggest a diffuse distribution of virus exposure throughout infected sites, with host-susceptibility factors probably influencing disease manifestation in individual cages. The narrow focus of the current study may limit application of the findings to other sites and year-classes. However, these data support the relevance of husbandry efforts to optimize fish health in regions affected by ISAV.

Tackling corruption in the pharmaceutical systems worldwide with courage and conviction.

Poor drug access continues to be one of the main global health problems. Global inequalities in access to pharmaceuticals are caused by a number of variables including poverty, high drug prices, poor health infrastructure, and fraud and corruption--the latter being the subject of this article. There is growing recognition among policy makers that corruption in the pharmaceutical system can waste valuable resources allocated to pharmaceutical products and services. This, in turn, denies those most in need from life-saving or life-enhancing medicines. As a result, international organizations, including the World Health Organization and the World Bank are beginning to address the issue of corruption in the health sector broadly and the pharmaceutical system specifically. This is encouraging news for improving drug access for the global poor who are most harmed by corruption as they tend to purchase less expensive drugs from unqualified or illegal drug sellers selling counterfeit or sub-standard drugs. In our paper, we illuminate what are the core issues that relate to corruption in the pharmaceutical sector. We argue that corruption in the pharmaceutical system can be detrimental to a country's ability to improve the health of its population. Moreover, unless policy makers deal with the issue of corruption, funding allocated to the pharmaceutical system to treat health conditions may simply be wasted and the inequality between rich and poor in access to health and pharmaceutical products will be aggravated.

Assessment of infectious salmon anaemia virus prevalence for different groups of farmed Atlantic salmon, Salmo salar L., in New Brunswick.

Abstract Infectious salmon anaemia (ISA) virus (ISAV) has been causing disease in New Brunswick since 1996. As a control measure, all fish in an outbreak cage are killed. The objective of this study was to compare ISAV prevalence in cages experiencing an outbreak with healthy cages from the same farm, neighbouring farms and distant farms. Atlantic salmon from five different groups were tested using an RT-PCR test. Groups included moribund fish from a cage experiencing an outbreak (A), healthy fish from an outbreak cage (B), healthy fish from a negative cage from a farm experiencing an outbreak in a different cage (C), healthy fish from a negative farm near an outbreak farm (D), and healthy fish sampled at a negative farm located in an area with only negative farms (E). Apparent prevalences (standard error) for the different groups (A-E) were 0.94 (+/-0.026), 0.41 (+/-0.062), 0.29 (+/-0.040), 0.08 (+/-0.037) and 0.08 (+/-0.037), respectively. All groups were significantly different (P < 0.002) from each other except for groups B and C and groups D and E. Because the prevalence of the virus was significantly higher in the outbreak cage (B) compared with other sites, early harvest of outbreak cages will remove one source of virus. However, ISA negative cages (C) that remain on the positive farm may potentially act as a viral reservoir.

Structural polymorphism and endotoxic activity of synthetic phospholipid-like amphiphiles.

The physicochemical characteristics and in vitro biological activity of various synthetic hexaacyl phospholipid dimers were compared with the respective behavior of bacterial endotoxins (lipopolysaccharide, LPS). The structural variations of the synthetic amphiphiles include different stereochemical (R,S) configurations about their ester- and amide-linkages for the acyl chains and differences in the length of the serine backbone spacer. The temperature of the gel to liquid crystalline phase transition of the acyl chains (T(c)) lies between 10 and 15 degrees C for the compounds with the shortest backbone and decreases rapidly for the compounds with longer backbones. The phase transition enthalpies (8-16 kJ x mol(-1)) are considerably lower than those of lipid A from hexaacyl endotoxins (28-35 kJ x mol(-1)). In contrast, the dependence of T(c) on Mg(2+) and water content shows a behavior typical for endotoxins: a significant increase with increasing Mg(2+) and decreasing water concentrations. The aggregate structure is sensitively dependent not only on the length of the backbone spacer but also on the different stereochemical variations. It can be directly correlated with the biological activity of the compounds. Thus, as with natural lipid A, the capacity to induce cytokine production in mononuclear cells is directly related to the affinity to form nonlamellar cubic or inverted hexagonal H(II) aggregate structures. Together with the data on the transport and intercalation of the dimers into phospholipid liposomes mediated by the lipopolysaccharide-binding protein (LBP), our conformational concept of endotoxicity and cell activation can be applied to these non-LPS structures: endotoxically active compounds incorporate into membranes of immune cells and cause conformational changes at the site of signaling proteins such as Toll-like receptors or K(+)-channels due to their conical molecular shape.

Use of nonergot alkaloid-producing endophytes for alleviating tall fescue toxicosis in sheep.

Nonergot alkaloid-producing endophytes from New Zealand were inserted into tall fescue (Festuca arundinacea) cultivars in an attempt to address the problem of fescue toxicosis in grazing sheep. A 3-yr grazing study was conducted to determine lamb performance and to evaluate toxicosis in lambs grazing nonergot alkaloid-producing endophyte-infected (AR542 or AR502), endophyte-free (E-), or wild-type toxic endophyte-infected (E+) Jesup tall fescue or nonergot alkaloid-producing endophyte-infected (AR542) Georgia-5 tall fescue. Replicated 0.11-ha tall fescue paddocks were established at the central Georgia Branch Station during September 1997 and stocked with lambs from spring 1998 through autumn 2000. Mean ergot alkaloid concentrations were higher (P < 0.01) in E+ forage than in AR542, AR502, and E- tall fescue, and ergot alkaloid concentrations in E- plants and plants infected with AR542 and AR502 were low. Forage availability did not differ (P = 0.92) across treatments during autumn and was higher (P < 0.05) in Georgia-5 AR542 than in Jesup AR502 and E+ pastures. Initial serum prolactin (PRL) concentrations did not differ (P = 0.58) across treatments during autumn, but were higher on Jesup AR542 than E+ during spring. Post-treatment serum PRL concentrations were depressed (P < 0.01) on E+ compared with AR542, AR502, and E- in both spring and autumn. Signs of heat stress were observed in E+ lambs during periods of high ambient temperatures. Mean post-treatment rectal temperature and mean stocking rate exhibited treatment x year interactions (P < 0.05). Lamb ADG was higher (P < 0.05) on AR542, AR502, and E- than on E+ tall fescue. Similarly, gain/hectare was higher (P < 0.015) on AR542, AR502, and E- than on E+. Tall fescue pastures containing AR542 and AR502 endophytes yielded lamb performance that did not differ from that on E- tall fescue and which was superior to performance on E+ tall fescue. Depressed PRL concentrations and elevated rectal temperatures as indicators of toxicosis were evident only in lambs grazing E+ tall fescue, suggesting that nonergot alkaloid-producing endophyte-infected tall fescue is a viable alternative for alleviating tall fescue toxicosis.

Offspring resulting from direct transfer of cryopreserved bovine embryos produced in vitro in chemically defined media.

The present work was designed to study the in vitro and in vivo viability, as assessed by blastocyst formation, pregnancy rate and term delivery of bovine embryos produced under completely defined conditions with or without insulin-like growth factor I (IGF-I) following direct transfer after cryopreservation. Slaughterhouse-derived bovine oocytes were matured for 24h, fertilized with frozen-thawed spermatozoa and cultured in vitro under completely defined conditions with or without exposure to IGF-I (5 ng/ml). Only those embryos classified as excellent or good quality blastocysts were frozen. Each blastocyst was individually loaded into a straw, seeded and pre-cooled to -7 degrees C. After 10 min at -7 degrees C straws were frozen further to -30 degrees C at a rate of 0.3 degrees C/min and then plunged into liquid nitrogen. Synchronized recipient cows received one embryo in the horn ipsilateral to the corpus luteum (CL). Pregnancies were diagnosed by ultrasonography 35-45 days after embryo transfer (ET). IGF-I failed to improve cleavage rate, as well as blastocyst production, when added during in vitro culture (IVC). Pregnancy outcome was not significantly improved in cows that received an IGF-I-treated embryo compared with controls (4/10 versus 3/10, respectively). Five out of six calves delivered to date were born alive and healthy. We have shown that it is possible to obtain healthy live offspring from frozen-thawed embryos produced under chemically defined conditions after direct transfer.

CT guided percutaneous fixation of sacroiliac fractures in trauma patients.

BACKGROUND: Open reduction and internal fixation of unstable pelvic fractures has been advocated to minimize complications and avoid further injury. We have recently performed CT guided percutaneous fixation of sacroiliac joints as an alternative to open repair. METHODS: From May 1, 1998 to April 30, 1999, our Level II trauma center admitted 76 patients with pelvic fractures, all due to blunt trauma. Twenty patients with unstable sacroiliac fracture-distractions underwent 22 percutaneous fixation procedures under general anesthesia in the radiology department by the third hospital day. Procedure times averaged 82 minutes. Localization with CT guidance was performed by the radiologist using 3-D images followed by percutaneous screw placement by the orthopaedic surgeon. RESULTS: There was minimal procedural blood loss and no post-procedural wound complications. There was one operative delay due to respiratory difficulties and one postoperative death unrelated to the pelvic fracture. All patients were mobilized on the first post-procedural day. CONCLUSION: CT guided fixation of unstable pelvic fractures minimizes blood loss during a short procedure with few subsequent complications and allows early mobilization of the patients.